key: cord-350904-wyg8ikph
authors: Gubernatorova, E.O.; Gorshkova, E.A.; Polinova, A.I.; Drutskaya, M.D.
title: IL-6: relevance for immunopathology of SARS-CoV-2
date: 2020-05-20
journal: Cytokine Growth Factor Rev
DOI: 10.1016/j.cytogfr.2020.05.009
sha: 
doc_id: 350904
cord_uid: wyg8ikph

COVID-19 mortality is strongly associated with the development of severe pneumonia and acute respiratory distress syndrome with the worst outcome resulting in cytokine release syndrome and multiorgan failure. It is becoming critically important to identify at the early stage of the infection those patients who are prone to develop the most adverse effects. Elevated systemic interleukin-6 levels in patients with COVID-19 are considered as a relevant parameter in predicting most severe course of disease and the need for intensive care. This review discusses the mechanisms by which IL-6 may possibly contribute to disease exacerbation and the potential of therapeutic approaches based on anti-IL-6 biologics.

At the end of 2019 and the beginning of 2020, first, China and then the rest of the world have been confronted with an outbreak of a new airborne transmitted coronavirus disease 2019 (COVID- 19) , a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Just a few months later, there are already millions infected worldwide and with borders closed and strict travel bans imposed local transmission patterns are in place in most countries [1] . COVID-19 mortality rate appears to be in the range of 3,4-5,5% [2] , which is significantly higher than that for seasonal flu caused by the influenza virus (1%), but lower than for both severe acute respiratory syndrome (SARS) (15%) [3] and Middle East respiratory syndrome (MERS) (34%) [4] . At the same time, the COVID-19 transmission rate is much greater than those of MERS or SARS, and poses a real threat to life for a large number of people worldwide, especially, in older patients with other co-morbidities [5] . Thus, in the absence of effective vaccines and treatments, early detection and the ability to define prognostic parameters predicting the course of the disease appear to be of particular interest. lymphocyte reduction [29] . Thus, virus infection of macrophages, firstly, enhances viral spread and, secondly, triggers destructive events in the immune organs such as spleen and LNs. Recent data from the experiments using SARS-CoV-2 capsid or live virus infection of cultured T cell lines (MT-2 and A3.01) provides first evidence that SARS-CoV-2 could also infects T cells. However, expression level of ACE2 on T cells is low and, thus, CD147 is considered to mediate SARS-CoV-2 entry into T cells [17] .

After virus binds to ACE2 (Fig.1) , serine protease, TMPRSS2, cleaves the viral spike protein. Then another protease, Furin, subsequently releases spike fusion peptide, and the virus enters the host cell through an endosomal pathway [18, 30, 31] . Following viral replication, assembly and release, the infected cells may undergo apoptosis or necrosis, triggering the inflammatory response with production of pro-inflammatory cytokines and activation of macrophages and Th1 cells, as well as production of IFNγ, IL-17A, IL-21, and IL-22 by neutrophils, Th17 and CD8 + cells. In turn, SARS-CoV-2 infection of recruited immune cells may increase their apoptosis and exacerbate lymphocytosis [32, 33] , and, finally, may lead in some patients to life-threatening conditions, such as respiratory distress syndrome, cytokine storm, and secondary hemophagocytic lymphohistiocytosis.

COVID-19 mortality is strongly associated with the development of severe respiratory distress syndrome, which requires invasive ventilation. It is important to identify those patients who are most likely to develop a severe form of the disease as early as possible. Based on the existing statistics, a number of clinical predictors of the disease deterioration and mortality, including the presence of secondary infections, lymphopenia [34] , comorbidities such as cardiovascular and chronic respiratory diseases, diabetes, hypertension, obesity and cancer [35] , increased cytokine production and serum ferritin [36] have been reported. The other study showed that the elevated serum creatinine, D-dimers, lactate dehydrogenase, C-reactive protein, procalcitonin, as well as increased white blood cell counts may indicate impending respiratory failure and the need for invasive oxygen supply [37] . Interestingly, in recently published reports elevated interleukin-6 (IL-6) level was proposed as a relevant parameter predicting the unwanted course of the disease and the need for mechanical ventilation [38] [39] [40] . These assumptions are consistent with data from a clinical trial in China that demonstrated on a small number of patients the efficacy of IL-6 neutralization during exacerbation of COVID-19 associated pneumonia [41] (Supplementary Table 1). IL-6 is a cytokine with pleotropic functions ranging from hematopoiesis and metabolic regulation to inflammation, autoimmunity and acute phase response. IL-6 modulates host defense through a number of immune stimulating mechanisms: control of monocytes and their differentiation into macrophages [42] , modulation of antigen-dependent B cell differentiation [43] , increased IgG production by B cells [44] , and promotion of Th2 response by inhibiting Th1 polarization [45] . Several studies revealed strong correlation between IL-6 levels in the serum and the upcoming respiratory failure [46] [47] [48] . It was shown, that even moderately elevated IL-6 levels above 80 pg/ml were sufficient to identify COVID-19 infected patients with a high risk of respiratory failure [37] . Moreover, serum SARS-CoV-2 nucleic acid (RNAaemia), which is strongly associated with cytokine storm, is closely correlated with extremely high IL-6 serum levels [47] . It was also suggested that serial measurement of circulating IL-6 might be important in identifying disease progression or, when evaluated immediately after COVID-19 diagnosis confirmation, may predict the upcoming respiratory failure or, alternatively, asymptomatic disease among SARS-CoV-2 infected patients [49] .

Therefore, it would be valuable to explore the potential contribution of IL-6 in the events occurring during SARS-CoV-2 infection. The next section will discuss the mechanisms by which IL-6 may possibly affect the disease exacerbation and the potential of therapeutic approaches based on anti-IL-6 biologics.

Controversy concerning IL-6 functions during viral lung infections IL-6 is one of the key proinflammatory cytokines during infection onset, especially, at the mucosal sites [50] . However, the impact of IL-6 on the disease outcome may vary significantly (Fig. 2) . On one hand, IL-6-dependent Th17 activation and differentiation are important for effective neutrophil migration, IL-6 together with IL-15 modulate cytolytic capacity of CD8 + T cells [51, 52] , and, finally, IL-6, as a pyrogenic cytokine, contributes to thermostatic regulation which is important for effective anti-viral response [53, 54] . Studies, using IL-6-deficient mice, showed that IL-6 ameliorates acute lung injury in influenza A virus (IAV) infection [55] . IL-6deficient mice infected with influenza virus exhibited higher lethality, as well as increased weight loss and fibroblast accumulation in the lungs associated with virus-induced apoptosis of lung epithelial cells and neutrophils [56] indicating that IL-6 may promote repair following virusinduced lung injury [57] . Finally, early IL-6 signaling promotes IL-27-dependent maturation of Treg cells in the lungs and resolution of viral immunopathology in mouse model of respiratory syncytial and influenza virus infection [58] .

On the other hand, IL-6 has been implicated in the progression of viral infections. In this regard, IL-6 synergizes with IL-1b and TNF to upregulate trypsin expression, which activates matrix metalloproteinases and causes the breakdown of basal membrane and extracellular matrix, which, in turn, results in increased tissue permeability and edema [59] . Th1 cell-derived IFNγ is essential for effective antiviral immune response. However, IL-6 may inhibit Th1 polarization by stimulating CD4 + cells to differentiate into Th2 cells or by suppressing IFNγ expression [60, 61] . Moreover, IL-6 promotes Th17 cell differentiation and IL-17A secretion, which, in turn, activates the expression of anti-apoptotic molecules, such as Bcl-XL, favoring survival of virus-infected cells in the model of persistent viral infection [62] . At the same time, IL-17 promotes the migration [63] , and survival [64] of neutrophils which, in turn, contribute to the pathogenesis of COVID-19-driven ARDS [65] . Finally, in contrast to influenza virus infection, IL-6-deficient mice infected with murine pneumonia virus are characterized by better survival than WT mice with decreased lung edema and diminished neutrophil recruitment [66] .

Taking into account that in several experimental models of viral lung infections IL-6 demonstrates either pathogenic [66] or protective [55] effects in vivo, the role of this cytokine in SARS-CoV-2 infection should be carefully evaluated. Moreover, the consequences of IL-6 induction in COVID-19 may vary depending on the infection stage and on the host immune status.

Patients with the most severe outcome of SARS-CoV-2 displayed high serum levels of proinflammatory cytokines responsible for cytokine storm induction [36, 67] . Interestingly, the majority of severe COVID-19 cases with respiratory distress syndrome were associated with high systemic IL-1b, TNF and IL-6 levels, suggesting a direct connection between proinflammatory cytokine induction and adverse effects of COVID-19 [34] . As SARS-CoV-2 shows 79% nucleotide identity to SARS-CoV, major pathogenic mechanisms, including cytokine storm and extensive lung damage during SARS and COVID-19 infection may be similar. Cytokine storm is a condition caused by extensive activation of the immune system, and, as a result, extremely high production of cytokines and chemokines. Since cytokine storm can lead to multiple organ failure, it is important to understand the mechanisms driving this condition.

In lower respiratory tract SARS-CoV-2 infects predominantly type 2 alveolar epitheliocytes, the cell type which does not participate in active gas exchange. Following replication and disengagement of the lung epithelial layer, virus enters the underlying tissues and infects or is being captured by macrophages, dendritic cells and neutrophils, resulting in further viral spread [29] (Fig. 3 ). At the same time, damaged epitheliocytes release danger molecules which drive the activation of lung epithelium and resident immune cells. Thus, even at the early onset of viral infection, its penetration of the mucosa to the epithelial layer activates the innate immune response. Adaptive immunity is also activated during COVID-19, mainly by antigen presenting dendritic cells, which produce large amounts of cytokines, including IL-6, IL-1b and TNF and migrate to the regional lymph nodes to present viral antigen to naïve T cells, pushing their differentiation and migration into the affected tissue [68] . Specific humoral response represented by viral-specific antibody-producing B cells is also in place [69] . Replication of the virus results in further damage of affected organs together with self-boosting immune response manifesting to uncontrolled overexpression of inflammatory mediators in severe cases. Another mechanism driving cytokine storm during viral infections is increased blood vessel permeability which enables infiltration of effector cells, producing additional amounts of inflammatory molecules and exacerbating hyper cytokine production [70] . In addition, leakiness of blood vessels allows virus to spread to other tissues and organs, compromising their functions. Finally, under persistence of inflammatory factors, an increased number of inflammatory exudates and erythrocytes enter the alveoli, resulting in lung damage and respiratory failure syndrome.

As mentioned above, severe COVID-19 induced pneumonia is marked by hyperactivation of the immune system and excessive production of IL-6 [36, 67] . The main source of pathogenic IL-6 appears to be myeloid cells as their number is significantly increased among PBMC [69] and in BALF of severe COVID-19 patients [71] . Myeloid cell recruitment and activation in the lungs is associated with increased mortality and morbidity in SARS-CoV mouse model [72] . Human primary macrophages and dendritic cells can be infected, but they fail to support productive replication of SARS-CoV [73, 74] , unlike alveocytes, in which virus can replicate very quickly. At the same time, SARS-CoV and, apparently, SARS-CoV-2-infected macrophages demonstrate up-regulation of IL-6 production and low expression of interferons [29, 73] . Interestingly, patients requiring intensive care and invasive lung ventilation display negative correlation between IL-6, TNF and IL-1b concentrations and CD4 + and CD8 + T cell counts [75] , confirming previous studies in animal models, which suggested that cytokine storm actually dampens adaptive immunity against SARS-CoV infection [76] . Moreover, production of IFNγ by CD4 + T cells tended to be lower in severe as compared to moderate cases, suggesting that SARS-CoV-2 infection induces lymphopenia with the suppression of antiviral IFNγ production [36] . Furthermore, it has been suggested that this pathogenic IL-6 is likely to be produced by highly inflammatory macrophages [71] , but not by alveolar macrophages, which are almost absent in the lung aspirates of severely affected patients [77] . At the same time, it should be noted that complete ablation of IL-6 at the very early stages of viral infection may result in depressed Tfh cell maturation and delayed antiviral antibody response [78] .

It is known that acute inflammation and cytokine storm, as its extreme manifestation, can have a significant effect on hemodynamics and also on platelets and erythrocytes. The dysregulated coagulation cascade and the subsequent formation of intra-alveolar or systemic fibrin clots are prominent findings in previous zoonotic coronavirus infections (SARS and MERS) orchestrated by CRS [79] [80] [81] . COVID-19 patients also show significant changes in coagulative status (i.e. low platelet count, increased D-dimer, fibrinogen levels) and dysfunction of microvessels in pulmonary circulation [82, 83] , thus, thrombosis of the pulmonary capillaries is believed to contribute to rapidly developing hypoxia. The role of IL-6 in inflammatory hypercoagulation is controversial: IL-6 can increase the rate of fibrotic clot formation in whole blood, but the effect is less pronounced than it is shown for IL-1 or IL-8 [84] . On the other hand, IL-6 is important for thrombus formation being a regulator of MMPs and other thrombolysisassociated genes in macrophages [85] .

Other characteristic feature of cytokine release syndrome is change in iron homeostasis and hyperferritinemia as indicated by high levels of serum ferritin [86] . In COVID-19 patients ferritin elevation correlated with poor prognosis [36] , as it was an indication of hemolytic events caused by hypercoagulation and hemophagocytosis. In general, inadequate macrophage activation leads to pathologic phagocytosis of erythrocytes and reutilization of heme iron using ferritin [87] . In line with this, high systemic ferritin may serve as an indicator of developing macrophage activation syndrome, rather than a factor driving COVID-19 pathogenesis.

Another key proinflammatory cytokine, TNF, is also released abundantly during cytokine storm, caused by SARS-CoV-2 infection. Serum TNF levels were found to be elevated in severely affected COVID-19 patients [34] . Previously, it was shown for SARS-CoV that its spike protein is able to modulate TNF converting enzyme (TACE)-dependent shedding of the ACE2 ectodomain [88] . TACE expression is coupled to TNF production. Therefore, it is hypothesized that the use of TNF inhibitors may also show some efficacy in preventing viral entry [89] , as well as in decreasing immunopathology associated mortality, as it was shown in preclinical studies in mice infected with severe respiratory syncytial virus [90] . Moreover, anti-TNF therapy was effective in decreasing the IL-6 and IL-1b serum levels in lethal bacteremia, suggesting that such treatment may provide complex anti-inflammatory effect [91] . Data obtained from COVID-19 infected patients with inflammatory bowel diseases undergoing anti-TNF therapy support safety of such intervention in the context of SARS-CoV-2 treatment [92, 93] . These findings argue for a potentially protective effect of TNF inhibition in COVID-19 and further studies are needed to address this possibility.

Hypertension has been suggested as a risk factor for severe COVID-19 outcomes [94] . Early data from the literature already assumed an association between blood pressure and circulating IL-6 levels in otherwise healthy individuals [95] . Moreover, several studies reported an increased IL-6 expression in patients with hypertension [96, 97] . IL-6-transgenic mice, characterized by elevated plasma IL-6 levels, displayed pulmonary hypertension [98, 99] . Taken together, this data suggest that IL-6 might be connected with increased risk of respiratory failure in hypertensive patients with COVID-19.

One of the mechanisms regulating blood pressure and electrolyte balance is angiotensin-renin system. It is comprised of two pathways, which are normally functioning in the state of dynamic equilibrium: ACE2-Angiotensin II-Angiotensin 1 Receptor axis, activating vasoconstriction and inflammatory response, and ACE2-Angiotensin 1-7-Mas receptor axis, supporting vasodilation and suppression of inflammation (Fig. 4, A) [100] . Changes in reninangiotensin system activity are related to the pathogenesis of hypertension and of inflammatory lung diseases, in particular, acute lung injury caused by viral infections [15, 101] .

SARS-CoV2 uses ACE2 as an entry site, thus, reducing ACE2 availability, promoting an imbalance between the ACE2-Angiotensin II-Angiotensin 1 receptor axis and the ACE2-Angiotensin 1-7-Mas receptor axis [15, 102] . In line with this, recent studies have reported that COVID-19 patients have increased Angiotensin II compared to healthy individuals [103] . Altogether, the abovementioned data suggests that COVID-19 infection leads to imbalanced angiotensin conversion and a shift towards pro-inflammatory signaling mediated by Angiotensin 1 receptor axis [104] (Fig. 4, B) .

Angiotensin II is known to significantly increase the expression of IL-6 in a dosedependent manner [105] through pleiotropic activation of NF-kB transcription factors [106] , [107] . Angiotensin 1 receptor downstream activation of NADPH oxidase results in elevated oxidative stress, in particularly, superoxide that activates transcriptional mechanisms that directly promotes IL-6 gene expression. In turn, plasma IL-6 concentrations correlate with blood pressure, plasma Angiotensin II levels and vascular hypertrophy, suggesting an important role of IL-6 in the development and maintenance of hypertension, specifically, that mediated by Angiotensin II [108, 109] . IL-6 promotes Angiotensin 1 receptor expression sensitizing the vascular wall to angiotensin II-dependent signaling mechanisms. Activated cells can release J o u r n a l P r e -p r o o f cytokines, including IL-6, which promote expression of adhesion molecules and induce endothelial activation, inflammatory cell infiltration and vascular inflammation [110] . This further drives oxidative stress and IL-6 expression. Therefore, it is plausible that IL-6 and Angiotensin II activate each other through a positive feedback mechanism. In support of this hypothesis, ACE2 protects against lethal avian influenza A H5N1 infection [111] through prevention of oxidative stress and acute respiratory distress syndrome. Moreover, it was recently reported that in COVID-19 patients with hypertension Angiotensin receptor blockade attenuated the inflammatory response, possibly through IL-6 inhibition [102, 112] . Taking together, Angiotensin II accumulation due to SARS-CoV-2-mediated ACE2 downregulation may cause Angiotensin 1 receptor downstream activation of NADPH oxidase, which, in turn, leads to elevated ROS production and to induction of transcriptional mechanisms that directly promote IL-6 expression, implicated in inflammation-induced injury and immunopathology.

Chronic inflammation is the one common feature of hypertension, diabetes, obesity and agethe risk factors associated with COVID-19 severe outcomes. Elderly, obese and diabetic persons are affected by a low-grade chronic inflammation and are characterized by systemically increased levels of proinflammatory cytokines, which may contribute to and facilitate the cytokine storm, the main cause of COVID-19 mortality.

Among conditions, predisposing patients infected with SARS-CoV-2 to severe outcomes, diabetes is the most prominent. It is estimated that mortality rate of those with COVID-19 and diabetes is about 16% [8] to 35% [113] . IL-6 is known for its dual role in autoimmune diabetes, as it is involved in the development of insulin resistance and β-cell dysfunction and, at the same time, has anti-inflammatory effects and improves glucose metabolism [114] . Recent clinical data demonstrates significantly elevated systemic IL-6 in COVID-19 patients with diabetes as compared to those without diabetes [115] . COVID-19 may exacerbate the pre-existing diabetes, since its entry site, ACE2, is expressed in the pancreas, with a potential role in the development of insulin resistance and impaired insulin secretion [116] . IL-6 may be the link between diabetes and severe COVID-19 outcomes through its ability to modulate T cell response. Some indirect evidence to support this comes from mouse studies of closely related MERS-CoV infection demonstrating that abnormal elevation of IL-17A produced by IL-6-dependent Th17 cells exacerbates disease severity in diabetic mice [117] . Consistent with that finding, patients with COVID-19 have a higher proportion of Th17 cells in the blood [118] , suggesting that diabetics due to improper activation of Th1 and Th17 cells may have a compromised anti-viral immune response [31] .

Obese patients with COVID-19 are more likely to develop severe respiratory distress syndrome [119, 120] . Just as diabetics, obese patients have higher concentration of proinflammatory cytokines both in steady state [121] and, apparently, during COVID-19 infection [8] . In addition to decreased anti-viral T cell response, enhanced IL-6 production by adipose tissue in obese patients [122] may alter innate anti-viral immune response by neutrophils [121] and cause uncontrolled replication of the virus at the early stages of infection.

From the very beginning of COVID-19 pandemic, age was identified as a risk factor [38] , supporting the idea that ACE2 may be a marker of cell senescence [123] . Myofibroblasts, which increase in number with age, express high levels of ACE2 [124] , thus, myofibroblasts are more susceptible to SARS-CoV-2, and elderly people, bearing higher proportion of myofibroblasts, might be more susceptible to COVID-19 infection (reviewed in [125] ). IL-6 is a critical inflammatory regulator of senescence-associated secretory phenotype (SASP) [126] . Therefore, IL-6 overexpression may correlate both with senescent status of cells and tissues, as well as with increased expression of ACE2. In line with this idea, hydroxychloroquine, an anti-malaria drug, which is now approved in some countries for COVID-19 treatment, effectively reduced the salivary and serum levels of IL-6 in patients with Sjorgen's syndrome [127] . Moreover, azithromycin, prescribed together with hydroxychloroquine, can target and selectively remove senescent cells [128] and, thus, provide anti-fibrotic activity by protecting the lungs from inflammation-induced injury [129, 130] .

Another issue facing elderly patients with COVID-19 is a compromised activation status of their effector T cells. These cells may display limited function during prolonged infection as a result of their exhaustion, associated with the surface expression of such immune-inhibitory factors as PD-1 [75] . Since aging itself is a process known to promote reorganization of the T cell landscape [131] and IL-6 is a SASP predictor and regulator, T cell exhaustion in the elderly patients with COVID-19 is much more evident due to higher basal concentration of IL-6, which can enhance the exhaustion process [132, 133] .

Smoking is another potential risk factor for SARS-CoV-2 infection. Smokers are more vulnerable to influenza virus infections [134, 135] and are more likely to develop chronic obstructive pulmonary disease (COPD) [136] . Enhanced ACE2 expression had been reported in the lungs of healthy smokers [137, 138] . In line with that, studies in mice have established that cigarette smoke can trigger the expansion of a subpopulation of respiratory epithelial cells that express ACE2 in a dose-dependent manner [139] . Patients with COPD, as well as active smokers, have increased ACE2 expression in the lungs [140] , which may potentially explain a fourfold increased risk of adverse development and severe outcome of COVID-19 [141, 142] . Taken together, these recent reports suggest that smokers may be at higher risk of infection. Examination of factors, predisposing to severe COVID-19 in Wuhan, China, revealed, that 19.2% of patients with severe disease were smokers [143] . On the other hand, preliminary meta-analysis based on Chinese patients suggest that active smoking was not associated with the severity of COVID-19 [144] , indicating that impact of smoking on COVID-19 progression is controversial and requires further assessment.

Intuitively, patients with pre-existing asthma should display higher proportion of COVID-19 severe cases. However, the prevalence of asthma in COVID-19 patients in Wuhan study was markedly lower (0,9%) than that reported in the adult population of Wuhan (6,4%) [143] . One possible explanation is a shift toward Th2-type immune response in asthmatics as opposed to Th1-associated inflammatory response induced by SARS-CoV-2 infection [118] . Recent study reveals that TMRSS2 expression in upper respiratory tract correlates positively with type 2 response genes, especially with IL-13, whereas ACE2 expression is suppressed by IL-13. Considering low numbers of cells co-expressing these proteases in the upper respiratory tract, it has been proposed that in the context of IL-13-dependent reduction in ACE2 expression allergy should promote resistance to infection [145] . In line with this, it was shown that ACE2 expression is decreased in nasal and bronchial epithelium of allergic individuals following allergen challenge, suggesting, that asthma-associated immune response actually protects from COVID-19-induced pathology [146] . Nevertheless, further studies are required to reveal the impact of COVID-19 severity in patients with preexisting asthma.

Meta-analysis studies of COVID-19 cases in China from December 2019 to February 2020 report lower incidence of the disease [147] and risk of death [35] in women than in men. Similar data on association of gender with poorer prognosis for males were obtained earlier for SARS-CoV [148] , [149] and MERS-CoV [150, 151] . In connection to SARS-CoV-2, the X-linked ACE2 gene is of a particular interest. Significant fraction of genes encoded on the X chromosome undergo dosage compensation, however, ACE2 is located at Xp22, i.e. the area in which genes may escape from X chromosome inactivation [152] , possibly contributing to gender disparity in disease susceptibility. Gender differences in immune responses are known to depend not only on genetic, but also on endocrine factors [153, 154] . High doses of estradiol acting through estrogen receptors decrease production of proinflammatory cytokines via suppressing NF-kB signaling pathway [155] . In relation to COVID-19 the effects of estrogens on IL-6 and on disease progression is of particular interest. Estrogen may suppress LPS-mediated IL-6 expression in mouse macrophages by both blocking of NF-kB activation [155, 156] and inhibiting p38 MAPK phosphorylation [156] . Furthermore, downregulation of IL-6 expression in Kupffer cells appears to be ERα-dependent [157] . Overall, immunomodulatory effects of estrogens may contribute to decreased susceptibility to SARS-CoV-2 infection in women and this question requires further study.

One of the common complications from the respiratory viral infections, including SARS [158] and COVID-19 [159] , is lung fibrosis. This is characterized by alveolar epithelial cell injury, recruitment and activation of fibroblasts and subsequent production of extracellular matrix (ECM) in the presence of specifically activated immune cells. Fibrosis develops as an exaggerated repair process following injury associated with abnormal immune response leading to chronic progressive disease [160] . Histological examination of lung biopsies from COVID-19 patients show massive apoptosis of pneumocytes, hyaline membrane formation, fibromyxoid exudates [161] which are manifestations that are characteristic for ARDS and represent key events preceding development of fibrosis (reviewed in [162] ). Significant pro-fibrotic M2-like SPP1 + macrophage infiltration was also described for COVID-19 correlating with the disease severity [71] . Damage to the epithelial layer caused by the virus further attracts various immune cells participating in inflammation-repair balance (monocytes, macrophages, granulocytes and T cells). In addition, some viral components, such as N-protein and papain-like protease, can directly stimulate production of TGF-β, one of the pro-fibrotic hallmarks in respiratory epithelium, similar to what has previously been reported for SARS-CoV [163, 164] .

The role of IL-6 had been extensively studied in bleomycin model of lung fibrosis in mice. Bleomycin is a chemotherapeutic antibiotic which causes damage of tissues lacking bleomycin hydrolase, predominantly, in the lungs [165] . Mice with genetic ablation of IL-6 were characterized by impaired fibrosis [166] . However, in the same model mice with pharmacological rather than genetic inhibition of IL-6 demonstrated opposing phenotypes depending on the phase of inflammation-repair cycle. Specifically, IL-6 neutralization at the early inflammatory phase (day 2 following bleomycin-induced lung injury) resulted in apoptosis of pneumocytes, which further contributed to pulmonary fibrosis, whereas IL-6 blockade at the early fibrotic stage (day 8 following bleomycin-induced lung injury) significantly ameliorated lung fibrosis [167] . Interestingly, treatment of mice with recombinant soluble gp130Fc at the late stage of chronic bleomycin model attenuated lung fibrosis, emphasizing the importance of sIL-6Ra and IL-6 trans-signaling in mediating this condition [168] . It was further suggested that M2like infiltrating macrophages are the major source of soluble IL-6Ra in fibrotic foci, whereas pulmonary fibroblasts are the recipient cells, which proliferate and produce extracellular matrix under trans-IL-6 activation. Finally, overexpression of IL-6 in respiratory tract mediated by adenoviral vectors also resulted in the exacerbation of fibrosis and was associated with increased levels of M2-macrophages with pro-fibrotic features [169] . These pro-fibrotic macrophages are also characterized by increased IL-6Ra expression [168] . ACE2 expression is reported for lung, heart, kidney, intestine, liver and brain. Thus, similar fibrosis-associated complications should be expected, not just for respiratory tract, but also for other tissues and organs in correlation with viral load and severity of cytokine release syndrome. Summarizing the data available at the moment from infection-free experimental models of fibrosis, one can conclude that IL-6 may affect fibroblast proliferation and functions directly or through potentiation of a distinct macrophage phenotype. Taking into account the importance of this cytokine at the repair stage, anti-IL-6 therapy may prove beneficial not only in acute phase, but also in subacute proliferative phase of COVID-19-related ARDS.

J o u r n a l P r e -p r o o f SARS-CoV-2 tropism to neural system is of particular interest while neurological symptoms, such as dizziness, headache, ataxia and anosmia, are often found in mild COVID-19 patients and develop early in the infection [170] . ACE2 expression in CNS is attributed to the nuclei in brain stem and is associated with cardio-respiratory control [171, 172] . Recent study based on scRNA sequencing suggests co-expression of ACE2 and TMPRSS2 in olfactory epithelial cells, but not in mature olfactory sensory neurons, which were initially considered as the most obvious target population for the virus in CNS [173] . Even without the understanding of the exact mechanisms of SARS-CoV-2 penetration and distribution in CNS, it should be noted that as a result of the disseminated intravascular coagulopathy and cytokine storm caused by infection, blood-brain-barrier permeability is significantly increased, which can lead to negative consequences for CNS functioning [174, 175] .

An effective therapeutic approach should include a combination of specific antiviral drugs, which inhibit viral dissemination and limit direct virus-induced cytopathic effects coupled with antiinflammatory therapeutics, directed against immunopathology induced by a viral infection [176] . SARS-CoV-2-induced immunopathology exhibits features of systemic hyper-inflammation reminiscent both of cytokine storm or macrophage activation syndrome and secondary haemophagocytic lymphohistocytosis [177] . Since overexpression of IL-6 appears to be associated with severe COVID-19 outcomes, neutralizing antibodies used to treat a number of autoimmune diseases by targeting exacerbated inflammatory immune response of the host may provide a life-saving approach by preventing the cytokine release syndrome. In line with that, patients responding to CD19 CAR T cell therapy experience cytokine release syndrome [178] , which is well managed by IL-6 neutralizing antibodies [179] . In a non-randomized, open-label clinical trial, 21 patients with severe or critical COVID-19 were treated with a single dose of Tocilizumab, in addition to routine therapy [180] . 90% of patients recovered, suggesting that anti-IL-6 might be a powerful potential rescue therapy in managing acute respiratory distress syndrome of COVID-19 and inhibiting the most adverse outcome. Peripheral mononuclear cell scRNA-seq profiling data obtained from these patients indicate that treatment with Tocilizumab does not reduce the number of cytotoxic CD8 + and plasma B cells, thus, does not interfere with robust adaptive immune response [69] . Preliminary data from 21 patients with COVID-19 who developed acute respiratory distress syndrome and participated in a compassionate-use program at Papa Giovanni XXIII hospital in Bergamo, Italy, indicate that intravenous introduction of Siltuximab reduced C-reactive protein level in all patients and significantly improved clinical conditions with a reduced need for ventilation in 33% of patients. 43% of patients showed stabilization of their conditions, and 24% of patients experienced a worsening of the disease and required intubation [181] .

Sarilumab is a monoclonal antibody that works by inhibiting the IL-6 pathway through binding and blocking the IL-6 receptor. Recently, another clinical trial was initiated, which will evaluate the effects of Sarilumab in patients with severe COVID-19. This U.S.-based multicenter, double-blind, phase 2/3 trial will begin at medical centers in New York and is anticipated to enroll up to 400 patients [182] .

The overview of initiated clinical trials of anti-IL-6 therapeutics in COVID-19 patients is presented in Supplementary Table 1. In summary, strong scientific evidence of the beneficial impact of IL-6 inhibitors in the modulation of the COVID-19 infection requires further clinical data.

In the face of a pandemic, affecting millions of people worldwide, the need to develop new approaches or reassess the existing ones in the treatment of severe viral infections is more J o u r n a l P r e -p r o o f pressing than ever. Despite the fact that humanity experienced viral infections causing deadly pneumonia twice in the past 20 years, there are still no drugs specific for coronaviruses. The evidence discussed in this review suggests that for patients with risk factors, especially those with high systemic levels of IL-6, clinically approved neutralizing antibodies against IL-6 or its receptor, IL-6R, in combination with standard treatment protocols may provide benefit. Gaining a deeper understanding of the factors that affect the immune response and mechanistic link of these factors to disease severity is crucial for effective clinical management of COVID-19 in severely affected patients.

This work was supported by the Ministry of Science and Higher Education of the Russian Federation (grant 075-15-2019-1660).

The authors declare that there is no conflict of interest.

Binding of virion to ACE2 is followed by serine protease, TMPRSS2, cleavage of the viral spike protein and induction of internalization of the complex with subsequent reduction of ACE2 surface availability. Then another protease, Furin, releases spike fusion peptide, and the virus enters the host cell through an endosomal pathway.

COVID-19 CORONAVIRUS PANDEMIC

Update 49 -SARS case fatality ratio, incubation period

World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV)

Likelihood of survival of coronavirus disease 2019. The Lancet Infectious Diseases

Coronavirus diversity, phylogeny and interspecies jumping

Coronavirus pathogenesis

Diabetes is a risk factor for the progression and prognosis of COVID-19

Clinical Characteristics of Coronavirus Disease 2019 in China

A Novel Coronavirus from Patients with Pneumonia in China

Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Inhibition of severe acute respiratory syndrome virus replication by small interfering RNAs in mammalian cells

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

A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury

Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV

SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2

SARS-CoV-2 invades host cells via a novel route: CD147-spike protein

How, with whom and when: an overview of CD147-mediated regulatory networks influencing matrix metalloproteinase activity

Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum

CD147 facilitates HIV-1 infection by interacting with virus-associated cyclophilin A

Function of HAb18G/CD147 in invasion of host cells by severe acute respiratory syndrome coronavirus

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

Influenza and SARScoronavirus activating proteases TMPRSS2 and HAT are expressed at multiple sites in human respiratory and gastrointestinal tracts

SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells

The Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Directly Decimates Human Spleens and Lymph Nodes

Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

COVID-19 Pandemic, Corona Viruses, and Diabetes Mellitus

Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease

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 patients infected with 2019 novel coronavirus in Wuhan

Existing Conditions of COVID-19 Cases and Deaths

Clinical and immunologic features in severe and moderate Coronavirus Disease

Level of IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients

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

Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19

Correlation Analysis Between Disease Severity and Inflammation-related Parameters in Patients with COVID-19 Pneumonia

A multicenter, randomized controlled trial for the efficacy and safety of tocilizumab in the treatment of new coronavirus pneumonia (COVID-19)

IL-6 switches the differentiation of monocytes from dendritic cells to macrophages

CD40 ligand triggers interleukin-6 mediated B cell differentiation

IL-6 promotes the differentiation of a subset of naive CD8+ T cells into IL-21-producing B helper CD8+ T cells

The two faces of IL-6 on Th1/Th2 differentiation

Interleukin-6 in COVID-19: A Systematic Review and Meta-Analysis

Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely correlated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients

The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality

Interleukin-6 as a potential biomarker of COVID-19 progression

The role of IL-6 in host defence against infections: immunobiology and clinical implications

Anti-viral CD8 T cells and the cytokines that they love

IL-6 trans-signalingdependent rapid development of cytotoxic CD8+ T cell function

Immune-induced fever is mediated by IL-6 receptors on brain endothelial cells coupled to STAT3-dependent induction of brain endothelial prostaglandin synthesis

Fever and the thermal regulation of immunity: the immune system feels the heat

IL-6 ameliorates acute lung injury in influenza virus infection

Essential role of IL-6 in protection against H1N1 influenza virus by promoting neutrophil survival in the lung

Interleukin-6 limits influenzainduced inflammation and protects against fatal lung pathology

Early IL-6 signalling promotes IL-27 dependent maturation of regulatory T cells in the lungs and resolution of viral immunopathology

IL-1beta is a key cytokine that induces trypsin upregulation in the influenza virus-cytokine-trypsin cycle

The Role of Interleukin 6 During Viral Infections

TLR ligand induced IL-6 counterregulates the anti-viral CD8(+) T cell response during an acute retrovirus infection

Th17 cells enhance viral persistence and inhibit T cell cytotoxicity in a model of chronic virus infection

Interleukin 17 (IL-17) manipulates mouse bone marrow-derived neutrophils in response to acute lung inflammation

IL-17 Promotes Neutrophil-Mediated Immunity by Activating Microvascular Pericytes and Not Endothelium

Targeting potential drivers of COVID-19: Neutrophil extracellular traps

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med

Preventing COVID-19-induced pneumonia with anticytokine therapy

Tocilizumab treatment in severe COVID-19 patients attenuates the inflammatory storm incited by monocyte centric immune interactions revealed by singlecell analysis

Into the eye of the cytokine storm

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

Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice

Severe acute respiratory syndrome and the innate immune responses: modulation of effector cell function without productive infection

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

Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Front Immunol

Evasion by stealth: inefficient immune activation underlies poor T cell response and severe disease in SARS-CoV-infected mice

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

B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1

Elevated plasma tissue-type plasminogen activator (t-PA) and soluble thrombomodulin in patients suffering from severe acute respiratory syndrome (SARS) as a possible index for prognosis and treatment strategy

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past

Prominent changes in blood coagulation of patients with SARS-CoV-2 infection

The potential of low molecular weight heparin to mitigate cytokine storm in severe COVID-19 patients: a retrospective clinical study

Simultaneous presence of hypercoagulation and increased clot lysis time due to IL-1beta, IL-6 and IL-8

Crucial Involvement of IL-6 in Thrombus Resolution in Mice via Macrophage Recruitment and the Induction of Proteolytic Enzymes

Extreme Hyperferritinemia: Causes and Impact on Diagnostic Reasoning

The Immunology of Macrophage Activation Syndrome

Modulation of TNFalpha-converting enzyme by the spike protein of SARS-CoV and ACE2 induces TNF-alpha production and facilitates viral entry

Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed

Inhibition of tumor necrosis factor reduces the severity of virus-specific lung immunopathology

Antibodies to cachectin/tumor necrosis factor reduce interleukin 1 beta and interleukin 6 appearance during lethal bacteremia

SECURE-IBD Database Public Data Update

Covid-19 and immunomodulation in IBD. Gut

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention

Blood pressure and inflammation in apparently healthy men

Plasma ghrelin and interleukin-6 levels correlate with body mass index and arterial blood pressure in males with essential hypertension

Plasma interleukin-6 and tumor necrosis factor-alpha can predict coronary endothelial dysfunction in hypertensive patients

IgG1 plasmacytosis in interleukin 6 transgenic mice

Interleukin-6 overexpression induces pulmonary hypertension

Intrapulmonary activation of the angiotensin-converting enzyme type 2/angiotensin 1-7/G-protein-coupled Mas receptor axis attenuates pulmonary hypertension in Ren-2 transgenic rats exposed to chronic hypoxia

Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury

Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension

Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury

Cross-talk between inflammation and angiotensin II: studies based on direct transfection of cardiomyocytes with AT1R and AT2R cDNA

Induction of interleukin-6 expression by angiotensin II in rat vascular smooth muscle cells

Angiotensin II induces interleukin-6 transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor-kappa B transcription factors

ERK and p38 MAPK, but not NF-kappaB, are critically involved in reactive oxygen species-mediated induction of IL-6 by angiotensin II in cardiac fibroblasts

Angiotensin II-induced endothelial dysfunction is temporally linked with increases in interleukin-6 and vascular macrophage accumulation

Hypoxia/reoxygenation stimulates endothelial cells to promote interleukin-1 and interleukin-6 production. Effects of free radical scavengers

The Science Underlying COVID-19: Implications for the Cardiovascular System

Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections

Angiotensin II Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors Usage is Associated with Improved Inflammatory Status and Clinical Outcomes in COVID-19 Patients With Hypertension

Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy

IL-6 signalling pathways and the development of type 2 diabetes

Association of Blood Glucose Control and Outcomes in Patients with COVID-19 and Pre-existing Type 2 Diabetes

The sweeter side of ACE2: physiological evidence for a role in diabetes

Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection

Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan

High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation

Obesity hypoventilation syndrome and severe COVID-19

Individuals with obesity and type 2 diabetes have additional immune dysfunction compared with obese individuals who are metabolically healthy

Systemic low-grade inflammation is related to both circulating and adipose tissue TNFalpha, leptin and IL-6 levels in obese women

Upregulation of angiotensin converting enzyme 2 by shear stress reduced inflammation and proliferation in vascular endothelial cells

Functional angiotensin-converting enzyme 2 is expressed in human cardiac myofibroblasts

COVID-19 and chronological aging: senolytics and other antiaging drugs for the treatment or prevention of corona virus infection?

Senescence promotes in vivo reprogramming through p16(INK)(4a) and IL-6

Hydroxychloroquine treatment for primary Sjogren's syndrome: its effect on salivary and serum inflammatory markers

Azithromycin and Roxithromycin define a new family of "senolytic" drugs that target senescent human fibroblasts

Azithromycin attenuates acute radiation-induced lung injury in mice

Role of prophylactic azithromycin to reduce airway inflammation and mortality in a RSV mouse infection model

Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes

Correlation of Serum IL-6 Level with Exhaustion of Cytomegalovirus-specific T Cells After Hematopoietic Stem Cell Transplantation

Interleukin-6 Rescues Lymphocyte from Apoptosis and Exhaustion Induced by Chronic Hepatitis C Virus Infection

Cigarette smoking and the occurrence of influenza -Systematic review

Smoking and Influenza-associated Morbidity and Mortality: A Systematic Review and Meta-analysis

Differences in chronic obstructive pulmonary disease phenotypes between non-smokers and smokers

Tobacco Smoking Increases the Lung Gene Expression of ACE2, the Receptor of SARS-CoV-2

Smoking Upregulates Angiotensin-Converting Enzyme-2 Receptor: A Potential Adhesion Site for Novel Coronavirus SARS-CoV-2 (Covid-19)

Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract

ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19

The impact of COPD and smoking history on the severity of Covid-19: A systemic review and meta-analysis

Does comorbidity increase the risk of patients with COVID-19: evidence from meta-analysis

Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan

Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19)

Type 2 and interferon inflammation strongly regulate SARS-CoV-2 related gene expression in the airway epithelium

Association of Respiratory Allergy, Asthma and Expression of the SARS-CoV-2 Receptor, ACE2

COVID-19 patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis

Do men have a higher case fatality rate of severe acute respiratory syndrome than women do?

SARS in Singapore--predictors of disease severity

Prevalence of comorbidities in the Middle East respiratory syndrome coronavirus (MERS-CoV): a systematic review and meta-analysis

The pattern of Middle East respiratory syndrome coronavirus in Saudi Arabia: a descriptive epidemiological analysis of data from the Saudi Ministry of Health

The ACE2 gene: its potential as a functional candidate for cardiovascular disease

Sex differences in immune responses

Sex-Specific SARS-CoV-2 Mortality: Among Hormone-Modulated ACE2 Expression, Risk of Venous Thromboembolism and Hypovitaminosis D

Crossroads of estrogen receptor and NF-kappaB signaling

Estrogen inhibits LPS-induced IL-6 production in macrophages partially via the nongenomic pathway

Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production

The pathology and pathogenesis of experimental severe acute respiratory syndrome and influenza in animal models

Clinical and computed tomographic imaging features of novel coronavirus pneumonia caused by SARS-CoV-2

The diversity of myeloid immune cells shaping wound repair and fibrosis in the lung

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Mechanical ventilation-associated lung fibrosis in acute respiratory distress syndrome: a significant contributor to poor outcome

Severe acute respiratory syndrome-associated coronavirus nucleocapsid protein interacts with Smad3 and modulates transforming growth factor-beta signaling

Correlation between TGF-beta1 expression and proteomic profiling induced by severe acute respiratory syndrome coronavirus papain-like protease

The Bleomycin Model of Pulmonary Fibrosis

Role of interleukin-6 in bleomycin-induced lung inflammatory changes in mice

Bidirectional role of IL-6 signal in pathogenesis of lung fibrosis

Blockade of IL-6 Trans signaling attenuates pulmonary fibrosis

Overexpression of OSM and IL-6 impacts the polarization of pro-fibrotic macrophages and the development of bleomycin-induced lung fibrosis

Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: a retrospective case series study

Overexpression of angiotensinconverting enzyme 2 in the rostral ventrolateral medulla causes long-term decrease in blood pressure in the spontaneously hypertensive rats

Angiotensin-converting enzyme 2 overexpression in the subfornical organ prevents the angiotensin II-mediated pressor and drinking responses and is associated with angiotensin II type 1 receptor downregulation

Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia

The meteorology of cytokine storms, and the clinical usefulness of this knowledge

Hypothetical pathophysiology of acute encephalopathy and encephalitis related to influenza virus infection and hypothermia therapy

COVID-19: combining antiviral and anti-inflammatory treatments

The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease

Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T-cell Therapy for Acute Lymphoblastic Leukemia

Harnessing CAR T Cell Insights to Develop Treatments for Hyperinflammatory Responses in COVID-19 patients

Effective treatment of severe COVID-19 patients with tocilizumab

Use of siltuximab in patients with COVID-19 pneumonia requiring ventilatory support

Sanofi and Regeneron begin global Kevzara® (sarilumab) clinical trial program in patients with severe COVID-19

We thank Prof. S. A. Nedospasov and Dr. K.-S. N. Atretkhany for critical reading of manuscript. We thank P.V. Matveev for assistance with figure preparation.

J o u r n a l P r e -p r o o f SARS-CoV-2 replicates in alveolar epithelial cells. After the virions are released, they can infect or are being captured by macrophages, dendritic cells and neutrophils. At the same time, damaged epithelial cells produce alarmins, which are sensed by the neighboring epithelial and myeloid cells. All these events lead to release of proinflammatory cytokines, increase of alveolar vessel permeability and cell recruitment to the site of infection, forming positive loop for pathological activation of IL-6, IL-1, TNF and other proinflammatory cytokines. Due to high permeability of pulmonary vessels under inflammatory conditions, SARS-CoV-2 can inseminate distant ACE2-expressing tissues (intestine, kidney, pancreas), and trigger burst of inflammation at distant sites. Ain healthy state pro-inflammatory signaling of Angiotensin II via Angiotensin 1 receptor (AT1R) is stabilized by Angiotensin 1-7 (ACE2-Angiotensin I proteolysis product) signaling via Mas receptor (MasR) that has anti-inflammatory effect.Bvirus-mediated down-regulation of ACE2 leads to Angiotensin II accumulation in the absence of Angiotensin 1-7 and acceleration of its proinflammatory effect. AT1R downstream activation of NADPH oxidase results in elevated ROS directly promoting IL-6 expression. In its turn, IL-6 can positively regulate AT1R levels. Thus, by acting together these processes J o u r n a l P r e -p r o o f exacerbate hypertension, edema, infiltration of immune cells and inflammation in COVID-19 affected lungs.