key: cord-0726321-9hm2l9j8
authors: Salazar, Fabián; Bignell, Elaine; Brown, Gordon D.; Cook, Peter C.; Warris, Adilia
title: Pathogenesis of Respiratory Viral and Fungal Coinfections
date: 2021-11-17
journal: Clin Microbiol Rev
DOI: 10.1128/cmr.00094-21
sha: 83983d7ca4d8a2931cb2e9605362f594d318b2aa
doc_id: 726321
cord_uid: 9hm2l9j8

Individuals suffering from severe viral respiratory tract infections have recently emerged as “at risk” groups for developing invasive fungal infections. Influenza virus is one of the most common causes of acute lower respiratory tract infections worldwide. Fungal infections complicating influenza pneumonia are associated with increased disease severity and mortality, with invasive pulmonary aspergillosis being the most common manifestation. Strikingly, similar observations have been made during the current coronavirus disease 2019 (COVID-19) pandemic. The copathogenesis of respiratory viral and fungal coinfections is complex and involves a dynamic interplay between the host immune defenses and the virulence of the microbes involved that often results in failure to return to homeostasis. In this review, we discuss the main mechanisms underlying susceptibility to invasive fungal disease following respiratory viral infections. A comprehensive understanding of these interactions will aid the development of therapeutic modalities against newly identified targets to prevent and treat these emerging coinfections.

INTRODUCTION F ungal infections are major causes of human morbidity and mortality. These infec-

The realization that fungal coinfections complicate viral respiratory disease has only recently emerged. In retrospect, earlier case reports described the association of Aspergillus and influenza coinfection, but the significance was not appreciated (8) . During the 2009 H1N1 pandemic, increasing numbers of cases with IAPA were described in the literature, resulting in proposed disease definitions and clinical management guidelines (10, 11) . Furthermore, the recent update of the U.S. clinical practice guidelines regarding diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenza has included fungal coinfection as a complication of influenza (10) . Based on recent clinical observations and diagnostic test results in patients with IAPA, a new clinical algorithm has been proposed to better classify the certainty of the diagnosis of invasive Aspergillus disease (23) (24) (25) . A similar pattern has been observed during the current COVID-19 pandemic, with hundreds of cases of fungal coinfections being described (26, 27) . International efforts to better classify CAPA has also led to proposed novel disease definitions and research and clinical guidelines (2, 28, 29) . The recognition that patients with severe viral pneumonia have an increased susceptibility to developing fungal coinfections asks for an analysis of the reported clinical epidemiology to provide insights into the clinical importance of fungal-viral coinfections. Underlying medical conditions resulting in lung injury, such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD), are considered independent risk factors for developing invasive fungal infections (30) and therefore are covered in this review.

Influenza viruses are classified into types A, B, C, and D based on genetic and antigenic differences (4) . Influenza A viruses are predominantly responsible for seasonal annual epidemics, and they have caused a number of pandemics in humans (4, 31) . Worldwide, 3 to 5 million people develop severe influenza infection, leading to up to half a million deaths every year. Of the hospitalized patients, 5 to 10% need admission to an intensive care unit (ICU). A feared complication is the development of acute respiratory distress syndrome (ARDS), which is associated with high mortality rates (32). The first report of pulmonary aspergillosis following influenza bronchopneumonia dates back to 1952 (33). After that, several clinical cases have been reported (34-38), but it was not until the 2009 H1N1 pandemic that the number of reports started to increase dramatically (24, 39) . One of the first detailed descriptions of the association between influenza H1N1 and Aspergillus coinfection showed that 23% of critically ill patients with influenza admitted to the ICU developed IPA (39). A large number of other centers have reported comparable experiences, but the incidence of Aspergillusinfluenza virus coinfection shows huge variation, with incidences reported between 7% and 32% (24, 32, (40) (41) (42) (43) (44) (45) (46) (47) (48) (49) (50) (51) . Despite such variations, a number of important observations have been made supporting the fact that fungal coinfections do play a significant role in the disease severity and outcome of influenza pneumonia. First, one of the larger clinical studies that included more than 400 patients admitted to the ICU over a period of 7 years identified influenza as an independent risk factor for the development of IPA (24) . Second, pulmonary fungal coinfections outnumbered the cases of bacterial coinfection among influenza patients admitted to two ICUs in the Netherlands (16 versus 13 out of 45 patients, respectively) (32). Increased mortality rates of 51% to 66% have been reported in patients with IAPA compared to 15% to 28% in patients without and with bacterial coinfections (24, 49) . Even though the majority of reported cases have been associated with influenza A virus, cases associated with influenza B virus have also been described (52, 53). In the last decade, novel avian influenza viruses have emerged in Asia associated with mortality rates of up to 50%. A study from China collected data from 335 patients with avian influenza H7N9 between 2013 and 2018, and 5.4% of those were diagnosed with IPA (54).

The ongoing COVID-19 pandemic, caused by SARS-CoV-2, has affected millions of people and caused more than four and a half million deaths worldwide by September 2021. About 5% of COVID-19 patients infected with SARS-CoV-2 require ICU management; these patients might be at high risk of developing secondary infections, including IPA (55-58). Reports from the previous SARS epidemic in 2003, caused by SARS-CoV-1, pointed to the occurrence of Aspergillus infection in those patients treated with corticosteroids for virus-induced inflammation (59-61); however, no systematic studies were performed to determine rates of incidence. During the current pandemic, secondary bacterial (22) and fungal coinfections, mainly due to Aspergillus spp. (Table 1) , are increasingly being reported (62-97). Overall, hundreds of patients with CAPA have been reported from many countries in Europe, Asia, Australia, and America (27) . As with IAPA, incidences exhibit great variability, with some studies reporting incidences of CAPA as low as 1% of ICU cases and others reporting extremely high incidences of up to 35% in ICU settings in Europe (56, [98] [99] [100] . In a case series from the Netherlands, the mortality rate among patients with CAPA was 67% compared to 32% in patients with severe COVID-19 without signs of IPA (101) . Importantly, in a recent prospective study from Germany, COVID-19 was independently associated with IPA (95) . Some studies suggest that CAPA might be underdiagnosed due to difficulties obtaining respiratory samples. Concerns over aerosolization of respiratory secretions and the SARS-CoV-2 virus have restricted the number of invasive procedures performed, such as bronchoalveolar lavage (102, 103) . Moreover, there are inherent difficulties in obtaining a clear diagnosis of Aspergillus infection, whereas others have suggested that the incidence of Aspergillus infection in COVID-19 patients is not as high as previously predicted (104) (105) (106) (107) . Whether these discrepancies are associated with the extent to which specific fungal diagnostic tests are employed is at present unclear.

Recently, thousands of COVID-19-associated mucormycosis (CAM) cases have been reported in the literature, mostly from India (108, 109) . Importantly, mucormycosis associated with influenza has also been described (110) . Major risk factors include patients receiving systemic corticosteroid treatment or suffering from uncontrolled diabetes (111, 112) . Hyperglycemia increases the expression of the glucose-regulated protein (GRP78), which acts as a receptor for the CotH protein kinase present in Rhizopus spores, helping the fungus to adhere and invade endothelial and nasal epithelial cells (113) (114) (115) . In addition, beyond their immunosuppressive function, treatment with corticosteroids can cause diabetic ketoacidosis, further increasing susceptibility to CAM (116, 117) . A recent review of the literature described that CAM exhibits a mortality of up to 49%, with rhino-orbital cerebral mucormycosis being the most common manifestation of the disease, followed by pulmonary mucormycosis (109) . Notably, a significant proportion of surviving patients suffered life-changing morbidities, including loss of vision. Diagnosis of CAM is challenging, as the clinical and radiological signs of pulmonary and disseminated mucormycosis are nonspecific and may overlap with findings associated with COVID-19. Furthermore, mucormycosis is caused by a variety of Mucorales species (Rhizopus arrhizus is the predominant species in India), with some of them exhibiting poor susceptibility to antifungal therapy (118) . Recently, the European Confederation of Medical Mycology (ECMM) and the International Society for Human and Animal Mycology (ISHAM) provided a comprehensive guideline of recommendations for the clinical management of CAM patients, including diagnosis, treatment, and prevention (119) . Early recognition, better diagnostics, and more effective antifungals are required to improve the outcome of these patients, especially in low and middle-income countries.

Fungal coinfections complicating viral infections with pathogens other than Aspergillus have also been reported. PCP caused by the fungal pathogen Pneumocystis jirovecii is the most common AIDS-defining disease, with up to half a million cases worldwide annually (3) . Influenza complicated by PCP has been observed in HIV-infected patients (120) (121) (122) . Therefore, influenza vaccination has been suggested as a prophylactic measure to reduce the risk of developing PCP secondary to influenza in HIV patients (123) . Patients with deficiencies in adaptive immunity or individuals undergoing immunosuppression therapy are also at risk of developing PCP associated with influenza infection (124, 125) . Recently, cases of COVID-19 and Pneumocystis coinfections have been reported (81, 126, 127) , some of them associated with HIV comorbidity (79, (128) (129) (130) . Since SARS-CoV-2 and PCP have common clinical and radiological features, coinfection with Pneumocystis is likely underappreciated in patients with SARS-CoV-2 (128, (131) (132) (133) (134) (135) (136) (137) (138) and there are several clinical case studies reporting misdiagnosis (139, 140) . Cryptococcus infections affect primarily immunocompromised hosts like HIV-infected individuals and solid organ transplant recipients. Infection starts in the lungs, and it can then disseminate into the central nervous system, causing meningitis that accounts for more than 200,000 cases worldwide annually (3).

Only a few cases of influenza with concomitant cryptococcal infection have been reported in the literature (141) (142) (143) , all of them with either the H1N1 or H7N9 strain (142) . The scarcity of case studies could be a result of underdiagnosis, so special attention is needed in regions with a high prevalence of HIV/AIDS, including sub-Saharan Africa. Candida auris is a multidrug-resistant fungal pathogen classified as an "urgent threat" by the U.S. Centers for Disease Control and Prevention (CDC) due to its ability to cause life-threatening systemic infections in critically ill patients. Several outbreaks of C. auris infection in COVID-19 patients have been reported (144) (145) (146) (147) (148) (149) , in some cases associated with corticosteroid treatment (150) (151) (152) (153) (154) . C. auris is difficult to identify by standard laboratory methods, which can lead to misidentification, causing outbreaks in health care settings often associated with high mortality. Therefore, advancing diagnostic methods is essential for early detection and control of this emerging pathogen.

Immune responses against one pathogen can significantly influence immunity to a secondary nonidentical pathogen. This phenomenon, termed heterologous immunity, has been studied mainly in the context of viral infections and vaccines but could also play a role during viral-fungal coinfections (155, 156) . Studies on the copathogenesis between viral and fungal coinfections are scarce, unlike studies regarding viral and bacterial coinfections. Most reports have attributed destruction of the airway epithelium and suppression of cellular immunity (including defective antigen-specific cytotoxic T lymphocyte responses and impaired phagocyte activities such as phagocytosis, production of cytokines, and reactive oxygen species [ROS], formation of neutrophil extracellular traps [NETs] , and killing abilities) as the causes responsible for fungal coinfections (157) (158) (159) . Several of the mechanisms that account for fungal susceptibility in individuals suffering from influenza could also be at play during SARS-CoV-2 infection, including the effects on tissue integrity and functionality and the dysregulation of immune responses and effector functions (160) . Despite these similarities, the pathophysiology of SARS-CoV-2 infection is different from that of influenza at numerous levels, including viral tropism, viral replication, and incubation period as well as the effects on the host defense (161) (162) (163) (164) (165) .

The outcome of host-pathogen interactions depends on numerous factors, including dose, route of infection, and virulence properties of the pathogen, as well as several host factors that include innate and adaptive immunity. Initiation of protective antiviral immunity depends on the recognition of viral RNA in the endosomal or cytosolic compartment by Toll-like receptor 3 (TLR3) and TLR7 or by retinoic acid-inducible gene (RIG)-I-like receptors (RLRs) (RIG-I and melanoma differentiation-associated protein 5 [MDA5]), respectively. Viral recognition by innate immune cells, including dendritic cells (DCs) and macrophages, triggers a signaling cascade leading to both NF-k Bmediated induction of proinflammatory cytokines (interleukin 6 [IL-6], tumor necrosis factor [TNF], IL-1), and IFN regulatory factor 3 (IRF3) and IRF7-mediated induction of type I (IFN-a and IFN-b) and type III (IFN-l) interferons (IFNs). IFNs are crucial for effective antiviral immunity; for example, in epithelial cells, IFN signaling inhibits viral replication and orchestrates an effective adaptive antiviral immune response (4, 166, 167) . Conversely, antifungal immunity strongly relies on C-type lectin receptors (CLRs) that play a key role in the recognition of fungal glucans, glycolipids, and glycoproteins by phagocytes (mainly macrophages and neutrophils) and in the activation of innate host defense mechanisms, including phagocytosis, respiratory burst, formation of NETs, autophagy, and chemokine and cytokine production (168) . These mechanisms promote fungal killing but also influence activation of the adaptive immune system (169) (170) (171) (172) (173) . Understanding how these mechanisms interact in a synergistic or antagonistic manner is fundamental to dissecting their roles during viral-fungal coinfections. In the next section, the major mechanisms that mediate susceptibility to fungal coinfections in individuals suffering from severe viral pneumonia are discussed: from innate immune mechanisms, including the role of the epithelium, phagocytes, and antigen-presenting cells (APCs), to T cell responses and adaptive humoral and cytotoxic responses.

The respiratory epithelium is composed of a variety of cells, including a pseudostratified epithelium of ciliated and secretory cells lining the trachea and most proximal airways. A cuboidal epithelium lines the small airways, and squamous type I alveolar cells (involved in the process of gas exchange) and cuboid type II alveolar cells (which secrete pulmonary surfactant) form the alveoli (174) . In healthy individuals, inhaled airborne fungal conidia are easily trapped in the mucus and eliminated mechanically by ciliated cells from the upper respiratory tract. However, due to their small size (2 to 3 mm), Aspergillus conidia (asexual spores) can reach the lower respiratory tract and interact with the airway epithelium, at either the bronchial or alveolar level (175) . Upon reaching airway epithelial cells, fungal conidia are taken up and trafficked through the endosomal system, culminating with the formation of the phagolysosome by fusion of late phagosomes with lysosomes. This organelle has an acidic pH and contains many degradative enzymes that facilitate destruction and clearance of fungal conidia from the host. However, upon injury or disease (disrupting barrier integrity), conidia may escape this process and eventually germinate, facilitating tissue invasion (175) . Different respiratory viruses preferentially bind and infect specific epithelial cells expressing specific receptors along the respiratory tract. For instance, cell entry of influenza virus is mediated by the binding of the viral hemagglutinin to terminal sialic acids that are attached via either an a2,3 or a2,6 linkage. Human influenza virus, such as H1N1, binds preferentially to a2,6-linked sialyloligosaccharide receptors, which predominate in nonciliated epithelial cells from the upper respiratory tract, whereas avian influenza virus, such as H5N1 and H7N9, binds to a2,3 linkages, which are more prevalent in ciliated epithelial cells from the lower respiratory tract (31, (176) (177) (178) (179) . Lower respiratory tract infection enables deep lung infection by other pathogens, including fungal pathogens. Angiotensinconverting enzyme 2 (ACE2) is the cellular receptor for SARS-CoV and the new SARS-CoV-2 (180) (181) (182) (183) (184) . Both SARS-CoV and SARS-CoV-2 primarily target type II pneumocytes, consistent with their ACE2 expression (161); however, SARS-CoV-2 replicates abundantly in upper respiratory epithelia and is efficiently transmitted (185, 186) . Of note, SARS-CoV and SARS-CoV-2 can also infect alveolar macrophages that support viral replication (185, (187) (188) (189) . Both influenza virus and SARS-CoV-2 can cause pneumonia, which occurs when infection and inflammation involve the alveoli and lung parenchyma. Therefore, productive viral infection of specific respiratory epithelial cells along the respiratory tract will determine the clinical symptoms as well as the susceptibility to fungal infections (179) .

Respiratory viral infection causes multiple changes in the lungs that can weaken antifungal defenses, facilitating secondary fungal invasion. These effects can be grouped into three major aspects, including changes to the extracellular matrix components that facilitate adhesion, compromise of epithelial cytoskeletal machinery that modifies the dynamics of internalization, and damage of the epithelium that compromises barrier integrity (190) .

Disruption of tracheal epithelial integrity after influenza infection affects the mechanical removal of subsequent pathogens, facilitating secondary infections (191, 192) . In the more severe cases, damage to the epithelium can alter the surface display of numerous transmembrane proteins, exposing sites for fungal adherence in the tracheobronchial tree. For instance, injured cells or cells in an intermediate state of differentiation may express apical receptors such as a5b1 integrin (expressed upon lung inflammation and injury to control cell migration during wound healing [193] ), to which Aspergillus fumigatus can adhere (194, 195) . Moreover, airway fibrinogenolysis and disruption of epithelial tight junctions by Aspergillus-secreted proteases such as alkaline protease 1 (Alp1) during and after germination can trigger allergic inflammation and further contribute to epithelial cell pathology in the context of coinfections (196) (197) (198) (199) . All of the above suggest that during influenza infection, the chronicity of the disease might determine susceptibility to secondary fungal infections. Lung tissue disruption during SARS-CoV-2 infection has also been shown to be an important factor in determining the severity of the disease, which likely contributes to susceptibility to coinfections (200, 201) . Moreover, COVID-19-driven inflammation affects alveolar epithelial regeneration and induces the expansion of pathological fibroblasts that promote fibrosis and impair regeneration (202, 203) . Of note, using a model of influenza infection, mice experiencing an acute inflammatory response with limited bystander tissue damage do not show susceptibility to a secondary bacterial infection (204) . Whether the same holds true for secondary fungal infections is unknown.

Exposure of the substratum during severe viral pneumonia presents additional opportunities for fungal cells to adhere. In addition, changes in the airways during tissue damage and repair may provide adherence sites during recovery (205) . During tissue remodeling, exposure of basement membrane and extracellular matrix components, such as fibronectin, laminin, or collagen, in areas of incomplete healing or where fibrin and fibrinogen deposition have taken place (observed during SARS-CoV-2 infection [206] ) could facilitate fungal adhesion to the basal lamina (175, 207) . All of the above might be significant in patients suffering from idiopathic pulmonary fibrosis, a condition characterized by the thickening and stiffening of the tissue surrounding the alveoli that shares several risk factors with COVID-19 (208) and has been independently associated with both influenza and Aspergillus infections (209, 210) .

Several respiratory viruses, including influenza virus, can hijack the cytoskeletal system to their benefit in order to direct the cellular machinery to the production of viral particles. This could be particularly relevant during Aspergillus infections, since upregulation of several genes involved in cytoskeleton reorganization has been observed during Aspergillus infection (211, 212) . Actin polymerization has been suggested to be crucial for internalization of conidia (213) . In this context, in vitro studies have shown that Aspergillus-derived mycotoxins, such as gliotoxin, can promote actin cytoskeleton dynamics and internalization of A. fumigatus (214) . Importantly, influenza infection alters the levels, structures, and functions of F-actin and microtubules in host cells (215) . In addition, influenza infection downregulates the levels and/or activities of proteins involved in the regulation of F-actin and microtubule dynamics, such as Arp2/3 (involved in actin polymerization and the formation of branched actin networks) (216) . Notably, components of the Arp2/3 complex have been shown to be upregulated in response to Aspergillus conidia and to mediate internalization of conidia (212) . Another example is phospholipase D, which plays a fundamental role in lipid metabolism and cytoskeleton rearrangement and whose activity is stimulated following influenza infection (217) . This enzyme mediates rapid endocytosis of the virus and at the same time can promote A. fumigatus internalization (218, 219) . The complex interaction between influenza viruses and cytoskeleton components, including actin microfilaments, intermediate filaments, and microtubules, could therefore underlie mechanisms of susceptibility to fungal pathogens.

The epithelium is very important in orchestrating innate immune responses to both viral and fungal infections. The lung epithelium produces several soluble factors that form the first barrier of defense against fungal infections. Airway epithelial cells, particularly from the upper airways, secrete mucins that act as a barrier against fungal invasion. Binding of conidial lectins (FleA) to glycan moieties on gel-forming mucins (MUC5AC and MUC5B) allow them to become trapped within the mucus barrier, unable to reach the underlying epithelium and subsequently cleared from the airways by mucociliary clearance (220, 221) . Surfactant proteins (SP-A and SP-D) and ficolins are involved in fungal opsonization and phagocytosis. Chemokines promote neutrophil recruitment and antimicrobial peptides (AMPs; including LL-37 and defensins) and are involved in fungal killing (222, 223) . Influenza virus itself can interact with some of these glycosylated proteins, affecting their mode of action. For instance, neuraminidase helps the virus to gain access to airway epithelial cells by catalyzing the cleavage of sialic acids presented by decoy receptors, such as mucins (224) (225) (226) . Fungal recognition through sialylated mucins is a critical step in the mucociliary clearance and macrophage killing that prevents Aspergillus pneumonia (220). SARS-CoV-2 can inhibit protein translation, which abolishes innate immune responses by the epithelium (i.e., IFN-dependent induction of IFN-stimulated genes) (227) . Cross talk between alveolar epithelial cells and other immune cells, including DCs, is crucial for effective pathogen clearance and recovery from injury ( Fig. 1) (228) . Importantly, epithelial cells can control overinflammation by expressing anti-inflammatory mediators such as the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (229) . Disruption of these immune-regulatory mechanisms as a result of viral infection could lead to uncontrolled exacerbated inflammation, increasing tissue damage, immunopathology, and susceptibility to fungal coinfections as mentioned above.

In severe cases of influenza, obstruction of the small airways caused by the sloughing of cells and the release of fibrinous material into the airways leads to the decrease of oxygen and carbon dioxide diffusion capacities. This hypoxic milieu can significantly influence the course of Aspergillus infection by affecting fungal virulence and host immune responses (230) (Fig. 1) . Importantly, oxygen tension has notable effects on the macroscopic and biofilm morphotypes of Aspergillus fumigatus (colony furrowing and percentage of vegetative nonconidiating mycelia), leading to increased host inflammation, rapid disease progression, and mortality in a murine model of invasive aspergillosis (231) . Aspergillus-derived secondary metabolites (i.e., gliotoxin) can further contribute to increased localized and systemic hypoxia by inhibiting angiogenesis and tissue repair (232) . Therefore, the metabolic adaptability of Aspergillus spp. to low-oxygen environments could be critical for the ability to cause infection following influenza (175, (233) (234) (235) . Interestingly, hypoxia inducible factor 1a (HIF1a), a transcription factor that controls immune cell metabolism and function during hypoxic conditions, has been shown to be important in controlling influenza virus replication (236) and for protection against pulmonary Aspergillus infection (237). Beyond the epithelium, hypoxia contributes to endothelial cell activation with the release of several soluble mediators, including proinflammatory cytokines, platelet-activating factor, and adhesion molecules, all of which amplify tissue destruction and inflammation into the small airways (238) . Damage of alveolar integrity can enable fungal spores to reach blood vessels ( Fig.  1 ). Recently, it was shown that a major receptor involved in sensing of Aspergillus 1,8dihydroxynaphthalene (DHN)-melanin, named melanin-sensing lectin (MelLec), is highly expressed on endothelial cells that line the internal surfaces of vessels (239) . Therefore, destruction of alveolar epithelial integrity could enable deep penetration of fungal conidia and invasion through MelLec-expressing endothelial cells. Compromised endothelial sensing of conidia through MelLec could also facilitate Aspergillus infection, as has been shown in murine models of infection (239) .

Type I and type III IFNs induce an IFN-stimulated gene signature that has the capacity to interfere with every step of viral replication (4, 166, 167) . Besides their role during viral infections, IFNs play an essential role in driving antifungal responses in the lungs. Type I and type III IFNs are expressed with distinct kinetics during IPA, and both are essential for the activation of neutrophils (240, 241) . Upon Aspergillus recognition, recruited monocytes (via CCR2) are an important early source of type I IFNs that induce optimal expression of IFN-l. Type III IFN production by hematopoietic and nonhematopoietic cells at the mucosa acts on neutrophils to activate their antifungal response, including ROS production (240, 241) . Controlled IFN signaling may be a crucial factor in determining whether secondary fungal infections are cleared at mucosal sites (5, 242, 243) . Sustained uncontrolled IFN production can lead to tissue damage and immunopathology; e.g., type I IFNs cause lymphopenia (244) , which has been associated with severe cases of influenza and SARS-CoV-2 infection, increasing susceptibility to secondary infections (245) (246) (247) (248) (249) (250) (251) (252) (253) . Furthermore, not only type I but also type III IFNs can impair microbial control during coinfections (254, 255) . Excessive or prolonged production of IFN-l can interfere with lung repair during influenza recovery, which reduces epithelial proliferation and differentiation, increasing disease severity and susceptibility to coinfections (256, 257) (Fig. 2) .

Type II IFNs can be detrimental during influenza infection (258, 259) and contribute to susceptibility to secondary bacterial infections by depleting alveolar macrophages and suppressing their phagocytic capacity (260) (261) (262) (263) (264) (265) . IFN-g also impacts memory Th17 responses that attenuate bacterial clearance following influenza infection (266) . Therefore, blocking IFN-g has been exploited as a therapeutic strategy in several experimental models (267) (268) (269) . However, type II IFNs might have a protective role during fungal coinfections. IFN-g production by Th1 cells and invariant natural killer T (iNKT) cells (innate-like lymphocytes that express a conserved ab T-cell receptor [TCR] chain) is required for the activation of phagocytes (270) and restraining of inflammation during fungal clearance (271) . Moreover, postinfluenza Cryptococcus coinfection has been associated with reduced levels of IFN-g (272) . Consequently, IFN-g therapy has proven to be beneficial as an adjunctive therapy in patients with chronic granulomatous disease (CGD) (who are deficient in the NOX complex) and undergoing transplantation (273), but its beneficial effects during fungal coinfections remain to be investigated.

Understanding the immune response that underpins influenza and COVID-19 is important for identifying potential mechanisms of susceptibility to fungal coinfections. Both are characterized by a cytokine release syndrome; nevertheless, they exhibit distinct immune response profiles (253) . In comparison to other highly pathogenic coronaviruses and common respiratory viruses, including influenza A virus, SARS-CoV-2 drives an imbalanced inflammatory response. Studies have shown that both SARS-CoV-2 and SARS-CoV infection drive a lower antiviral transcriptional response that is marked by low type I and III IFN levels and elevated chemokine expression, all of which might contribute to COVID-19 (274) (275) (276) (277) (278) (279) (280) . Low levels of IFNs have been associated with the presence of autoantibodies against type I IFNs (281-285) or inborn errors in genes involved in the regulation of type I and type III IFN immunity (286) . Conversely, other reports have shown upregulation of a type I IFN response in peripheral blood (287) that coexists with a proinflammatory TNF/IL-1b/IL-6-driven response in patients with COVID-19 compared to severe influenza patients (160, 250, 252) . Similar results have been observed at mucosal sites (288) (289) (290) . These discrepancies have been attributed to two differing outcomes (200, 291) , with a delayed type I IFN response causing enhanced viral persistence and pathological inflammation but an early robust type I IFN response controlling viral replication that results in a mild disease (275, 280, (292) (293) (294) (295) (296) (297) . In this context, a type I IFN response is critical for the development of ARDS and increased lethality during severe SARS-CoV infection (275, 292, 298) . More recently, studies have shown that the location where IFNs are being produced is also relevant. High levels of type III IFNs, and to a lesser extent type I IFNs, characterize the upper airways of patients with a mild pathology, while severe COVID-19 patients exhibit strong production of IFNs in the lower airways compared to subjects with other infectious or noninfectious lung pathologies (299, 300) . This suggests that hyperinflammation and dysregulation of the IFN pathway are likely important factors that contribute to the development of fungal coinfections in COVID-19 patients.

Effective elimination of pathogens relies on the recruitment and functions of several immune cells. These effector cells regulate important processes that are pivotal for controlling viral persistence and preventing fungal invasion. Impairment of phagocyte 4) Lung dendritic cells recognize, ingest, and kill Aspergillus conidia, acquire a fully mature state, and then migrate to draining lymph nodes. (5) Antigen presentation of fungus-derived peptides to naive CD4 1 and CD8 1 T cells occurs in the draining lymph nodes. (6) T cell activation leads to Th17 differentiation, which is pivotal for control of fungal infections at the airways. In particular, Th17 cells support neutrophil activation and the production of antimicrobial peptides (AMPs) by epithelial cells. (B) Mechanisms responsible for increased susceptibility to fungal infections in patients suffering severe viral pneumonia. (1 to 3) The lung epithelium undergoes different changes over the course of respiratory viral infections, including tissue disruption that facilitates secondary fungal invasion (1) and expression and/or exposure of receptors to which fungal pathogens can adhere (2) . In addition, germinated fungal spores themselves release molecules with the potential to increase permeability and tissue damage, such as proteases and mycotoxins (3). (4) The airway epithelium produces type I and type III interferons (IFNs), which have a significant impact on antifungal immunity at different levels. (5) IFN-a/b are also produced by alveolar macrophages. IFNs reduce epithelial cell proliferation and differentiation, increasing susceptibility to coinfections. IFNs suppress monocyte, macrophage, and neutrophil recruitment and effector responses that are essential for fighting fungal infections. IFNs act as negative regulators of inflammasome activation in response to fungal pathogens, thus affecting fungal clearance. IFNs dampen Th17 responses, leading to attenuation of AMP production and neutrophil recruitment that are required for antifungal clearance. (6) Desensitization of pattern recognition receptors (PRRs), which are essential for fungal recognition and antifungal immunity, contributes to susceptibility to coinfections. (7) Viral infections also interfere with antigen-presenting cell functionalities, affecting the subsequent immune response to fungal antigens. For instance, viral infection affects antigen presentation through interference with any of the three signals required for T cell activation, namely, MHC presentation, expression of cosignaling molecules, and/or production of cytokines. functions following influenza infection is among the most damaging consequences that increase susceptibility to secondary fungal infections (301) . Neutrophils are one of the most important innate effector cells for the control of fungal infections. Humans suffering from neutropenia or neutrophil dysfunction exhibit a dramatic increase in susceptibility to major fungal pathogens, including A. fumigatus (168) . This is particularly evident in CGD patients, whose neutrophils exhibit impaired fungal killing abilities (302) . Suppressed neutrophil recruitment (due to reduced chemokine production) and dysfunction (reflected in impaired myeloperoxidase [MPO] , ROS, and NET formation) during influenza virus infection increase susceptibility to secondary bacterial infection (303, 304) and contribute to the development of IPA (301, (305) (306) (307) (308) . Following influenza, IFN production and signaling through STAT1 impair neutrophil recruitment into the lungs and airways, augmenting fungal burdens (242, 301) .

Monocytes and macrophages are key effector cells in controlling fungal infection through direct killing and the production of proinflammatory mediators (168) . Influenza infection can result in depletion of alveolar macrophages and affect their functionalities, including inflammasome activation (263, 309, 310) , thereby increasing disease severity and susceptibility to coinfections. Cross talk between neutrophils and monocytes/macrophages is important to combat respiratory infections, as neutrophils can drive macrophage inflammasome activation during respiratory viral infection (311) (312) (313) and can prevent macrophage depletion during S. pneumoniae coinfection (314) . As macrophages are an important source of neutrophil chemoattractants, such as keratinocyte-derived cytokines (KC) and macrophage inflammatory protein-2 (MIP-2) (315), their depletion as seen in IAPA impairs neutrophil recruitment into the lungs (301). As described above, monocytes can trigger neutrophil activation and ROS production through type I IFN production (240, 241) . Furthermore, both monocytes and neutrophils can control maturation and expansion of DCs in the lung, which in turn activates neutrophil oxidative burst, which is essential for host defense against Aspergillus fumigatus (316) (317) (318) . This suggests that reduced numbers of neutrophils, monocytes, and macrophages in the lung tissue caused by influenza infection increases susceptibility to secondary fungal infections (Fig. 2) .

Single-cell technologies employed on blood samples from severe COVID-19 patients have revealed defective monocyte activation and dysregulated myelopoiesis with release of immature dysfunctional neutrophils into the circulation (251, 252, 277, 287, (319) (320) (321) (322) (323) . More recently, high-dimensional flow cytometry analyses have identified a redistribution of monocyte subsets toward intermediate monocytes (a transitional population between classical and nonclassical monocytes that exhibits a hyperinflammatory signature) and the appearance of monocytic myeloid-derived suppressor cell-like cells (324) (325) (326) . Defective monocyte and neutrophil responses render these patients highly susceptible to invasive fungal infections. However, despite their protective role, excessive phagocyte activation and/or recruitment can also cause lung damage and immunopathology, leading to increased susceptibility to coinfections (168, (327) (328) (329) (330) (331) (332) (333) (334) . Elevated levels of plasma granulocyte-macrophage colony-stimulating factor (GM-CSF) are observed in fatal COVID-19 cases, but not in influenza cases, and may explain the excessive monocyte and neutrophil recruitment leading to tissue destruction (335) . Furthermore, a substantial induction of monocyte/macrophage and neutrophil-associated chemokines has been observed in the lungs of patients with severe COVID-19 (201, 251, 289, (336) (337) (338) (339) . While mechanistic studies on CAPA and IAPA have not been undertaken with the same level of resolution, the impact of these inflammatory processes on fungal secondary infection is evident from an in vivo model of influenza and Cryptococcus gattii coinfection. Increased neutrophil and macrophage recruitment into the lungs during influenza infection predisposed mice to more severe lung damage and increased fungal burden in the brain, resulting in increased morbidity and mortality (272) . In addition, viral infection has been shown to strongly augment macrophage expulsion of Cryptococcus via a nonlytic mechanism (vomocytosis) which could potentially influence cryptococcal dissemination in the host (340) . The mononuclear phagocyte system and, in particular, tissue-resident monocytes and macrophages expressing the fractalkine receptor CX3CR1 are important in controlling fungal growth and dissemination at different tissue locations in mice and humans (341, 342) . In the context of influenza infection, CX3CR1 1 lung macrophages mediate pulmonary immune pathology and mortality through production of high levels of TNF and nitric oxide synthase 2 (NOS2) (343) . However, under certain conditions, such as those involved in airway bacterial colonization, these cells could acquire an anti-inflammatory phenotype that controls influenza-mediated immunopathology (344, 345) , suggesting that specific tissue environmental factors might affect the phenotype and function of these mononuclear phagocytes (MNPs). Importantly, CX3CR1 1 MNPs are essential in sensing intestinal microbial dysbiosis and in shaping immune responses in the airways during homeostasis and inflammation (346) (347) (348) (349) (350) . For instance, fungal dysbiosis and colonization with specific fungi in the gut can exacerbate the development of allergic airway diseases through fungal sensing by gut-resident MNPs (346) (347) (348) (349) (350) (351) (352) (353) (354) (355) . Bacterial dysbiosis as a result of antibiotic use has been associated with augmented severity of influenza infection and increased risk of developing secondary infections (345, 356, 357) . Influenza infection itself can cause intestinal dysbiosis that contributes to secondary infections through alterations of the killing activities of alveolar macrophages (345, 357, 358) (Fig. 3) . Alterations in the mycobiome have also been reported in COVID-19 patients (359), but whether this affects the functionalities of tissue-resident MNPs in a way comparable to that observed for influenza is unknown. Even though most of these mechanisms are still uncertain, these studies do suggest that MNPs could play a significant role in driving susceptibility to fungal coinfections in individuals suffering from severe viral pneumonia.

Nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays a critical role in the innate immune antiviral response (313, 360, 361) and in shaping adaptive immune responses (360, (362) (363) (364) . The NLRP3 inflammasome is activated by tissue/cellular damage in a twostep process that is dependent on microbial and host-derived signals. First, NF-k B signaling is induced (i.e., through activation of TLR or TNF receptor signaling), resulting in increased expression of pro-IL-1b and pro-IL-18. Next, signal two (i.e., potassium efflux, uric acid, and mitochondrial damage among others) leads to complex assembly, activation of caspase-1, and secretion of IL-1b and IL-18, causing the recruitment of monocytes, macrophages, and neutrophils to the site of infection (364) . Influenza viruses (312, 313, (365) (366) (367) , as well as most respiratory viruses, including SARS-CoV-2, activate the NLRP3 inflammasome using viroporins (virally encoded hydrophobic proteins that oligomerize in the membrane of host cells, leading to the formation of hydrophilic pores) (157, (368) (369) (370) . Nevertheless, several influenza virus-derived components (i.e., nonstructural proteins NS1 and PB1-F2) can inhibit the inflammasome, causing viral pathogenicity and immunopathology and increasing the susceptibility to bacterial coinfections (366, (371) (372) (373) (374) (375) (376) (377) . Additionally, during influenza-associated bacterial coinfection, IL-1 signaling plays a protective role by preventing alveolar macrophage depletion (314) and supporting Th17 immunity (378) . Notably, type-I IFNs can act as negative regulators of IL-1b expression and inflammasome activation in response to fungal pathogens, thus affecting fungal clearance (379, 380) . Inflammasome activation, through the polysaccharide galactosaminogalactan, is important for protective responses during fungal infection (381) (382) (383) (384) (385) (386) , such as neutrophil recruitment. Therefore, this mechanism might be playing a crucial role in facilitating IAPA (Fig. 2) . Excessive inflammasome activation can lead to uncontrolled inflammation (202, 387, 388) , facilitating bacterial coinfections (389, 390) and potentially fungal coinfections. Tight regulation of the inflammasome is important to avoid hyperinflammation and immunopathology that might increase susceptibility to IAPA and/or CAPA. The importance of a balanced regulation of the inflammasome has been shown in patients with cystic fibrosis or CGD suffering from inflammasome-driven immunopathology and at risk for developing invasive fungal infections (271, 383, 384) .

One of the most important effector mechanisms in host defense against A. fumigatus is the NADPH oxidase (NOX) complex. This is highlighted by the increased susceptibility to IPA in patients with CGD (302, 391) . Conversely, ROS production during viral infection, including influenza infection, promotes virus pathogenicity and immunopathology. Therefore, regulation of ROS production could constitute a synergistic copathogenesis mechanism during viral-fungal coinfections. Oxidative stress during influenza infection induces formation of oxidized phospholipids that can result in acute lung injury and cytokine production by lung macrophages through TLR4 signaling (392) . In fact, inhibition of NOX2 reduced lung injury and dysfunction, as well as lowering influenza burdens, suggesting that NOX2-derived ROS production promotes viral infection (392) (393) (394) (395) (396) (397) . Single-stranded RNA viruses, such as influenza virus, activate NOX2 in endocytic compartments of alveolar macrophages, resulting in endosomal hydrogen peroxide generation, which suppresses antiviral and humoral signaling networks (398) . These data correlate with studies in mice deficient in NOX2 and in CGD patients, who have elevated circulating type I IFNs and autoantibodies, supporting the notion that low levels of ROS result in an enhanced immune response to viruses (399, 400) . Modulation of NOX2derived ROS production during influenza infection increased susceptibility to bacterial infections (304, 401) . A fine balance of NOX2 activity and ROS production is therefore required to control viral infections and to improve coinfection outcomes. However, more studies are required to better clarify their precise roles during fungal coinfections.

Other immune cells are emerging as important players during IAPA and CAPA. For instance, NK cells are crucial for direct killing of fungal pathogens as well as controlling the fungicidal activity of other immune cells such as neutrophils (402) . NK cell-depleted mice have increased susceptibility to fungal pathogens, including A. fumigatus (168) . NK cell functions are impaired during influenza and SARS-CoV-2 infection (250, 251, 321, 328, (403) (404) (405) (406) , which has been linked with increased susceptibility to coinfections (407) . Of note, recent studies have shown that asymptomatic COVID-19 patients or those who have recovered have elevated levels of NK cells, which was not observed in patients with severe COVID-19, suggesting an important role in controlling disease severity (321, 404, 408, 409) . Furthermore, circulating NKT cell frequency (a subset that features characteristics of both T cells and NK cells) was identified as a predictive biomarker for patient outcome (322) .

Platelets are also emerging as key mediators of immune responses. Thrombocytopenia often coincides with neutropenia in patients at high risk for developing IPA (410) . Importantly, an increased platelet count has been suggested as one of the main predictors of coinfections in patients suffering from severe influenza (411) and recently has been associated with disease severity in COVID-19 patients (412, 413) . Interestingly, platelets express ACE2, and in vitro exposure to SARS-CoV-2 potentiates platelet activation and aggregation (414) , which might be an important mechanism leading to the vascular complications observed in COVID-19 patients and increasing susceptibility to coinfections.

There are two major types of DC lineages, myeloid conventional DCs (cDCs) and lymphoid plasmacytoid DCs (pDCs) which both arise from DC precursors. During influenza infection, pDCs are a major source of type I IFNs, causing the expansion of antigen-specific T cells (415) (416) (417) (418) . pDC-derived type I IFNs also inhibit viral replication in airway epithelial cells following SARS-CoV-2 infection (419-421). They play a nonredundant role in host defense against Aspergillus infection. Recognition of Aspergillus hyphae by pDCs results in the release of proinflammatory cytokines, including TNF and IFN-a, and the formation of extracellular traps (422) (423) (424) . More recently, it was shown that recruitment of pDCs into the lungs activates neutrophil NADPH activity to promote clearance of inhaled conidia (316) . Importantly, severe COVID-19 patients show gene expression signatures of apoptosis in pDCs that correlate with reduced pDC frequency (278, 405, 419, 421) . Dysregulation of pDCs might contribute to depressed IFN signatures affecting susceptibility to fungal coinfections.

In contrast, cDCs are important players in antigen presentation and activation of T cells that underpin adaptive immune responses. Upon antigen recognition, uptake, and processing, DCs acquire a fully mature state and migrate to the draining lymph nodes, where they present antigen-derived peptides in the context of major histocompatibility complex (MHC) molecules to CD8 1 T cells or CD4 1 T cells (425) . Impairments of DC functionalities following severe viral pneumonia can be classified as having short-lived and long-term effects. Short-lived effects are reversible as soon as the viral infection is cleared and include modulation of DC antigen presentation capabilities and interference with signaling pathways. It is well recognized that some viral pathogens, in particular DNA viruses such as herpesviruses, can interfere with the antigen presentation pathway (426, 427) , while RNA viruses, including influenza virus, by an unknown mechanism seem to preferentially target the cross-presentation pathway (which occurs when exogenous antigens, normally loaded into major histocompatibility complex class II [MHC-II] molecules, are shuttled into the MHC-I pathway) (428-432) (Fig. 2) . DCs are susceptible to SARS-CoV-2 infection, which attenuates the IFN response via viral antagonism of STAT1 phosphorylation (433) . However, whether these mechanisms have implications during secondary fungal infections is unknown.

Heterologous immunity can significantly impact DC phenotype and the ability of DCs to activate optimal immune responses to fungi. For instance, desensitization of pattern recognition receptors (PRRs) (i.e., TLR2, TLR4, and TLR5) associated with reduced chemokine production and NF-k B activation has been reported during viral infections (434, 435) . In vitro studies have suggested that exposure to a viral infection affects DC cytokine production to a subsequent secondary challenge (436, 437) . In addition, upregulation of inhibitory signals, such as CD200R, desensitizes APCs (DCs and macrophages), increasing their threshold of activation, a mechanism shown to contribute to bacterial coinfections (204) (Fig. 2) . Nevertheless, in COVID-19 patients, CD200R expression was shown to be reduced in peripheral blood DCs, which could contribute to the expression of proinflammatory cytokines, tissue damage, disease severity, and mortality (324) . More recently, it has been suggested that SARS-CoV-2 infection results in significantly reduced numbers of DCs, with functional impairment reflected in reduced maturation and cytokine production necessary to perform antigen presentation to activate T cells (324, 337, (438) (439) (440) (441) . Some of these long-lasting mechanisms could persist for weeks or even months after recovery, considerably increasing susceptibility to fungal coinfections. Remarkably, preexposure to Pneumocystis results in enhanced antigen processing, maturation, and trafficking abilities of DCs, which causes an accelerated influenza virus-specific primary immune response and viral clearance (442) .

CLRs expressed by myeloid cells, including DCs and macrophages, are crucial for tailoring immune responses to pathogens. A recent study showed that several CLRs, including dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN), liver/lymph node-specific intercellular adhesion molecule 3-grabbing integrin (L-SIGN), liver/lymph node sinusoidal endothelial cell C-type lectin (LSECtin), and macrophage galactose-type lectin (MGL), participate in SARS-CoV-2 recognition and induction of proinflammatory mediators (IL-1b, IL-8, CXCL10, CCL2, and CCL3) that correlate with disease severity (443, 444) . DC-SIGN also mediates binding and internalization of A. fumigatus conidia by DCs (445) , and it is expressed by alveolar macrophages in the lung (446) . However, it is not clear whether DC-SIGN is required for activation of innate immune signaling or if it is involved in the initial stages of Aspergillus pulmonary infection and dissemination (446) . Importantly, DC-SIGN polymorphisms are associated with the development of IPA, suggesting that it might be involved in the pathogenesis of this infection (447) . Therefore, the potential convergence of CLR-driven innate and/or adaptive immune responses in the setting of SARS-CoV-2 and Aspergillus coinfection should be further explored, as it might influence copathogenesis and disease progression.

Resolution of lung inflammatory disease after influenza virus infection sets a different threshold for innate immune activation (204) . This altered homeostasis could have a significant impact on the threshold of responsiveness to the next pathogen. Engagement of PRRs on the surface of APCs induces epigenetic functional reprogramming that affects their sensitivity to a second challenge, a process referred to as "trained immunity" (448) . Even though myeloid cells are typically short-lived during inflammation, these phenomena can occur in bone marrow progenitors (448) (449) (450) (451) (452) and impact monocytes, macrophages, and DC populations during fungal infections (453) . In particular, TNF production during invasive cryptococcosis induces a stable state of DC phenotypic programming (DC1/M1like), rendering the DCs resistant to both antigen-and cytokine (IL-4)-induced alternative activation (DC2/M2-like). This reprogramming was also shown in bone marrow DC precursors and was demonstrated to be essential for Th1/Th17 immune protection (454) . Interestingly, DC differentiation from bone marrow precursors is impaired during the course of a viral infection, leading to susceptibility to secondary infections (455, 456) . In addition, recent studies have shown that DCs undergo a metabolic reprogramming early during influenza infections that results in significant changes in innate immune functions of DCs, including reduced motility and T cell activation (457) . How long this reprogramming persists and whether it may impact fungal coinfections are unknown and will require more study.

Several functional studies have established the role for specific DC subsets (pDCs, cDCs, and inflammatory DCs) in immunity against influenza virus infection (458) (459) (460) (461) (462) . However, we still know very little about the role of different pulmonary DC subsets during fungal infections (463) . Therefore, substantially more work is needed to separate which subsets are needed at which phase of the response to prevent IAPA or CAPA.

CD4 1 T cells produce several antimicrobial soluble factors that control the spread of viral and fungal infections. They are also required for class switching of antibodies and for optimal CD8 1 T cell memory responses (4) . The type I IFN response during influenza infection can directly affect adaptive immunity to fungi by dampening Th17 responses via the suppression of IL-23, a cytokine that is crucial for the expansion and maintenance of Th17 cells (464) . Defective Th17 responses can lead to attenuation of the AMP production and neutrophil recruitment required for antifungal clearance (168, 465) . This suggests that defective Th17 responses are a significant factor during IAPA, as has been shown during bacterial coinfections (464) (465) (466) (467) (Fig. 2) . Th1 responses are important in controlling systemic fungal dissemination (169) , but they might be detrimental during respiratory fungal coinfections. STAT1 knockout (KO) mice, which have defective Th1 cell differentiation and increased Th17 immune activation, are less susceptible to coinfections than wild-type controls (467) . Remarkably, it has been shown that COVID-19 patients with moderate disease displayed a progressive reduction of both antiviral (characterized by the dominance of the transcription factor T-bet and the expression of IFN-g) and antifungal (orchestrated by the RORgt-induced cytokines IL-17 and IL-22) responses whereas patients with severe disease maintained these elevated responses throughout the course of the disease (200) . This suggests that dysregulation of T cell responses could be an important factor that contributes to the development of fungal coinfections in COVID-19 patients.

Another important T cell population that plays a significant role during recovery and resolution of inflammation is Foxp3 1 regulatory T cells (Tregs). Influenza virus-specific Tregs can be detected for a prolonged time after viral clearance (468) and can reduce expansion of CD4 1 and CD8 1 effector T cells (469) (470) (471) while suppressing neutrophil-driven cytokine release into the airways, contributing to the resolution of disease (472) . This Treg-mediated dampening of inflammation likely impacts immunity to subsequent infections such as Aspergillus infections (5) . Indeed, Tregs can control immunity and tolerance to Aspergillus at different stages of the immune response (473, 474) . However, early during infection, they might have a detrimental role by suppressing neutrophil functions through secretion of IL-10 and expression of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) (which acts to inhibit T cell activation) (475) (Fig.  2) . Tregs can also facilitate processes of tissue repair that can further sustain this antiinflammatory state (306) . Functional assessments of how the altered dynamics of T cell populations during viral infection affects antifungal capabilities could help to understand their role during fungal coinfections.

B cell and CD8 1 T cell responses are critical for pathogen neutralization and clearance and play a major part in the memory response that prevents reinfection (4, 476, 477) . Respiratory viral infections could influence susceptibility to subsequent fungal infections by targeting adaptive immune components at different levels, including cross-presentation, CD8 1 T cell activation, and B cell activation and antibody production. The contribution of CD8 1 T cells in host immunity against fungal infections in not well understood, and several studies have suggested that they might play a protective role in the setting of CD4 1 T cell deficiency (478) (479) (480) . Studies have suggested that influenza viruses might interfere with the cross-presentation pathway (428) (429) (430) (431) (432) . In particular, DCs that capture dead cells containing influenza virus are unable to activate CD8 1 T cell clones specific to cell-associated antigens of captured dead cells (431) . Moreover, influenza virus-infected DCs exhibit impaired cross-presentation of influenza virus-derived and other exogenous antigens (430) . Although it has not yet been demonstrated, these mechanisms could have significant implications during fungal coinfections.

The role of protective humoral immunity against fungal infections is not well defined, and it is still very controversial (481) (482) (483) (484) (485) . Therefore, studies focusing on understanding the role of humoral immunity during viral and fungal coinfections are scarce. Of note, monoclonal antibodies targeting Candida albicans can confer protection against lethal pulmonary infections by Gram-negative bacteria in mice (486) , while Pneumocystis infection can protect mice against subsequent influenza infection due to the enhancement of the influenza virus-specific antibody response (487) . Susceptibility mechanisms could include the activation of low-affinity cellular responses and/or production of nonneutralizing antibodies that could facilitate coinfections (488) (489) (490) . Interestingly, meningeal IgA plasma cells that are dependent on the presence of gut commensals can confer protection against fungal invasion into the brain (484) . Therefore, alteration of these fungus-specific antibodies could facilitate fungal dissemination during coinfections (Fig. 3) .

The immune response to a pathogen is greatly influenced by the individual's immune history (491, 492) . Cross-reactivity of adaptive immune lymphocytes can either confer protection or drive susceptibility to subsequent infections. Heterologous immunity refers to the ability of one pathogen to modify the immune response to a related or unrelated pathogen that could boost or weaken protective immunity, break tolerance, or induce immunopathology (488) . This phenomenon has been shown for closely related but also unrelated pathogens, including parasites, protozoa, bacteria, and viruses (493) (494) (495) . Literature on heterologous immunity to fungi is limited. One study shows that a modified heat-labile bacterial toxin (LTK63) improved the immune response to subsequent infection with Cryptococcus neoformans by increasing pathogen-specific CD8 1 T cell and IgA responses in the nasal mucosa (496) . Furthermore, segmented filamentous bacterial colonization during pulmonary Aspergillus infection augments antifungal Th17 immunity (172) . Interestingly, heterologous immunity to a single, ubiquitous member of the fungal microbiota is fundamental for systemic induction of protective antifungal Th17 responses and immunopathology (355) . In particular, the commensal C. albicans is the main inducer of Th17 responses in peripheral blood that later can be expanded in the lungs by cross-reactive airborne A. fumigatus (355) . Further studies suggest that priming of these fungal crossreactive T cells by gut commensal fungi and selective recruitment of these cells to the lungs may be important factors in the pathogenesis of inflammatory airway diseases (355, 497) (Fig. 3) . Therefore, it is plausible that immune responses to commensal fungi may be altered during chronic viral infections, facilitating fungal coinfections. Interestingly, C. albicans colonization does not confer protection against influenza virus infection and rather exacerbates allergic airway inflammation susceptibility, indicating that fine-tuning of T cell responses is required to control immunity versus immunopathology (355, 497) . In this context, "pathogenic" Th17/Th1 versus "anti-inflammatory" Th17/Treg mixed responses could play differential roles during influenza-associated coinfections (170) .

Clinical studies have shown a huge variation in the incidence of IAPA and CAPA. This variation in incidence might be explained by the interplay of a number of factors with the copathogenesis of respiratory viral and fungal coinfections, including differences in environmental and/or genetic factors, type of circulating viral strain, treatment modalities for the critical illness, and the use of and access to fungal diagnostic tools. Environmental conditions can modulate host immune responses, including mucociliary clearance, tissue repair functions, and innate immune defenses (498) , as well as outbreaks of viral respiratory diseases by influencing virus stability and transmission rates (499) (500) (501) . Seasonal fluctuations in airborne fungal spore levels have also been determined for different genera, with the dominant genera varying depending on geographical location (502) (503) (504) (505) (506) (507) (508) (509) (510) . In some regions, seasonal variations in total airborne fungal counts have been shown to correlate with different environmental factors, including temperature, humidity, rainfall, and wind speed (502) (503) (504) (505) (506) (507) . Whereas most studies have suggested that A. fumigatus is present at low but persistent levels in the outdoor environment (502) , there are possible geographical links that need to be more fully explored. A study from Brazil showed that Aspergillus spp. were among the dominant species found in both indoor and outdoor environments (506), while a study from the Netherlands found that Aspergillus was present all year round and prevailed in the autumn and winter months (507) . Interestingly, a study from Canada described a positive association between Aspergillus hyphal fragments and wind speed (504) .

Genetic factors associated with increased susceptibility to influenza viral infection include genes involved with viral recognition and IFN signaling (Ifitm3, Irf7, Ifnar1, Ifnl1, Stat1, Sfpta1) (511) . Another set of genes are associated with disease exacerbation during influenza infection, including genes involved in inflammation (Par1, Tnfaip3, Nos2, Ptges2, and Ifi35) and tissue homeostasis (Epg5, Atg14, and Atg7) (511) . This is consistent with the idea of immunopathology contributing to disease severity and susceptibility to coinfections. Recent studies have identified several host factors critical for SARS-CoV-2 infection, including genes involved in cholesterol biosynthesis, autophagy, viral entry, and phosphatidylinositol biosynthesis, among others (512) (513) (514) (515) (516) (517) . Genes involved in fungal recognition and effector mechanisms (Ptx3, Tlr4, clec7a, Clec1a, Plg, Cxcl10, Ifng, Il10) are associated with increased susceptibility to invasive aspergillosis in patients undergoing hematopoietic stem cell transplant. A second set of genes (S100b, Rage, Nod2) are involved with hyperactivity of innate recognition pathways (518) (519) (520) . These susceptibility mechanisms have also been reiterated in studies of other vulnerable populations, including patients with COPD, solid organ transplant recipients, and patients with hematological malignancies. Nevertheless, genetic studies are required to determine their role in a population of patients suffering from severe viral pneumonia.

Emergence of highly pathogenic viral strains increases susceptibility and modifies the kinetics of coinfections (521) . Viral polymorphisms that alter the tropism of influenza viruses from the upper to the lower respiratory tract and facilitate bacterial coinfections (5) could potentially increase susceptibility to fungal coinfections. Major subtypes of influenza virus strains linked to IAPA include H1N1, H5N1, and H7N9. Influenza virus strain H5N1 increases the production of proinflammatory cytokines and enhances viral replication in the lung, causing immunopathology and pulmonary fibrosis (209, 376, (522) (523) (524) , which are important contributing factors that drive secondary infections (168, 245, 327-334, 366, 371-377) . In contrast, strain H7N9 can inhibit the inflammasome (372) , an important effector mechanism against viral and fungal infections. variants have all shown to be highly transmissible, with some studies suggesting an association with higher mortality and escape from natural and vaccine-induced immunity (525) (526) (527) . However, whether these novel variants are associated with increased susceptibility to fungal coinfections is unknown. Of note, some authors have suggested an association between the delta variant and the emergence of mucormycosis in India (528, 529) ; however, so far there are no specific data to support this hypothesis.

Treatment modalities for severely ill patients could also increase susceptibility to respiratory fungal coinfections following severe viral pneumonia. This includes the use of antibiotic, antiviral, and/or immunomodulatory treatment. For instance, the use of antibiotics to prevent secondary bacterial infection can cause dysbiosis, a condition that has been linked to increased severity during respiratory viral infections and susceptibility to secondary infections (345, 356, 357) . The use of neuraminidase inhibitors has been suggested to increase susceptibility to fungal coinfections following influenza infection (44) and has been recently demonstrated to increase the susceptibility of mice to invasive aspergillosis (530) . The use of the corticosteroid dexamethasone as an immunosuppressive drug to treat ARDS, which was shown to reduce mortality in seriously ill COVID-19 patients (531) , is one of the major risk factors for developing CAPA and negatively affects immunity to Aspergillus (532) (533) (534) . Several studies have reported a relationship between the use of steroidal immunosuppressant (corticosteroids) and the incidence of IPA in critically ill COVID-19 patients (56, 73, 82, 89, [535] [536] [537] [538] [539] . A prospective study from ICUs in Wales showed that the use of high-dose systemic corticosteroids increased the likelihood of developing CAPA (16 out of 22 patients [72%] compared to 32 out of 57 patients without CAPA [56%]) (2) . Similar findings were observed in studies focused on patients with severe influenza (24, 540) . However, some studies have found no association between the use of corticosteroids and the incidence of hospital-acquired fungal infections in patients with COVID-19 (541, 542) , which has been suggested to be due to an early administration of low-dose corticosteroids for a short period (541) . Importantly, in some of these studies, additional risk factors might be at play, including a history of chronic respiratory disease. Recent clinical trials have suggested that combining corticosteroids with anti-IL-6 treatment (tocilizumab) improves the outcomes in terms of morbidity and mortality in severe COVID-19 patients (543, 544) . Nevertheless, COVID-19 patients receiving tocilizumab are reported to be at higher risk of developing CAPA (65, 69, 82, 545, 546) . As IL-6 is essential for inducing protective Th17 responses (170) (171) (172) and controlling the effector functions of phagocytes (547) , anti-IL-6 therapy increases the susceptibility for fungal infections. Earlier studies have documented an increased risk for developing bacterial and fungal infections in patients receiving tocilizumab in combination with corticosteroids for the treatment of rheumatoid arthritis (548) . A retrospective study conducted in Chicago involving 111 COVID-19 patients found that those receiving tocilizumab had a higher risk of developing fungal infections and increased mortality (549) . Strikingly, in a prospective study from Spain that includes 2,723 patients with COVID-19, all CAPA patients who received tocilizumab and corticosteroids had a fatal outcome (8 out of 8 patients) (89) . Prospective monitoring of these patients is needed to shed light on whether tocilizumab negatively impacts the susceptibility to and outcome of respiratory fungal coinfections. Furthermore, metanalyses of retrospective studies could help to elucidate the role of immunosuppressive agents in predisposing COVID-19 patients to fungal coinfections.

The epidemiology of, and the mortality associated with, coinfections complicating viral respiratory tract infections is difficult to assess with confidence. This is partly due to the fact that diagnosis of sequential infections is challenging, as the primary pathogen is often no longer detectable by the time the secondary infection presents itself (550) . Alternatively, if both infections present themselves at the same time, one could quickly override the other. Furthermore, the presence of a specific pathogen may be part of the airway commensal community rather than an indication of infection and disease (551) . Therefore, the specific attribution of the primary viral infection and coinfections to mortality is complex to unravel. In comparison to bacterial coinfections in viral respiratory disease, differentiation of fungal colonization versus infection and disease is even more challenging. Aspergillus spp. are ubiquitous in the environment, and as a consequence, our airways are exposed on a daily basis to its spores (conidia). In immunocompetent healthy individuals, these spores are cleared without infection and disease, while in immunocompromised patients and those with chronic lung disease, spore inhalation can lead to pulmonary aspergillosis (235) . Diagnosis of pulmonary aspergillosis is based on a combination of criteria that includes host factors, clinical and radiological features, and mycological studies (11, 552) . However, cultures from respiratory samples do not differentiate colonization from disease, antigen testing in serum has a low specificity, and specific changes on chest imaging and invasive diagnostics (e.g., bronchoscopy) are often not feasible due to the critical clinical condition of the patient and the risk of aerosolization in cases of viral pneumonia. The absence of rapid, sensitive, and specific fungal diagnostic tools is a major challenge. Optimal availability of, access to, and implementation of fungal diagnostic tools in routine clinical care will affect incidences reported and provide a real insight into the clinical epidemiology and burden of disease.

Viral-fungal coinfections are increasingly being recognized by the scientific and medical communities. The urgent need to obtain insight into the epidemiology, pathogenesis, and underlying immune mechanisms is driven by the additional mortality among patients with IAPA and CAPA (288) . Comprehensive epidemiological data are lacking, and therefore data from larger cohorts of patients are required to better assess the incidence, clinical features, and detailed characteristics of secondary fungal infections in influenza and COVID-19 patients, especially with the highly pathogenic emerging strains (553). Early diagnosis of fungal infection is critical for effective treatment. Current diagnostic methods lack sensitivity and specificity to differentiate colonization from infection and invasive disease. Systematic prospective studies that employ uniform diagnostic testing and criteria are urgently required to optimize the management of patients in the ICU, and first initiatives are been undertaken in this area (119, 133, 554, 555) . Azole-resistant A. fumigatus causing infections in COVID-19 (556) (557) (558) and influenza (47, 559, 560) patients is emerging, highlighting the importance of early causative diagnosis and surveillance during antifungal therapy. Developing treatment modalities in which both the virus and the fungus are being targeted could also be proven useful. Using unbiased approaches, studies have identified several immunotypes in hospitalized COVID-19 patients that could predict clinical outcome and disease trajectory (200, 561, 562) . Similar longitudinal studies could prove of value in identifying comparable profiles predicting the presence of fungal infections in these patients, which could have significant implications for therapeutic interventions.

Our understanding of how host-pathogen interactions are affected during polymicrobial infections is limited. We have summarized a number of immune pathways and mechanisms that may play a crucial role in the copathogenesis of viral and fungal lung infections. Interindividual heterogeneity of the immune system that is shaped by divergent exposure of immune cells to infections, vaccination, and lifestyle-related stimuli (diet, physical activity, and stress) will influence an individual's risk for acquiring fungal infections. Improved tools and models to study coinfections are needed to obtain better insight into the copathogenesis and immune pathways driving disease. Preliminary studies have shown a strong link between high viral replication and increased susceptibility to fungal coinfection, which suggest that the timing of coinfection is important in determining susceptibility and disease outcome (272) . Influenza infection induces several long-lasting changes at molecular levels, as shown by transcriptome, proteome, and metabolome analyses, which could affect susceptibility to fungal infections (563) . Studies with convalescent-phase samples from COVID-19 patients have suggested that the immune system does not fully recover after infection (250) . As with postacute viral syndromes described in survivors of other SARS epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19 beyond 1 month from the onset of symptoms (564, 565) . Long-term follow-up studies are needed to investigate the consequences on fungal immunity. Importantly, long-term metabolic dysregulation influences disease trajectory and immune response to COVID-19 (566) (567) (568) and might also affect susceptibility to secondary fungal infections. Host genetic factors such as polymorphisms in key immune receptors and signaling molecules involved in fungal sensing could also be playing a key role. Increasing our understanding of the copathogenesis of respiratory viral-fungal coinfections and the impact of the microbiomes in this interplay could help to develop better diagnostics and therapeutic modalities against newly identified targets. 

Hidden killers: human fungal infections

A national strategy to diagnose COVID-19 associated invasive fungal disease in the ICU

Global and multinational prevalence of fungal diseases-estimate precision

The co-pathogenesis of influenza viruses with bacteria in the lung

Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness

Influenza-pneumonia mortality in a group of about 95 cities in the United States

pandemic influenza A (H1N1): pathology and pathogenesis of 100 fatal cases in the United States

Bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza A (H1N1)-United States

Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenza

Revision and update of the consensus definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium

High incidence of pulmonary bacterial co-infection in children with severe respiratory syncytial virus (RSV) bronchiolitis

Antitussives in the treatment of acute transient cough in children

Bacterial involvement in parainfluenza virus infection in children

Presence of viral and bacterial pathogens in the nasopharynx of otitis-prone children. A prospective study

Cytomegalovirus and HIV: a dangerous pas de deux

Clinical features and short-term outcomes of 221 patients with COVID-19 in Wuhan

Bacterial and viral co-infections in patients with severe SARS-CoV-2 pneumonia admitted to a French ICU

Viral and atypical bacterial detection in acute respiratory infection in children under five years

Clinical impact of combined viral and bacterial infection in patients with community-acquired pneumonia

Risk of ruling out severe acute respiratory syndrome by ruling in another diagnosis: variable incidence of atypical bacteria coinfection based on diagnostic assays

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

AspICU Study Investigators. 2012. A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients

Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study

Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion

Invasive fungal disease complicating COVID-19: when it rains it spores

State-of-the-art review of secondary pulmonary infections in patients with COVID-19 pneumonia

Is the COVID-19 pandemic a good time to include Aspergillus molecular detection to categorize aspergillosis in ICU patients? A monocentric experience

Infectious Diseases Fungal Infection Study Group, ESCMID Study Group for Infections in Critically Ill Patients, Interregional Association of Clinical Microbiology and Antimicrobial Chemotherapy, Medical Mycology Society of Nigeria, Medical Mycology Society of China Medicine Education Association, Infectious Diseases Working Party of the German Society for Haematology and Medical Oncology, Association of Medical Microbiology, Infectious Disease Canada. 2020. Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance

A higher rate of pulmonary fungal infection in chronic obstructive pulmonary disease patients with influenza in a large tertiary hospital

Fatal aspergillosis complicating severe SARS-CoV-2 infection: a case report

Incidence of invasive pulmonary aspergillosis among critically ill COVID-19 patients

Ventilator-associated pneumonia involving Aspergillus flavus in a patient with coronavirus disease 2019 (COVID-19) from Argentina

Isolation of Aspergillus spp. in respiratory samples of patients with COVID-19 in a Spanish tertiary care hospital

Invasive pulmonary aspergillosis and hyperthermia in an immunocompetent patient with COVID-19

Epidemiology of invasive pulmonary aspergillosis among COVID-19 intubated patients: a prospective study

COVID-19-associated pulmonary aspergillosis: adding insult to injury

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Clinical features of 69 cases with coronavirus disease

Clinical and virological data of the first cases of COVID-19 in Europe: a case series

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

People living with HIV in the COVID-19 era: a case report

Critically ill patients with COVID-19 and candidaemia: we must keep this in mind

A complex COVID-19 case with rheumatoid arthritis treated with tocilizumab

Occurrence of invasive pulmonary fungal infections in severe COVID-19 patients admitted to the ICU

Warris A, Schwartz I. 2021. Editorial MMCR special issue "Covid-19 associated pulmonary aspergillosis

Invasive aspergillosis in patients with severe COVID-19 pneumonia

Pulmonary aspergillosis in critically ill patients with coronavirus disease 2019 (COVID-19)

Secondary bacterial infections in critical ill patients with coronavirus disease 2019

Incidence of co-infections and superinfections in hospitalized patients with COVID-19: a retrospective cohort study

Invasive pulmonary aspergillosis in the COVID-19 era: an expected new entity

Accuracy of galactomannan testing on tracheal aspirates in COVID-19-associated pulmonary aspergillosis

Prevalence of opportunistic invasive aspergillosis in COVID-19 patients with severe pneumonia

Detection of invasive pulmonary aspergillosis in COVID-19 with non-directed bronchoalveolar lavage

Fatal invasive pulmonary aspergillosis in COVID-19 patient with acute myeloid leukemia in Iran

Fatal coronavirus disease 2019-associated pulmonary aspergillosis; a report of two cases and review of the literature

Invasive pulmonary aspergillosis in critically ill patients with severe COVID-19 pneumonia: results from the prospective AspCOVID-19 study

COVID-19-associated invasive pulmonary aspergillosis in a tertiary care center in Mexico City

COVID-19-associated mold infection in critically ill patients

Shimabukuro-Vornhagen A. 2020. COVID-19 associated pulmonary aspergillosis

COVID-19-associated invasive pulmonary aspergillosis

2021. Incidence, diagnosis and outcomes of COVID-19-associated pulmonary aspergillosis (CAPA): a systematic review

COVID-19 associated pulmonary aspergillosis

Late histopathologic characteristics of critically ill COVID-19 patients: different phenotypes without evidence of invasive aspergillosis, a case series

Confirmed invasive pulmonary aspergillosis and COVID-19: the value of postmortem findings to support antemortem management

Rates of aspergillus co-infection in COVID patients in ICU not as high as previously reported

Bacterial and fungal coinfection among hospitalized patients with COVID-19: a retrospective cohort study in a UK secondary-care setting

Bacterial and fungal coinfection in individuals with coronavirus: a rapid review to support COVID-19 antimicrobial prescribing

Risks of ventilator-associated pneumonia and invasive pulmonary aspergillosis in patients with viral acute respiratory distress syndrome related or not to coronavirus 19 disease

Coronavirus disease (Covid-19) associated mucormycosis (CAM): case report and systematic review of literature

The emergence of COVID-19 associated mucormycosis: analysis of cases from 18 countries

The double-edged sword of systemic corticosteroid therapy in viral pneumonia: a case report and comparative review of influenza-associated mucormycosis versus COVID-19 associated mucormycosis

When uncontrolled diabetes mellitus and severe COVID-19 converge: the perfect storm for mucormycosis

COVID-19 associated mucormycosis (CAM): risk factors and mechanisms of disease

The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice

CotH3 mediates fungal invasion of host cells during mucormycosis

High GRP78 levels in Covid-19 infection: a case-control study

Mucor in a viral land: a tale of two pathogens

COVID-19 and orbital mucormycosis

Multicenter epidemiologic study of coronavirus disease-associated mucormycosis

ECMM/ISHAM recommendations for clinical management of COVID-19 associated mucormycosis in low-and middle-income countries

Case report: oseltamivir-induced resistant pandemic influenza A (H1N1) virus infection in a patient with AIDS and Pneumocystis jirovecii pneumonia

Possible pandemic H1N1 influenza complicated by Pneumocystis jirovecii pneumonia in an HIV-infected patient

Pneumocystosis as a complication of H1N1 influenza A infection in an HIV-positive patient on effective cART

Pneumonia in HIV-infected patients: a case-control survey of factors involved in risk and prevention

Influenza and Pneumocystis jirovecii pneumonia in an allogeneic hematopoietic stem cell transplantation recipient: coinfection or superinfection?

Utility of adding Pneumocystis jirovecii DNA detection in nasopharyngeal aspirates in immunocompromised adult patients with febrile pneumonia

A case of COVID-19 and Pneumocystis jirovecii co-infection

Pneumocystis jirovecii pneumonia in an immunocompetent patient recovered from COVID-19

Coronavirus disease 2019 and Pneumocystis jirovecii pneumonia: a diagnostic dilemma in HIV

Pneumocystis jirovecii pneumonia and severe acute respiratory syndrome coronavirus 2 coinfection in a patient with newly diagnosed HIV-1 infection

Concurrent COVID-19 and Pneumocystis jirovecii pneumonia in a severely immunocompromised 25-year-old patient

COVID-19: to be or not to be; that is the diagnostic question

It's not all about COVID-19: pneumocystis pneumonia in the era of a respiratory outbreak

Invasive fungal diseases during COVID-19: we should be prepared

The diagnostic trap occurred in two COVID-19 cases combined pneumocystis pneumonia in patient with

Man with dyspnea

The many faces of interstitial pneumonia: a case of presumed SARS-CoV-2 infection

Pneumocystis pneumonia, a COVID-19 mimic, reminds us of the importance of HIV testing in COVID-19

COVID-19 in HIV Investigators. 2020. COVID-19 in patients with HIV: clinical case series

Pneumocystis jiroveci pneumonia (PCP) misdiagnosed as pandemic influenza H1N1 in a renal transplant patient

HIV adult with fever and shortness of breath: influenza B misdiagnosed as Pneumocystis (carinii) jiroveci pneumonia (PCP)

Concomitant severe influenza and cryptococcal infections: a case report and literature review

Concomitant infections of influenza A H1N1 and disseminated cryptococcosis in an HIV seropositive patient

Cryptococccal meningoencephalitis after H1N1 influenza

Coinfections in patients hospitalized with COVID-19: a descriptive study from the United Arab Emirates

Candida auris Brazilian Study Group. 2021. Axillary digital thermometers uplifted a multidrug-susceptible Candida auris outbreak among COVID-19 patients in Brazil

Impact of the SARS-CoV-2 pandemic in candidaemia, invasive aspergillosis and antifungal consumption in a tertiary hospital

Spread of carbapenem-resistant gram-negatives and Candida auris during the COVID-19 pandemic in critically ill patients: one step back in antimicrobial stewardship? Microorganisms

Molecular epidemiological investigation of a nosocomial cluster of C. auris: evidence of recent emergence in Italy and ease of transmission during the COVID-19 pandemic

First Candida auris outbreak during a COVID-19 pandemic in a tertiary-care center in Lebanon

Outbreak of Candida auris infection in a COVID-19 hospital in Mexico

Emergence of Candida auris in Brazil in a COVID-19 intensive care unit

Candida auris invasive infections during a COVID-19 case surge

Multidrug-resistant Candida auris infections in critically ill coronavirus disease patients

Candida auris: a latent threat to critically ill patients with COVID-19

The impact of vaccines on heterologous adaptive immunity

Virus-induced T cellmediated heterologous immunity and vaccine development

COVID-19 associated pulmonary aspergillosis (CAPA)-from immunology to treatment

The role of co-infections and secondary infections in patients with COVID-19

Immunological response to COVID-19 and its role as a predisposing factor in invasive aspergillosis

Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19

SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues

The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: estimation and application

The many faces of the anti-COVID immune response

Influenza virus and SARS-CoV-2: pathogenesis and host responses in the respiratory tract

Influenza-and COVID-19-associated pulmonary aspergillosis: are the pictures different?

A virological view of innate immune recognition

Type I and type III interferons drive redundant amplification loops to induce a transcriptional signature in influenzainfected airway epithelia

Antifungal innate immunity: a perspective from the last 10 years

Innate immune activation and CD41 T cell priming during respiratory fungal infection

Pathogen-induced human TH17 cells produce IFN-gamma or IL-10 and are regulated by IL-1beta

CD103(1) dendritic cells control Th17 cell function in the lung

Pulmonary Th17 antifungal immunity is regulated by the gut microbiome

2020. T cell antifungal immunity and the role of C-type lectin receptors

Cilia and mucociliary clearance

Interactions of Aspergillus fumigatus conidia with airway epithelial cells: a critical review

Receptor binding by an H7N9 influenza virus from humans

H5N1 virus attachment to lower respiratory tract

Tropism of avian influenza A (H5N1) in the upper and lower respiratory tract

Respiratory virus infections: understanding COVID-19

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

Angiotensin-converting enzyme 2: a functional receptor for SARS coronavirus

Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor

Structural and functional basis of SARS-CoV-2 entry by using human ACE2

Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2

Coronavirus biology and replication: implications for SARS-CoV-2

Influenza A virus cell entry, replication, virion assembly and movement

Human cytomegalovirus entry into cells

Functional impairment of mononuclear phagocyte system by the human respiratory syncytial virus

Wunderink RG, Investigators NSS, NU SCRIPT Study Investigators. 2021. Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia

Influenza virusinduced lung injury: pathogenesis and implications for treatment

Influenza virus infection decreases tracheal mucociliary velocity and clearance of Streptococcus pneumoniae

Influenza virus infection: don't forget the role of the mucociliary system!

Expression of integrin cell adhesion receptors during human airway epithelial repair in vivo

Airway epithelial repair, regeneration, and remodeling after injury in chronic obstructive pulmonary disease

Aspergillus fumigatus CalA binds to integrin alpha5beta1 and mediates host cell invasion

Club cell TRPV4 serves as a damage sensor driving lung allergic inflammation

Airway fibrinogenolysis and the initiation of allergic inflammation

Selective cleavage of fibrinogen by diverse proteinases initiates innate allergic and antifungal immunity through CD11b

Involvement of secreted Aspergillus fumigatus proteases in disruption of the actin fiber cytoskeleton and loss of focal adhesion sites in infected A549 lung pneumocytes

Longitudinal analyses reveal immunological misfiring in severe COVID-19

COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis

A molecular single-cell lung atlas of lethal COVID-19

COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets

Lowering the threshold of lung innate immune cell activation alters susceptibility to secondary bacterial superinfection

Molecular mechanism of Aspergillus fumigatus adherence to host constituents

Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV

Anti-Aspergillus activities of the respiratory epithelium in health and disease

Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy

Pulmonary fibrosis induced by H5N1 viral infection in mice

Idiopathic pulmonary fibrosis with chronic necrotizing pulmonary aspergillosis: a case report

Functional genomics of human bronchial epithelial cells directly interacting with conidia of Aspergillus fumigatus

Transcriptome profiles of human lung epithelial cells A549 interacting with Aspergillus fumigatus by RNA-Seq

The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis

Gliotoxin induces cofilin phosphorylation to promote actin cytoskeleton dynamics and internalization of Aspergillus fumigatus into type II human pneumocyte cells

Friend or foe: the role of the cytoskeleton in influenza A virus assembly

Quantitative proteomic analyses of influenza virus-infected cultured human lung cells

Phospholipase D facilitates efficient entry of influenza virus, allowing escape from innate immune inhibition

Gliotoxin promotes Aspergillus fumigatus internalization into type II human pneumocyte A549 cells by inducing host phospholipase D activation

beta-1,3-Glucaninduced host phospholipase D activation is involved in Aspergillus fumigatus internalization into type II human pneumocyte A549 cells

FleA expression in Aspergillus fumigatus is recognized by fucosylated structures on mucins and macrophages to prevent lung infection

Aspergillosis and the role of mucins in cystic fibrosis

Role of soluble innate effector molecules in pulmonary defense against fungal pathogens

Compartment-specific and sequential role of MyD88 and CARD9 in chemokine induction and innate defense during respiratory fungal infection

Influenza A penetrates host mucus by cleaving sialic acids with neuraminidase

A beneficiary role for neuraminidase in influenza virus penetration through the respiratory mucus

The cell surface mucin MUC1 limits the severity of influenza A virus infection

Translational shutdown and evasion of the innate immune response by SARS-CoV-2 NSP14 protein

Alveolar epithelial cells orchestrate DC function in murine viral pneumonia

Non-hematopoietic cells contribute to protective tolerance to Aspergillus fumigatus via a TRIF pathway converging on IDO

Implications of hypoxic microenvironments during invasive aspergillosis

Fungal biofilm morphology impacts hypoxia fitness and disease progression

Aspergillus fumigatus inhibits angiogenesis through the production of gliotoxin and other secondary metabolites

Hypoxia enhances innate immune activation to Aspergillus fumigatus through cell wall modulation

Heterogeneity among isolates reveals that fitness in low oxygen correlates with Aspergillus fumigatus virulence

Aspergillus fumigatus morphology and dynamic host interactions

Deficiency of HIF-1alpha enhances influenza A virus replication by promoting autophagy in alveolar type II epithelial cells

Myeloid derived hypoxia inducible factor 1-alpha is required for protection against pulmonary Aspergillus fumigatus infection

Hypoxia-induced exocytosis of endothelial cell Weibel-Palade bodies. A mechanism for rapid neutrophil recruitment after cardiac preservation

Recognition of DHNmelanin by a C-type lectin receptor is required for immunity to Aspergillus

Type III interferon is a critical regulator of innate antifungal immunity

Dectin-1 promotes type I and III interferon expression to support optimal antifungal immunity in the lung

Type I IFNs mediate development of postinfluenza bacterial pneumonia in mice

Impact of type I and III interferons on respiratory superinfections due to; Multidrug-resistant pathogens

Type I interferons directly regulate lymphocyte recirculation and cause transient blood lymphopenia

Interferon-lambda mediates non-redundant front-line antiviral protection against influenza virus infection without compromising host fitness

Clinical significance of lymphocytopenia in patients hospitalized with pneumonia caused by influenza virus

Prolonged influenza virus infection during lymphocytopenia and frequent detection of drug-resistant viruses

Severe lymphopenia in hospitalized patients with influenza virus infection as a marker of a poor outcome

Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study

Single-cell landscape of immunological responses in patients with COVID-19

Comprehensive mapping of immune perturbations associated with severe COVID-19

Complex immune dysregulation in COVID-19 patients with severe respiratory failure

Single-cell sequencing of peripheral mononuclear cells reveals distinct immune response landscapes of COVID-19 and influenza patients

Interferon lambda inhibits bacterial uptake during influenza superinfection

Lambda interferon restructures the nasal microbiome and increases susceptibility to Staphylococcus aureus superinfection

2020. Type I and III interferons disrupt lung epithelial repair during recovery from viral infection

Type III interferons disrupt the lung epithelial barrier upon viral recognition

IFN-gamma increases susceptibility to influenza A infection through suppression of group II innate lymphoid cells

Lack of IFNgamma signaling attenuates spread of influenza A virus in vivo and leads to reduced pathogenesis

Influenza infection induces alveolar macrophage dysfunction and thereby enables noninvasive Streptococcus pneumoniae to cause deadly pneumonia

Severe pneumonia caused by coinfection with influenza virus followed by methicillin-resistant Staphylococcus aureus induces higher mortality in mice

Changes in Mycobacterium tuberculosis-specific immunity with influenza co-infection at time of TB diagnosis

Effects of influenza on alveolar macrophage viability are dependent on mouse genetic strain

Regulation of IFN-gamma by IL-13 dictates susceptibility to secondary postinfluenza MRSA pneumonia

Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection

Flu virus attenuates memory clearance of pneumococcus via IFN-gamma-dependent Th17 and independent antibody mechanisms

In vivo neutralization of pro-inflammatory cytokines during secondary Streptococcus pneumoniae infection post influenza A virus infection

Allergic airway disease prevents lethal synergy of influenza A virus-Streptococcus pneumoniae coinfection

Lethal synergism between influenza infection and staphylococcal enterotoxin B in mice

Innate recognition of cell wall beta-glucans drives invariant natural killer T cell responses against fungi

Noncanonical fungal autophagy inhibits inflammation in response to IFN-gamma via DAPK1

Influenza A virus as a predisposing factor for cryptococcosis

Immunotherapeutic approaches to treatment of fungal diseases

Imbalanced host response to SARS-CoV-2 drives development of COVID-19

Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice

Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients

Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans

A dynamic COVID-19 immune signature includes associations with poor prognosis

Global absence and targeting of protective immune states in severe COVID-19

Untuned antiviral immunity in COVID-19 revealed by temporal type I/III interferon patterns and flu comparison

Early nasal type I IFN immunity against SARS-CoV-2 is compromised in patients with autoantibodies against type I IFNs

Autoantibodies neutralizing type I IFNs are present in ;4% of uninfected individuals over 70 years old and account for

Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1

Auto-antibodies against type I IFNs in patients with lifethreatening COVID-19

Diverse functional autoantibodies in patients with COVID-19

Inborn errors of type I IFN immunity in patients with lifethreatening COVID-19

A single-cell atlas of the peripheral immune response in patients with severe COVID-19

Host-viral infection maps reveal signatures of severe COVID-19 patients

Heightened innate immune responses in the respiratory tract of COVID-19 patients

Temporal and spatial heterogeneity of host response to SARS-CoV-2 pulmonary infection

Dual nature of type I interferons in SARS-CoV-2-induced inflammation

Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology

Type I and type III interferons-induction, signaling, evasion, and application to combat COVID-19

Aging impairs both primary and secondary RIG-I signaling for interferon induction in human monocytes

Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling

Dynamic innate immune response determines susceptibility to SARS-CoV-2 infection and early replication kinetics

Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19

Disease-promoting effects of type I interferons in viral, bacterial, and coinfections

The interferon landscape along the respiratory tract impacts the severity of COVID-19

Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children

Influenza suppresses neutrophil recruitment to the lung and exacerbates secondary invasive pulmonary aspergillosis

Aspergillosis in chronic granulomatous disease

Influenza and bacterial superinfection: illuminating the immunologic mechanisms of disease

Influenza infection suppresses NADPH oxidase-dependent phagocytic bacterial clearance and enhances susceptibility to secondary methicillin-resistant Staphylococcus aureus infection

Both influenza-induced neutrophil dysfunction and neutrophil-independent mechanisms contribute to increased susceptibility to a secondary Streptococcus pneumoniae infection

Innate immune cell suppression and the link with secondary lung bacterial pneumonia

The methyltransferase Setdb2 mediates virus-induced susceptibility to bacterial superinfection

Influenza virus infection causes neutrophil dysfunction through reduced G-CSF production and an increased risk of secondary bacteria infection in the lung

Lethal influenza infection: is a macrophage to blame?

Depletion of alveolar macrophages during influenza infection facilitates bacterial superinfections

Neutrophils drive alveolar macrophage IL-1beta release during respiratory viral infection

Influenza virus activates inflammasomes via its intracellular M2 ion channel

The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA

IL-1 signaling prevents alveolar macrophage depletion during influenza and Streptococcus pneumoniae coinfection

Neutrophil chemokines KC and macrophage-inflammatory protein-2 are newly synthesized by tissue macrophages using distinct TLR signaling pathways

During Aspergillus infection, monocyte-derived DCs, neutrophils, and plasmacytoid DCs enhance innate immune defense through CXCR3-dependent crosstalk

Neutropenia enhances lung dendritic cell recruitment in response to Aspergillus via a cytokine-to-chemokine amplification loop

Neutrophils mediate maturation and efflux of lung dendritic cells in response to Aspergillus fumigatus germ tubes

Severe COVID-19 is marked by a dysregulated myeloid cell compartment

Elevated calprotectin and abnormal myeloid cell subsets discriminate Viral and Fungal Coinfections Clinical Microbiology Reviews severe from mild COVID-19

Multi-omics resolves a sharp disease-state shift between mild and moderate COVID-19

Distinct immunological signatures discriminate severe COVID-19 from non-SARS-CoV-2-driven critical pneumonia

Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19

Major alterations in the mononuclear phagocyte landscape associated with COVID-19 severity

Longitudinal profiling of respiratory and systemic immune responses reveals myeloid cell-driven lung inflammation in severe COVID-19

Metabolic programs define dysfunctional immune responses in severe COVID-19 patients

BCL6 modulates tissue neutrophil survival and exacerbates pulmonary inflammation following influenza virus infection

The influenza virus protein PB1-F2 increases viral pathogenesis through neutrophil recruitment and NK cells inhibition

Novel cellular targets of AhR underlie alterations in neutrophilic inflammation and inducible nitric oxide synthase expression during influenza virus infection

Activation of the aryl hydrocarbon receptor increases pulmonary neutrophilia and diminishes host resistance to influenza A virus

Impact of neutrophils on antiviral activity of human bronchoalveolar lavage fluid

Matrix metalloprotease 9 mediates neutrophil migration into the airways in response to influenza virus-induced toll-like receptor signaling

Two waves of pro-inflammatory factors are released during the influenza A virus (IAV)-driven pulmonary immunopathogenesis

TRAIL1 monocytes and monocyte-related cells cause lung damage and thereby increase susceptibility to influenza-Streptococcus pneumoniae coinfection

Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19

Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages

Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19

Tissue damage from neutrophil-induced oxidative stress in COVID-19

The spatial landscape of lung pathology during COVID-19 progression

Viral infection triggers interferon-induced expulsion of live Cryptococcus neoformans by macrophages

CX3CR1-dependent renal macrophage survival promotes Candida control and host survival

CX3CR1(1) mononuclear phagocytes control immunity to intestinal fungi

CCR21 monocyte-derived dendritic cells and exudate macrophages produce influenza-induced pulmonary immune pathology and mortality

Cx3CR1 expression identifies distinct macrophage populations that contribute differentially to inflammation and repair

Bacterial colonization dampens influenza-mediated acute lung injury via induction of M2 alveolar macrophages

Immunological consequences of intestinal fungal dysbiosis

Response to fungal dysbiosis by gut-resident CX3CR1(1) mononuclear phagocytes aggravates allergic airway disease

The chemokine CX3CL1/fractalkine regulates immunopathogenesis during fungal-associated allergic airway inflammation

Role of antibiotics and fungal microbiota in driving pulmonary allergic responses

Gut dysbiosis promotes M2 macrophage polarization and allergic airway inflammation via fungi-induced PGE(2)

Development of allergic airway disease in mice following antibiotic therapy and fungal microbiota increase: role of host genetics, antigen, and interleukin-13

Expansion of commensal fungus Wallemia mellicola in the gastrointestinal mycobiota enhances the severity of allergic airway disease in mice

Intestinal fungi are causally implicated in microbiome assembly and immune development in mice

Gut mycobiota in immunity and inflammatory disease

Human anti-fungal Th17 immunity and pathology rely on cross-reactivity against Candida albicans

Microbiota regulates immune defense against respiratory tract influenza A virus infection

Gut dysbiosis during influenza contributes to pulmonary pneumococcal superinfection through altered short-chain fatty acid production

Influenza virus affects intestinal microbiota and secondary salmonella infection in the gut through type I interferons

Alterations in fecal fungal microbiome of patients with COVID-19 during time of hospitalization until discharge

Inflammasome recognition of influenza virus is essential for adaptive immune responses

The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1

Induction of memory cytotoxic T cells to influenza A virus and subsequent viral clearance is not modulated by PB1-F2-dependent inflammasome activation

Critical regulation of early Th17 cell differentiation by interleukin-1 signaling

The role of the NLRP3 inflammasome in regulation of antiviral responses to influenza A virus infection

Activation of the NLRP3 inflammasome by IAV virulence protein PB1-F2 contributes to severe pathophysiology and disease

Influenza A virus NS1 protein inhibits the NLRP3 inflammasome

PB1-F2 peptide derived from avian influenza A virus H7N9 induces inflammation via activation of the NLRP3 inflammasome

Severe acute respiratory syndrome coronavirus viroporin 3a activates the NLRP3 inflammasome

Ion flux in the lung: virus-induced inflammasome activation

Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients

The RNA-and TRIM25-binding domains of influenza virus NS1 protein are essential for suppression of NLRP3 inflammasome-mediated interleukin-1beta secretion

PB1-F2 protein of highly pathogenic influenza A (H7N9) virus selectively suppresses RNA-induced NLRP3 inflammasome activation through inhibition of MAVS-NLRP3 interaction

Influenza A virus protein PB1-F2 translocates into mitochondria via Tom40 channels and impairs innate immunity

A novel cytotoxic sequence contributes to influenza A viral protein PB1-F2 pathogenicity and predisposition to secondary bacterial infection

Immunopathogenic and antibacterial effects of H3N2 influenza A virus PB1-F2 map to amino acid residues 62, 75, 79, and 82

PB1-F2 proteins from H5N1 and 20 century pandemic influenza viruses cause immunopathology

Expression of the 1918 influenza A virus PB1-F2 enhances the pathogenesis of viral and secondary bacterial pneumonia

Influenza A exacerbates Staphylococcus aureus pneumonia by attenuating IL-1beta production in mice

Type I interferon inhibits interleukin-1 production and inflammasome activation

Modulation of inflammasome-mediated pulmonary immune activation by type I IFNs protects bone marrow homeostasis during systemic responses to Pneumocystis lung infection

Turning up the heat: inflammasome activation by fungal pathogens

Aspergillus fumigatus stimulates the NLRP3 inflammasome through a pathway requiring ROS production and the Syk tyrosine kinase

IL-37 inhibits inflammasome activation and disease severity in murine aspergillosis

IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis

Concerted activation of the AIM2 and NLRP3 inflammasomes orchestrates host protection against Aspergillus infection

Galactosaminogalactan activates the inflammasome to provide host protection

ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways

ZBP1/DAI-dependent cell death pathways in influenza A virus immunity and pathogenesis

The inflammasome potentiates influenza/Staphylococcus aureus superinfection in mice

Enhanced IL-1beta production is mediated by a TLR2-MYD88-NLRP3 signaling axis during coinfection with influenza A virus and Streptococcus pneumoniae

IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans

Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury

An absence of reactive oxygen species improves the resolution of lung influenza infection

Influenza A virus and TLR7 activation potentiate NOX2 oxidase-dependent ROS production in macrophages

Inhibition of Nox2 oxidase activity ameliorates influenza A virus-induced lung inflammation

Suppressing production of reactive oxygen species (ROS) for influenza A virus therapy

NADPH oxidases as novel pharmacologic targets against influenza A virus infection

Endosomal NOX2 oxidase exacerbates virus pathogenicity and is a target for antiviral therapy

Reactive oxygen species deficiency induces autoimmunity with type 1 interferon signature

NADPH oxidase inhibits the pathogenesis of systemic lupus erythematosus

Nox2-derived oxidative stress results in inefficacy of antibiotics against post-influenza S. aureus pneumonia

Role of NK cells in influenza infection

Influenza virus targets class I MHC-educated NK cells for immunoevasion

Longitudinal single-cell immune profiling revealed distinct innate immune response in asymptomatic COVID-19 patients

Time-resolved systems immunology reveals a late juncture linked to fatal COVID-19

Functional exhaustion of antiviral lymphocytes in COVID-19 patients

Influenza infection leads to increased susceptibility to subsequent bacterial superinfection by impairing NK cell responses in the lung

Systems-level immunomonitoring from acute to recovery phase of severe COVID-19

Detection of SARS-CoV-2-specific humoral and cellular immunity in COVID-19 convalescent individuals

Baseline platelet count and creatinine clearance rate predict the outcome of neutropenia-related invasive aspergillosis

Bacterial co-infection with H1N1 infection in patients admitted with community acquired pneumonia

HCA Lung Biological Network, Deutsche COVID-19 Omics Initiative (DeCOI), et al. 2020. Longitudinal multi-omics analyses identify responses of megakaryocytes, erythroid cells, and plasmablasts as hallmarks of severe COVID-19

COVID-19 immune features revealed by a large-scale single-cell transcriptome atlas

SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19

Plasmacytoid dendritic cells activated by influenza virus and CD40L drive a potent TH1 polarization

Activation of influenza virus-specific CD41 and CD81 T cells: a new role for plasmacytoid dendritic cells in adaptive immunity

Plasmacytoid dendritic cells capture and cross-present viral antigens from influenza-virus exposed cells

Plasmacytoid dendritic cells require direct infection to sustain the pulmonary influenza A virus-specific CD8 T cell response

Differential plasmacytoid dendritic cell phenotype and type I Interferon response in asymptomatic and severe COVID-19 infection

SARS-CoV-2 induces human plasmacytoid predendritic cell diversification via UNC93B and IRAK4

Plasmacytoid dendritic cells produce type I interferon and reduce viral replication in airway epithelial cells after SARS-CoV-2 infection

A nonredundant role for plasmacytoid dendritic cells in host defense against the human fungal pathogen Aspergillus fumigatus

Toll-like receptor 9-dependent immune activation by unmethylated CpG motifs in Aspergillus fumigatus DNA

Recognition of Aspergillus fumigatus hyphae by human plasmacytoid dendritic cells is mediated by dectin-2 and results in formation of extracellular traps

Antigen presentation and T cell stimulation by dendritic cells

Viral evasion of T cell immunity: ancient mechanisms offering new applications

Giving CD41 T cells the slip: viral interference with MHC class II-restricted antigen processing and presentation

H9N2 avian influenza virus protein PB1 enhances the immune responses of bone marrowderived dendritic cells by down-regulating miR375

Developmental regulation of MHC II expression and transport in human plasmacytoid-derived dendritic cells

Influenza A virus infection of human primary dendritic cells impairs their ability to cross-present antigen to CD8 T cells

Influenza virus and poly(I:C) inhibit MHC class I-restricted presentation of cell-associated antigens derived from infected dead cells captured by human dendritic cells

Influenza A virus elevates active cathepsin B in primary murine DC

Attenuated interferon and proinflammatory response in SARS-CoV-2-infected human dendritic cells is associated with viral antagonism of STAT1 phosphorylation

Local modulation of antigen-presenting cell development after resolution of pneumonia induces longterm susceptibility to secondary infections

Sustained desensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection

Influenza A virusmediated priming enhances cytokine secretion by human dendritic cells infected with Streptococcus pneumoniae

Toll-like receptor 3/TRIF-dependent IL-12p70 secretion mediated by Streptococcus pneumoniae RNA and its priming by influenza A virus coinfection in human dendritic cells

Chemokine up-regulation in SARS-coronavirus-infected, monocyte-derived human dendritic cells

Acute SARS-CoV-2 infection impairs dendritic cell and T cell responses

Differential redistribution of activated monocyte and dendritic cell subsets to the lung associates with severity of COVID-19

Maturation signatures of conventional dendritic cell subtypes in COVID-19 suggest direct viral sensing

CD11c(1) cells primed with unrelated antigens facilitate an accelerated immune response to influenza virus in mice

SARS-CoV-2 exacerbates proinflammatory responses in myeloid cells through C-type lectin receptors and Tweety family member 2

CD209L/L-SIGN and CD209/DC-SIGN act as receptors for SARS-CoV-2

DC-SIGN mediates the binding of Aspergillus fumigatus and keratinophylic fungi by human dendritic cells

Dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin mediates binding and internalization of Aspergillus fumigatus conidia by dendritic cells and macrophages

Dectin-1 and DC-SIGN polymorphisms associated with invasive pulmonary Aspergillosis infection

Defining trained immunity and its role in health and disease

Modulation of myelopoiesis progenitors is an integral component of trained immunity

BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis

Hematopoietic progenitor cells as integrative hubs for adaptation to and fine-tuning of inflammation

beta-Glucan reverses the epigenetic state of LPS-induced immunological tolerance

Induction of autonomous memory alveolar macrophages requires T cell help and is critical to trained immunity

Epigenetic stabilization of DC and DC precursor classical activation by TNFalpha contributes to protective T cell polarization

Innate immune stimuli modulate bone marrow-derived dendritic cell production in vitro by toll-like receptor-dependent and -independent mechanisms

Alteration of Flt3-ligand-dependent de novo generation of conventional dendritic cells during influenza infection contributes to respiratory bacterial superinfection

Dynamic metabolic reprogramming in dendritic cells: an early response to influenza infection that is essential for effector function

Clearance of influenza virus from the lung depends on migratory langerin 1 CD11b 2 but not plasmacytoid dendritic cells

Resident CD8(1) and migratory CD103(1) dendritic cells control CD8 T cell immunity during acute influenza infection

Lung CD1031 dendritic cells efficiently transport influenza virus to the lymph node and load viral antigen onto MHC class I for presentation to CD8 T cells

Respiratory dendritic cell subsets differ in their capacity to support the induction of virus-specific cytotoxic CD81 T cell responses

Type 1 conventional CD103(1) dendritic cells control effector CD8(1) T cell migration, survival, and memory responses during influenza infection

Dendritic cells in lung immunopathology

Influenza A inhibits Th17-mediated host defense against bacterial pneumonia in mice

Influenza A virus exacerbates Staphylococcus aureus pneumonia in mice by attenuating antimicrobial peptide production

The role of IL-27 in susceptibility to post-influenza Staphylococcus aureus pneumonia

STAT1 is required for suppression of type 17 immunity during influenza and bacterial superinfection

Influenza matrix 1-specific human CD41 FOXP31 and FOXP3(-) regulatory T cells can be detected long after viral clearance

CD41 T helper cells use CD154-CD40 interactions to counteract T reg cell-mediated suppression of CD81 T cell responses to influenza

Influenza A virus infection results in a robust, antigen-responsive, and widely disseminated Foxp31 regulatory T cell response

Viral antigen induces differentiation of Foxp31 natural regulatory T cells in influenza virus-infected mice

Late engagement of CD86 after influenza virus clearance promotes recovery in a FoxP31 regulatory T cell dependent manner

Regulatory T cell specificity directs tolerance versus allergy against aeroantigens in humans

Antigen-specific expansion of human regulatory T cells as a major tolerance mechanism against mucosal fungi

Immunity and tolerance to Aspergillus involve functionally distinct regulatory T cells and tryptophan catabolism

Sinai Immunology Review Project. 2020. Immunology of COVID-19: current state of the science

The human antibody response to influenza A virus infection and vaccination

Generation of antifungal effector CD81 T cells in the absence of CD41 T cells during Cryptococcus neoformans infection

T cytotoxic-1 CD81 T cells are effector cells against pneumocystis in mice

TLR3 essentially promotes protective class I-restricted memory CD8(1) T-cell responses to Aspergillus fumigatus in hematopoietic transplanted patients

The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients

Defect in production of B cell differentiation factor-like activity by mononuclear cells from a boy with hypogammaglobulinemia

Adaptive immunity to fungi. Cold Spring Harb Perspect Med 5:a019612

Gut-educated IgA plasma cells defend the meningeal venous sinuses

Mucosal IgA prevents commensal Candida albicans dysbiosis in the oral cavity

Monoclonal IgM antibodies targeting Candida albicans Hyr1 provide cross-kingdom protection against gram-negative bacteria

Pneumocystis infection enhances antibody-mediated resistance to a subsequent influenza infection

Heterologous immunity: role in natural and vaccineinduced resistance to infections

Antibody-dependent infection of human macrophages by severe acute respiratory syndrome coronavirus

Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection

Immune history profoundly affects broadly protective B cell responses to influenza

Immune history shapes specificity of pandemic H1N1 influenza antibody responses

From original antigenic sin to the universal influenza virus vaccine

The doctrine of original antigenic sin: separating good from evil

The consequences of mixed-species malaria parasite co-infections in mice and mosquitoes for disease severity, parasite fitness, and transmission success

Innate imprinting by the modified heat-labile toxin of Escherichia coli (LTK63) provides generic protection against lung infectious disease

Commensal Candida albicans positively calibrates systemic Th17 immunological responses

Low ambient humidity impairs barrier function and innate resistance against influenza infection

Seasonality of respiratory viral infections

Environmental role in influenza virus outbreaks

Role of meteorological factors in the transmission of SARS-CoV-2 in the United States

Prevalence, persistence, and phenotypic variation of Aspergillus fumigatus in the outdoor environment in Manchester, UK, over a 2-year period

The effects of meteorological factors on airborne fungal spore concentration in two areas differing in urbanisation level

A year-round study on functional relationships of airborne fungi with meteorological factors

Airborne Aspergillus and Penicillium in the atmosphere of Szczecin

Indoor and outdoor atmospheric fungal spores in the Sao Paulo metropolitan area (Brazil): species and numeric concentrations

Volumetric aerobiological survey of conidial fungi in the North-East Netherlands. I. Seasonal patterns and the influence of metereological variables

Seasonal variation of the dominant allergenic fungal aerosolsone year study from southern Indian region

Profiles of airborne fungi in buildings and outdoor environments in the United States

A three-year-survey of microfungi in the air of Copenhagen 1977-79

Influenza pathogenesis: the effect of host factors on severity of disease

Identification of required host factors for SARS-CoV-2 infection in human cells

Genome-scale identification of SARS-CoV-2 and pan-coronavirus host factor networks

Genetic screens identify host factors for SARS-CoV-2 and common cold coronaviruses

Genome-wide CRISPR screens reveal host factors critical for SARS-CoV-2 infection

X-linked recessive TLR7 deficiency in ;1% of men under 60 years old with life-threatening COVID-19

Functional landscape of SARS-CoV-2 cellular restriction

Advances in understanding human genetic variations that influence innate immunity to fungi

Human genetic susceptibility to invasive aspergillosis

Genetic susceptibility to fungal infections: what is in the genes?

Kinetics of coinfection with influenza A virus and Streptococcus pneumoniae

A single mutation in the PB1-F2 of H5N1 (HK/97) and 1918 influenza A viruses contributes to increased virulence

A single N66S mutation in the PB1-F2 protein of influenza A virus increases virulence by inhibiting the early interferon response in vivo

H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice

New SARS-CoV-2 variants-clinical, public health, and vaccine implications

Understanding variants of SARS-CoV-2

India's massive COVID surge puzzles scientists

Mucormycosis: time to address this deadly fungal infection

COVID-associated mucormycosis (CAM): is the Delta variant a cause?

Neuraminidase and SIGLEC15 modulate the host defense against pulmonary aspergillosis

Dexamethasone in hospitalized patients with Covid-19-preliminary report

Corticosteroids block autophagy protein recruitment in Aspergillus fumigatus phagosomes via targeting dectin-1/Syk kinase signaling

Corticosteroid treatment is associated with increased filamentous fungal burden in allergic fungal disease

Glucocorticoids and invasive fungal infections

Risk factors associated with COVID-19-associated pulmonary aspergillosis in ICU patients: a French multicentric retrospective cohort

Clinical characteristics of invasive pulmonary aspergillosis in patients with COVID-19 in Zhejiang, China: a retrospective case series

Risk factors for invasive pulmonary aspergillosis in critically ill patients with coronavirus disease 2019-induced acute respiratory distress syndrome

Invasive pulmonary aspergillosis in patients with SARS-CoV-2 infection: a systematic review of the literature

Risk factors for fungal coinfections in critically ill COVID-19 patients, with a focus on immunosuppressants

Invasive aspergillosis in glucocorticoidtreated patients

Impact of corticosteroids in hospitalised COVID-19 patients

Impact of inflammatory response modifiers on the incidence of hospital-acquired infections in patients with COVID-19

Interleukin-6 receptor antagonists in critically ill patients with Covid-19

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Tocilizumab administration in COVID-19 patients: water on the fire or gasoline?

Invasive pulmonary aspergillosis after treatment with tocilizumab in a patient with COVID-19 ARDS: a case report

Impaired antifungal effector activity but not inflammatory cell recruitment in interleukin-6-deficient mice with invasive pulmonary aspergillosis

Risk of serious infections in tocilizumab versus other biologic drugs in patients with rheumatoid arthritis: a multidatabase cohort study

IL-6 inhibition in critically ill COVID-19 patients is associated with increased secondary infections

Impact of the 2009 influenza pandemic on pneumococcal pneumonia hospitalizations in the United States

Molecular diagnostic testing for Aspergillus

Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group

COVID-19 associated invasive aspergillosis: data from the UK National Mycology Reference Laboratory

European Society for Clinical Microbiology and Infectious Diseases Fungal Infection Study Group, ESCMID Study Group for Infections in Critically Ill Patients. 2020. Diagnosing COVID-19-associated pulmonary aspergillosis

Azole-resistant COVID-19-associated pulmonary aspergillosis in an immunocompetent host: a case report

Recovery of a triazoleresistant Aspergillus fumigatus in respiratory specimen of COVID-19 patient in ICU-a case report

Multi-triazole-resistant Aspergillus fumigatus and SARS-CoV-2 co-infection: a lethal combination

Post-influenzal triazole-resistant aspergillosis following allogeneic stem cell transplantation

Aspergillus fumigatus and pan-azole resistance: who should be concerned?

Deep immune profiling of COVID-19 patients reveals patient heterogeneity and distinct immunotypes with implications for therapeutic interventions

COVID-19 poses a riddle for the immune system

Targeting metabolic reprogramming by influenza infection for therapeutic intervention

Post-acute COVID-19 syndrome

High-dimensional characterization of postacute sequalae of COVID-19

COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status

Proteomic and metabolomic characterization of COVID-19 patient sera

Kynurenic acid underlies sex-specific immune responses to COVID-19

We declare there are no competing interests. Funding was provided by Wellcome and the Medical Research Council Centre for Medical Mycology (MR/N006364/2).

Fabián Salazar, Ph.D., is a postdoctoral research fellow at the laboratory of Professor Gordon Brown in the MRC Centre for Medical Mycology at the University of Exeter. He is currently working on understanding the underlying mechanisms by which C-type lectin receptors influence innate and adaptive immune responses during fungal infections. A biochemist by training, Fabian received his Ph.D. in 2016 from the School of Life Sciences at the University of Nottingham, investigating the role of C-type lectin receptors in allergen recognition and modulation of human allergic responses. His research interests include the study of the early immunological events that initiate protective immunity or drive susceptibility against fungal infections, with a particular focus on innate immune cells.Elaine Bignell, Ph.D., is a Professor of Medical Mycology and a Co-Director (Research) for the MRC Centre for Medical Mycology at the University of Exeter. Her work addresses the mechanistic basis of lung diseases caused by the major mould pathogen of humans, Aspergillus fumigatus. Major contributions to the field have included work on the role of Aspergillus pH sensing in pathogenicity, transcriptional regulation of host adaptation, and the mechanistic basis of tissue invasion during invasive fungal lung disease. A molecular geneticist by training, Elaine began her independent research career as an MRC New Investigator and by securing a fast-track to a Lectureship Award at Imperial College London. Elaine's research seeks a mechanistic understanding of fungal lung disease with a view to developing novel diagnostics and antifungal therapies. Her approach integrates infection models which transcend multiple experimental scales to address disease outcomes at the molecular, cellular, tissue, organ, and whole animal levels. In 2016, he was awarded the University of Manchester Dean's Prize and a Springboard award from the Academy of Medical Sciences. This has resulted in novel discoveries about the induction and regulation of type 2 inflammation at barrier sites. In 2020, he moved to the MRC CMM, where his group is investigating how innate immune cells in the lung orchestrate inflammation against fungal spores. This work will provide insights with the aim to improve therapeutic strategies for asthmatic and fungal diseases.Adilia Warris, M.D., Ph.D., is a professor of pediatric infectious diseases specialist with a specific interest in medical mycology. She is Co-Director of the MRC Centre for Medical Mycology at the University of Exeter, United Kingdom. She holds an honorary position in pediatric infectious diseases at Great Ormond Street Hospital in London, United Kingdom. Professor Warris' research profile has a strong translational focus, and specific areas of interest include host-fungus interactions in specific patient populations, antifungal resistance and antifungal stewardship, and epidemiology and management of fungal diseases in pediatric patient populations, in particular, those with primary immunodeficiency and cystic fibrosis.