cord-000647-uofygmeu	2012	However, since CTLs have been www.frontiersin.org observed in various mouse models and also in human patients, a possible protective role for Leishmania-specific cytotoxic T cells should not be excluded. major infection became less important also because of the strong evidence that Th1 cells were the primary cells involved in mediating protection against cutaneous leishmaniasis (Reiner and Locksley, 1995; Louis et al., 1998; Sacks and Noben-Trauth, 2002) . Vaccination of humans with heat-killed Leishmania or recombinant parasite proteins has so far failed to induce long-term immunity and only recovery from natural or experimental infection has provided proper protection. Pilot studies in the murine model of VL have also demonstrated that adoptive transfer of antigen-specific CD8 + T cells (Polley et al., 2006) or reactivation of CD8 + T cell responses through a therapeutic vaccine (Joshi et al., 2009) results in the control of parasite growth.
cord-001674-tp4o7fxx	2015	An exception is the C-terminal peptide of the endoplasmic reticulum (ER)-membrane-spanning ceramide synthase Trh4 that is surprisingly liberated by the signal peptide peptidase (SPP), the proteolytic enzyme involved in cleaving leader sequences. This intramembrane proteolysis by SPP is thought to be important for the clearance of the ER membrane by removing small protein remnants anchored at FIGURE 1 | Classical and alternative pathways for MHC class I presentation. Furin-processed antigens targeted to the secretory route were presented by MHC class I at the cell surface and could elicit functional CD8 T-cell responses in vivo in a TAP-independent fashion (75, 81) . Autophagy mediates transporter associated with antigen processing-independent presentation of viral epitopes through MHC class I pathway A transporter associated with antigen-processing independent vacuolar pathway for the MHC class I-mediated presentation of endogenous transmembrane proteins
cord-003091-uvfppirt	2018	Taking advantage of new adjuvants, innovative ags-delivery carriers and targeting strategies, it is now feasible to optimize the activation and ag presentation processes by the specific DCs subset that is the most effective in the initiation of the adaptive response needed in a given context. Indeed, MF59, an oil-in-water emulsion adjuvant, that allows long-lasting ag retention in draining LN and enhanced ag uptake by LN-resident DCs, promotes robust humoral responses via follicular DC activation (43) and CD4 + T cell immunity induction (44) . In addition to the use of NPs, targeting DC-specific receptors has become an attractive strategy for vaccine development due to the enforced efficiency of immune responses when compared to generic-delivering approaches. Moreover, vaccines based on the filamentous bacteriophage fd presenting an αDEC-205 scFv, efficiently induce DCs maturation via the activation of the TLR9-MyD88 pathway (144) , without adjuvants and further elicit potent antitumor responses when compared to non-tailored ag delivery (145) .
cord-003122-a3f4l6iu	2018	The segmentation of the influenza genome makes these additional trafficking requirements especially challenging, as each viral RNA (vRNA) gene segment must navigate the network of cellular membrane barriers during the processes of entry and assembly. To accomplish this goal, influenza A viruses (IAVs) utilize a combination of viral and cellular mechanisms to coordinate the transport of their proteins and the eight vRNA gene segments in and out of the cell. Influenza A viruses (IAVs) and type B viruses (IBVs) contain 8, negative-sense, single-stranded viral RNA (vRNA) gene segments ( Figure 1A ) (3, 4) , which encode transcripts for 10 essential viral proteins, as well as several strain-dependent accessory proteins ( Figure 1B) . In contrast to the early steps in IAV entry, vRNP trafficking to the nucleus following the fusion event is highly dependent on the host cell machinery and transport pathways [reviewed in Ref.
cord-003319-u88gznxq	2018	To determine whether co-expression of LAG3 and CD49b is exclusive to Foxp3 − Tr1 cell subset, we infected IL-10 GFP /Foxp3 RFP dual reporter mice with Nb, and analyzed the IL-10-producing T cells. Along with the model of parasitic infection shown in Figure 2 , our data suggest that co-expression of LAG3 and CD49b marks all IL-10-producing T cell lineages in the pulmonary system, and relative abundance of the marked T cell subsets is dependent on the type of immune response as shown in the disease models. Despite the shared feature of co-expression of LAG3 and CD49b by IL-10-producing Foxp3 + CD4 + , Foxp3 − CD4 + , and CD8 + T cells, we also observed interesting discrepancies in the proportional composition of these three IL-10 high T cell subsets that are all LAG3/CD49b double positive in the lung mucosa of different pulmonary inflammatory disease models, as well as in different anatomical locations in the same mice upon TCR activation in vivo.
cord-003368-f8f2utzx	2018	After in vitro stimulation of peripheral blood derived lymphocytes (PBL), we detected distinctly deviant expression levels of several master regulators of immune responses in BNP cells, pointing to a changed immune phenotype with severe dysregulation of immune response in BNP cows. As other authors claimed the possibility of a genetic predisposition of BNP dams for production of BNP inducing alloantibodies (22) (23) (24) , our studies focused on investigating a general difference in immune responses between PregSure BVD vaccinated control cows and BNP donors. In in vitro proliferation assays with T cell mitogen ConA we observed that 22% of the unvaccinated cows reacted similar to BNP dams by showing a hyperproliferative reaction to ConA (immune deviant (ID) phenotype; Figure 6A , reaction difference ID to controls or BNP to controls, * * * * p < 0.0001).
cord-003378-0ozhye9q	2018	In vitro, CC10 was found to significantly inhibit the expression of Fgl2 in IFN-γ-treated THP-1 cells and MHV-3-infected mouse peritoneal macrophages by western blot and real-time PCR. Our study found that Fgl2 was highly expressed in peripheral blood mononuclear cells (PBMCs) and in liver tissue of humans or mice with severe viral hepatitis, and was positively related to the severity of the disease (13, 14) . Compared to wild-type mice, CC10-knockout mice exhibited excessive airway inflammation Abbreviations: FH, fulminant hepatitis; MHV-3, murine hepatitis virus strain 3; Fgl2, Fibrinogen-like protein 2; CC10, Clara cell 10 KDa protein; ALF, acute liver failure; PFU, plaque-forming units; PBS, phosphate-buffered saline; ALT, alanine aminotransferase; AST, aspartate aminotransferase; PCA, pro-coagulant activity; HRP, horseradish peroxidase; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling. In this study, we investigated the role of CC10 in hepatitis virus strain 3 (MHV-3)-induced FH in mice and explored whether CC10 protein could regulate Fgl2 in the disease process.
cord-003545-corvd5cs	2019	The transcription level of EcAtg5 was significantly increased in cells infected with red-spotted grouper nervous necrosis virus (RGNNV). Further studies showed that overexpression EcAtg5 activated autophagy, decreased expression levels of interferon related cytokines or effectors and pro-inflammatory factors, and inhibited the activation of nuclear factor κB, IFN-sensitive response element, and IFNs. In addition, ectopic expression of EcAtg5 affected cell cycle progression by hindering the G1/S transition. Taken together, our results demonstrated that fish Atg5 exerted a crucial role in virus replication by promoting autophagy, down-regulating antiviral IFN responses, and affecting the cell cycle. To analyze the gene expression profiles in response to different viral infections, the transcription levels of EcAtg5 were examined in RGNNV or SGIV infected cells. The results showed that EcAtg5 plays crucial roles in virus replication via promoting autophagy, down-regulating antiviral IFN responses, and affecting cell cycle.
cord-003598-m2fsrwvw	2019	
cord-003656-7mzsaz7a	2019	Currently there are no commercially available vaccines against ostrich-infecting mycoplasmas and this study therefore set out to develop and evaluate the use of a DNA vaccine against mycoplasma infections in ostriches using an OppA protein as antigen. The ability of the DNA vaccines to elicit an anti-OppA antibody response was evaluated by ELISA using the recombinant OppA protein of Ms03 as coating antigen. In this study we report, for the first time, that a DNA vaccine can elicit a humoral immune response in ostriches using OppA as antigen. The controls were serum samples representing the week 0, 3, 6, and 9 sampling points of a single ostrich, randomly selected from the pCI-neo_oppA 1,200 µg group based on high titers produced after vaccination. In this study, DNA vaccines were developed for ostriches using the oppA gene of an ostrich-infecting mycoplasma (Ms03) as vaccine antigen.
cord-003685-jcvrqeew	2019	The APPs have demonstrated their role as early markers of inflammation in veterinary medicine, thus several APPs were tested in marine mammals, such as C-reactive protein (CRP), serum amyloid-A (SAA), and Haptoglobin (Hp). To examine the humoral response, species-specific antibodies against IgG were produced and used to evaluate serum IgG levels in killer whale by radial immunodiffusion assay (41) and by competitive ELISA in bottlenose dolphins (42, 43) . Serum total protein analysis were used to assess health status in several cetaceans species such as pantropical spotted dolphins (Stenella attenuata) (48), beluga (49) , minke whales (Balaenoptera acutorostrata) (50) and killer whales (51) as well as in other marine mammals, like harbor seals (Phoca vitulina) (52) and walruses (Odobenus rosmarus) (53) . The availability of sensitive markers of inflammation both for free-ranging and managed marine mammals is nowadays considered fundamental to evaluate the health status and, in rehabilitation setting, to monitor the response to therapy and to define the prognosis.
cord-003724-705h5l06	2019	Pemphigus vulgaris (PV) is an autoimmune bullous disease of the skin and mucous membranes characterized by the presence of circulating and tissue-bound autoantibodies against keratinocyte cell surface antigens, specifically desmoglein (Dsg) 1 and 3. The existence of both pathogenic and non-pathogenic anti-Dsg autoAbs has recently been underscored by isolation of human monoclonal antibodies (hMabs) from pemphigus patients. Then, considering that previous studies demonstrated the ability of intact autoAbs to enter living cells (8, 16, 17) , we addressed the potential pathogenicity of α-catenin-specific Mab PVF144 by evaluating its acantholytic activity in an in vitro keratinocyte dissociation assay. Further studies are needed: (i) to evaluate whether PVF144 may act synergistically with anti-Dsg antibodies using more informative approaches, such as in vitro organ culture or in vivo models; (ii) to assess the possible role of anti-α-catenin autoAbs in pemphigus initiation and evolution in vivo; and (iii) to characterize this novel antigen as a possible target of epitope spreading phenomena in PV.
cord-003825-tkqxb1ql	2019	The goals of our study were to compare the immune response to different killed and modified live vaccines against PRRS virus and to monitor the antibody production and the cell mediated immunity both at the systemic and local level. The goals of our study were to compare the immune response to different killed and modified live vaccines against PRRS virus and to monitor the antibody production and the cell mediated immunity both at the systemic and local level. Twenty-one days after the final vaccination, all piglets, including the control non-immunized group (C5), were i.n., infected with the Lelystad strain of PRRS virus. Twenty-one days after the final vaccination, all piglets, including the control non-immunized group (C5), were i.n., infected with the Lelystad strain of PRRS virus. Comparison of serum and oral fluid antibody responses after vaccination with modified live (MLV) porcine reproductive and respiratory syndrome virus (PRRSV) vaccine in PRRS endemic farms
cord-003828-bhfghcby	2019	
cord-003914-ss8vdpox	2019	title: Oral Immunization of Chickens With Recombinant Lactobacillus plantarum Vaccine Against Early ALV-J Infection plantarum) containing the gp85 protein was explored, and the effects of this vaccine on the prevention of subgroup J Avian Leukosis Virus (ALV-J) infection were assessed. plantarum group showed a significant rise in antibody levels after inoculation, and provide improved protection against ALV-J according to viremia detection. The ALV-J-NX0101 strain, pMD18T-env recombinant vector (containing the gp85 gene), gp85-specific mouse monoclonal anti-body (MAb JE9), ALV-J antibody test kit, and ALV P27 antigen enzyme-linked immunosorbent assay (ELISA) test kits (IDEXX USA Inc., Beijing, China) were donated by Prof. plantarum significantly triggered specific IgG and IgA antibodies against ALV-J, and enhanced the levels of IgG and sIgA compared to the control group (Figures 4, 5) . This study described the mucosal and systemic immune responses specific to ALV-J induced by an orally administered recombinant L.
cord-004151-9815ikzg	2020	To investigate CTL epitope applications in swine, SLA-1(*)1502-restricted peptide epitopes matching porcine reproductive and respiratory syndrome virus (PRRSV) strains were explored by crystallography, biochemistry, and the specific pathogen-free (SPF) swine experiments. Next, the potential SLA-1(*)1502-restricted peptide epitopes matching four typical genetic PRRSV strains were identified based on the peptide-binding motif of SLA-1(*)1502 determined by structural analysis and alanine scanning of the NSP9-TMP9 peptide. In an attempt to identify anti-PRRSV CTL epitopes in this study, first, predicted peptide epitopes derived from PRRSV were synthesized, and a trimolecular complex, the structure of the epitope from PRRSV-NSP9 (TMPPGFELY, termed NSP9-TMP9)-bound SLA-1 * 1502 (pSLA-1 * 1502), was solved. The purified complex (44 kDa) of pSLA-1 * 1502 with the NSP9-TMP9 peptide (amino acid sequence TMPPGFELY, derived from residues 198-206 of the PRRSV non-structural protein) was dialyzed against crystallization buffer (20 mM Tris-HCl pH 8.0, 50 mM NaCl) and concentrated to 12 mg/mL.
cord-004477-qu2o2iu1	2020	Immediately following viral infection, neonatal survival depends on innate immunity and passive protection by lactogenic immune factors such as pathogen-specific antibodies, until an adaptive immune response can develop. Wide-spread porcine reproductive and respiratory syndrome virus (PRRSV) and swine influenza virus (SIV) represent major health challenges in the large US swine production systems and possibly worldwide. In introducing the topic of anti-viral immunity, we emphasize the genetic diversity of viruses, the virus life cycle and the pathology that viral infection can cause. A more tedious procedure is to use only parts of the virus as the vaccine (subunit vaccines) that target the immune response to those viral epitopes that elicit VN antibodies. A second approach to vaccine development is use of live attenuated virus that has been genetically modified or cell culture adapted and cannot produce a disease in the host but can still replicate.
cord-015254-xtox2rxs	2020	We modeled neuropathic pain in rats by inducing chronic constriction injury (CCI) of the sciatic nerve and analyzed the effects on C-X-C motif chemokine 10 (CXCL10)/CXCR3 activation, BSCB permeability, and immune cell migration from the circulation into the spinal cord. In this study, we examined the integrity of the BSCB and the migration of circulating immune cells into the spinal cord after chronic constriction injury (CCI) of the sciatic nerve, which induces neuropathic pain. To the best of our knowledge, it is the first study to report that blocking CXCL10/CXCR3 signaling attenuates the increases in BSCB permeability and T cell infiltration of the spinal cord induced by peripheral nerve injury. Previous studies have indicated that increased BSCB permeability is a prerequisite for immune cell infiltration of the spinal cord during the development of neuropathic pain (41) , and we found that blocking CXCL10/CXCR3 signaling with anti-CXCL10 antibodies reduced the BSCB''s permeability to NaFlu, which suggests that CXCL10/CXCR3 signaling plays a critical role in CCI-induced BSCB dysfunction.
cord-020770-wpub7krf	2020	
cord-026866-0hlre9i6	2020	
cord-030385-btf502ju	2020	However, it has not been clarified whether β-glucan-induced trained immunity causes different responses to early sepsis between male and female mice. The changes of inflammatory cytokines expression, and macrophage polarization in male, female, and ovariectomized C57BL/6 mice in sepsis model were investigated. Macrophage polarization toward the M1 phenotype, which exhibited enhanced trained immunity, was related to the difference in sepsis resistance between female and male mice. Mechanistically, we found that E2 inhibited the nuclear translocation of RelB, which is a member of non-canonical pathway of NFκB and contributes to macrophage polarization to change the intensity of trained immunity. Our results showed that females expressed higher IL-6 and TNFα than males in sepsis, and trained immunity exacerbated this trend (Figures 1I,J) . The in vitro trained immunity model was established with RAW264.7 and J774 ( Figure 5C ) cell lines derived from male and female mice, respectively.
cord-030803-6i0e2zkd	2020	STAT5a and STAT5b have distinct target genes in immune responses (15) , and STAT5b is the transcription factor that induces Tfh. Tfh can induce B-cells to produce IgM antibodies and IL-21 produced by Tfh facilitates B cell isotype switching to IgG (16, 17) . Type 2 myeloid dendritic cells (CD141+ mDC2) are the antigen presenting cells Eradicable immune responses include TH1, TH2, TH17, and THαβ. Initiation of eradicable immunity also requires innate lymphoid cells to produce the initial cytokines that drive different immunological pathways. THαβ immune responses against self-antigens present as type 2 antibody-dependent cytotoxic hypersensitivity, such as the acute stage of myasthenia gravis or Graves'' disease (37) . The effector cells of TH1-like immune responses include suppressive macrophages (M2), ILC1, suppressive CD8 T cells (CD28-CD8+Treg), IgA1producing B-cells, iNKT1 cells, and IFN-γ-/TGF-β-producing CD4 T cells (24, 40, 56) . TH3 immune responses induce type 2 antibody-dependent cytotoxic hypersensitivity, including the chronic stage of Systemic Lupus Erythematosus (SLE) (69) .
cord-032953-qy4b2l2f	2020	title: Passive Immunization Delays Disease Outcome in Gilthead Sea Bream Infected With Enteromyxum leei (Myxozoa), Despite the Moderate Changes in IgM and IgT Repertoire The results showed that, fish injected with parasite-specific antibodies (spAbs) became infected with the parasite, but showed lower disease signs and intensity of infection than the other groups, indicating a later establishment of the parasite. 1 https://www.genome.jp/tools-bin/clustalw To study the IgM and IgT repertoire in the fish used as serum donors for passive immunization, cDNA from anterior intestine of SUR and NAI donor fish were used as template in PCR amplifications for each primer combination (F + R). Thus, we studied the IgM and IgT repertoire in the GSB that acted as SUR and NAI serum donors for the passive immunization trial. The repertoire analysis was performed on the anterior intestine, as previous studies revealed that in this particular organ IgM and IgT transcript expression increased upon re-exposure to the parasite in resistant fish (29) .
cord-033488-du8heorx	2020	(A) Sera from five mice from each group immunized with a negative control (wild-type crude extract, G1) or a positive control (commercial vaccine, G2) or the crude extract containing COE-GCN4pII (G3) were mixed, diluted 200 times and used as a primary antibody for detecting 1 µg of purified PEDV antigen. Different levels of PEDV-specific IgG (B), IgA (C), and IgM (D) antibodies in each mouse sera group were calculated as the reciprocal of the geometric mean titer of the five mice of each group vaccinated with the negative control (wild-type crude extract, G1) or the positive control (commercial vaccine, G2) or the crude extract containing COE-GCN4pII (G3). Therefore, plant crude extract containing the trimeric COE protein had the level of IgG antibodies similar to that of commercial vaccines against the PEDV DR13 strain after the third injection. Therefore, we concluded that plant crude extract containing the trimeric COE protein had a strong immunogenicity and induced a neutralizing antibody titer similar to that of the commercial vaccine against the attenuated PEDV DR13 strain.
cord-034310-izpt032p	2020	Furthermore, studies in apoE−/− mice suggest that T cells reactive to mCRAMP are functionally active in atherosclerosis and may be involved in modulating plaque calcification. Given the role of anti-microbial peptides as potential selfantigens in atherosclerosis, and the possible association with acute events, we tested if the cleaved fragment of hCAP-18, the cationic antimicrobial peptide LL-37, would induce differential T cell immune responses in patients with ACS. In this study, we showed that: (a) LL-37 stimulation of PBMCs from patients with ACS induced the persistence of CD8+ TEM cell response compared to patients with stable CAD or selfreported controls; (b) Immunization of apoE−/− mice with mCRAMP, the cationic fragment of CRAMP, increased CD8 CM T cell activation and cytolytic activity; and (c) Adoptive transfer of T cells from mice immunized with mCRAMP was associated with smaller atherosclerotic aortic plaque area, and absence of aortic sinus plaque calcification.
cord-252568-b8sbvy0g	2017	There is evidence that these particles display adjuvant characteristics, promoting cell recruitment, antigen-presenting cell activation, cytokine production, and inducing a humoral immune response. However, many NPs have been shown to stimulate immune responses, including cell recruitment, activation of antigen (Ag)-presenting cells (APCs), and induction of cytokine and chemokine release. Among the vaccines targeting extracellular bacteria and toxin, two were formulated with lipopolysaccharide (LPS) in glycopeptide Ag. The use of glycoantigen and LPS can trigger an intense response through TLR4 and B cell receptor activation; the presence of gold NPs (AuNPs) may have minimal influence on this response. To understand the possible uses of MeNPs as platforms for vaccines against infectious diseases, analysis is needed of the impact of different physicochemical characteristics of NPs on the innate immune response (Figure 1) .
cord-253108-p3wlw5d4	2013	Following more than a decade of studies aimed at elucidating the mechanisms that mediate Treg activity, interest was rekindled in the mid-1990s with the transformational research of Sakaguchi and colleagues, who specifically identified a population of CD4+CD25+ T cells that had suppressive function, which were coined as naturally occurring thymic-derived Tregs, or natural Abbreviations: APC, antigen-presenting cell; DC, dendritic cell; EAE, experimental autoimmune encephalitis; Ebi3, Epstein-Barr virus-induced gene 3; IL, interleukin; iTreg, induced regulatory T cell; NIMA, non-inherited maternal antigen; NK, natural killer; nTreg, natural regulatory T cell; PAP, prostatic acid phosphatase; TGF, transforming growth factor; Treg, regulatory T cell. When activated in these conditions, iTregs gain potent suppressive functions, inhibiting T-cell proliferation and effector functions in an antigen non-specific fashion, and play a central role in mediating regulation and propagating infectious tolerance in a variety of malignancies, including infectious diseases and cancer.
cord-253862-jl1zhg13	2020	
cord-254192-86ksgl5t	2019	Here, to resolve the mechanism responsible for the disparity between IFN-λ3 and type I IFN in anti-mucosal virus infection, we compared the transcription profiles induced by the two IFNs in porcine intestinal epithelial (IPEC-J2) cells by RNA-Seq. Our results showed that the pretreatment of IPEC-J2 cells with IFN-λ3 resulted in the differential expression of 983 genes. Here, to resolve the mechanism responsible for the disparity between IFN-λ3 and type I IFN in anti-mucosal virus infection, we compared the transcription profiles induced by the two IFNs in porcine intestinal epithelial (IPEC-J2) cells by RNA-Seq. Our results showed that the pretreatment of IPEC-J2 cells with IFN-λ3 resulted in the differential expression of 983 genes. In this study, we comprehensively compared the transcriptional profiling of IFN-λ3-and IFN-α-induced genes in a porcine intestinal epithelial cell line (IPEC-J2) and verified the RNA-Seq results by reverse transcriptase quantitative PCR (RT-qPCR) in vitro, and further confirmed the transcriptional profile difference in crypt-derived porcine enteroids.
cord-254809-o454k6ae	2020	Third, according to an analysis of nearly 45,000 confirmed cases, 19% of patients with COVID-19 have been identified as severe cases and critically ill cases, involving severe pneumonia and metabolic disorders, developing into acute respiratory distress syndrome (ARDS), multiple organ dysfunctions (MODS), and even septic shock and death (9, 12) . In this study, we investigated mild cases and severe cases infected with SARS-CoV-2, as well as healthy young children and adults. Our study suggests that monocytes, neutrophils, and T-lymphocytes are associated with the onset and progress of COVID-19 infection, and immunopathogenesis was involved in ARDS, metabolic disorders, and MODS in severe cases. We collected the data of patients with COVID-19, including the clinical records, laboratory results and chest computed tomography (CT) scan images of mild and severe cases in the hospital. Extremely high levels of circulating lymphocytes and monocytes would benefit to fight against SARS-CoV-2 infection, which might be associated with the low morbidity of COVID-19 in young children.
cord-255034-x100xo2t	2020	
cord-255578-0ltb9dpa	2020	title: Deficiency of Mouse FHR-1 Homolog, FHR-E, Accelerates Sepsis, and Acute Kidney Injury Through Enhancing the LPS-Induced Alternative Complement Pathway Deficiency of factor H-related protein 1 (FHR-1), which is a regulator of AP, has been considered as a susceptible factor for atypical hemolytic uremic syndrome (aHUS) and other types of nephropathy when an inducer such as infection exists. We found that murine FHR-1 homolog (FHR-E) deficiency enhanced lipopolysaccharide (LPS)-induced AP activation both in vitro and in vivo and that Cfhr1 knockout mice exhibited more severe sepsis and AKI in response to LPS challenge. These results indicated that FHR-E deficiency promoted LPS-induced sepsis and AKI through AP over-activation, providing a mouse model for studying AP regulation and sepsis. In this study, Cfhr1 was deleted on C57BL/6 mouse to study the function of FHR-E on AP and the effect of FHR-E deficiency on LPS-induced sepsis.
cord-256582-x2grfhov	2019	Moreover, activation of CLEC2 by dengue virus (DV) and H5N1 influenza virus (IAV) induces the release of extracellular vesicles (EVs), which further enhance NETosis and proinflammatory cytokine production via CLEC5A and Toll-like receptor 2 (TLR2). Among these Sykcoupled C-type lectins, activation of CLEC5A by flaviviruses and influenza virus induces the production of inflammatory cytokines and NETosis, while these viruses also activate CLEC2 in platelets to elease extracellular vesicles (EVs), which further enhance inflammatory cytokine release and NETosis via CLEC5A and TLR2 in macrophages and neutrophils. Thus, blockade of CLEC5A-mediated signaling in DV infected cells provides a promising strategy for attenuating systemic vascular leakage and increasing the survival rate of patients suffering from DHF/DSS; this approach might also be applicable to other virus-induced inflammatory diseases (1). These viruses are captured by high affinity receptors (DC-SIGN and MR) to induce inflammatory cytokine release via activation of CLEC5A and CLEC2. Extracellular vesicles from CLEC2-activated platelets enhance dengue virus-induced lethality via CLEC5A/TLR2
cord-256998-or73in8m	2020	Among the more notable responses in other early preclinical studies, nearly half of mice bearing established B16F10 melanomas experienced complete tumor regression following 2 weekly treatments with pIL-12+EP (124) . In preclinical studies, a single intratumoral injection of mRNA encoding murine IL-12 (mIL-12) increased IFNγ expression and genes associated with a Th1 response in MC38 tumor-bearing mice (190) . In a useful comparison against other cytokines, one study demonstrated that Ad-IFN-γ had no greater antitumor activity than an empty Ad vector, whereas AdmIL-12 induced complete regressions of P815 mastocytomas in >80% of treated mice (219) . Antitumor activity on xenografts of human lung tissues indicated that liposomal encapsulation is a promising approach capable of eliminating tumor cells and inducing lymphocyte infiltration 2 weeks after i.t. injection. Immunotherapy of established tumors in mice by intratumoral injection of an adenovirus vector harboring the human IL-2 cDNA: induction of CD8 + T-cell immunity and NK activity
cord-257116-6td3efjw	2017	title: Cellular RNA Helicase DDX1 Is Involved in Transmissible Gastroenteritis Virus nsp14-Induced Interferon-Beta Production In summary, our data revealed a potential coactivator role of host RNA helicase DDX1 to the induction of IFN-β response initiated by TGEV and demonstrated that nsp14 is an important IFN inducer among the TGEV-encoded proteins. In this study, we found that TGEV infection significantly facilitated IFN-β production as well as activation of the transcription factors IFN regulatory factor 3 (IRF3) and nuclear factor-kappaB (NF-κB) in porcine kidney (PK-15) cells. In summary, our data revealed a potential coactivator role of host RNA helicase DDX1 to the induction of IFN-β response initiated by TGEV and demonstrated that nsp14 is an important IFN inducer among the TGEVencoded proteins. Nsp14 interacts with cellular DExD/H helicase DDX1 to activate IFN-β in a NF-κB dependent manner, and DDX1 is associated with TGEV-induced IFN-β production, revealing a potential coactivator role of host RNA helicase DDX1 on virus and viral protein induced innate immune responses.
cord-257662-viy65y72	2014	Myeloid cells, including monocytes and macrophages, play an important role in this balance, particularly through the activities of the arginine-hydrolyzing enzymes nitric oxide synthase 2 (Nos2; iNOS) and arginase 1 (Arg1). In this review, we highlight recent studies of viral infections where myeloid cell polarization -resulting in expression of iNOS or Arg1 -contribute to viral control or the development of chronic virus infection and mediate the resolution of tissue damage or cause immunopathology. It was further shown that genetic deletion of myeloid cell Arg1 resulted in enhanced viral control in inflamed muscle tissue and reduced tissue pathology following RRV infection in mice (69) , suggesting an important role for Arg1-expressing macrophages in the persistence of these chronic viruses. In the absence of iNKT cells, influenza A (PR/8 strain) infection was shown to induce the expansion of CD11b + GR-1 + MDSCs in the lungs of mice, which suppressed influenza-specific T cell and antibody responses through the activity of both arginase and NOS, resulting in higher viral titers and increased mortality (81) .
cord-259131-36udb7uc	2019	AM expression of proinflammatory cytokines TNF-α, IL-6, IL-1β, and chemokine RANTES drastically increased 2-wpi compared to AMs of naïve macaques (p < 0.0001 for all), but dropped significantly with progression to chronic infection. AM expression of proinflammatory cytokines TNF-α, IL-6, IL-1β, and chemokine RANTES drastically increased 2-wpi compared to AMs of naïve macaques (p < 0.0001 for all), but dropped significantly with progression to chronic infection. In addition, the low proinflammatory cytokine response in chronic infection was not associated with an increase in IL-10-expressing AMs. To investigate AM activation, BAL cells obtained from naïve and acute and chronically infected macaques at weeks 2, 4, 8, 12, and 20 wpi, were incubated with native gp120 from R5 tropic SIV or LPS for 6 h, and intracellular expression of MIP-1β and IL-6 was assessed (Figures 3A,B) . Decreased Fc receptor expression on innate immune cells is associated with impaired antibody-mediated cellular phagocytic activity in chronically HIV-1 infected individuals
cord-259748-x7dq1sy4	2020	
cord-260452-js4nr4d8	2017	Both the pathogen-associated molecule pattern derived from virions and intracellular stress molecules involved in the process of viral infection lead to activation of the NLRP3 inflammasome, which in turn triggers inflammatory responses for antiviral defense and tissue healing. IL-1β and IL-18 serve to activate myriad downstream cell responses, and orchestrate innate and adaptive immunity through MyD88/IRAK4/TRAF6-mediated NF-κB signaling and the JNK/p38 mitogen-activated protein kinase pathways (60-63), which may represent key events for the NLRP3 inflammasome-dependent antiviral defense. In BV-2 mouse microglia cells infected by Japanese encephalitis virus, the NLRP3 inflammasome induces production of IL-1β and IL-18 rapidly (within 3 h of exposure) and of TNF-α, CCL2, and IL-6 later (within 6 h after exposure) (40) ; the findings suggest that the NLRP3dependent protective inflammatory response is a very early phase innate immune response against RNA viral infection.
cord-261367-i1n8x0uc	2020	Instead, mice with iBALT had reduced Th2-associated mRNA expression, less eosinophil recruitment to the lungs and airways, attenuated goblet cell hyperplasia and reduced mucus production following pulmonary sensitization and challenge with OVA. To test the effect of iBALT on the immune response to a pulmonary allergen, we administered LPS (or PBS) to neonatal mice as described above, allowed the mice to rest until they were 7 weeks old, then intranasally sensitized the iBALT and control groups with 100 µg OVA in combination with low dose (0.1 µg) LPS on days 49, 50, and 51 and challenged them on days 63, 64, 67, and 68 with 25 µg OVA ( Figure 1E ). Together, these data suggest that the spatial distribution of effector Th2 cells and Tregs is affected by the presence of iBALT (they cluster together), which may explain how iBALT and control mice can have similar numbers of Th2 cells in their lungs, but have so profoundly different outcomes in terms of eosinophil accumulation and histopathology.
cord-262375-1ex2ow07	2020	All confirmed patients were clinically classified according to the "Novel Coronavirus Pneumonia Treatment Scheme of the National Health Commission of the People''s Republic of China (version 7)" at the time of admission (4), as follows: (1) general type: symptoms such as fever and respiratory tract complaints were present, and manifestations of pneumonia could be seen on imaging; (2) serious type: any of the following criteria were met: (1) respiratory distress, respiratory rate (RR) ≥ 30 times/min; (2) resting oxygen saturation ≤ 93%; or (3) arterial partial oxygen pressure (PaO 2 )/oxygen absorption concentration (FiO 2 ) ≤ 300 mmHg (1 mmHg = 0.133 kPa); (3) critical type: any of the following criteria were met: (1) respiratory failure and a need for mechanical ventilation, (2) shock, or (3) a combination of factors with other organ failure requiring ICU care.
cord-262575-06i2nv0t	2020	title: Case Report: Canakinumab for the Treatment of a Patient With COVID-19 Acute Respiratory Distress Syndrome Severe cases of COVID-19 present with serious lung inflammation, acute respiratory distress syndrome and multiorgan damage. SARS-CoV-2 infection is associated with high cytokine levels, including interleukin-6 and certain subsets of immune cells, in particular, NK, distinguished according to the cell surface density of CD56. Cytokine levels are inversely correlated with lymphocyte count, therefore cytokine release syndrome may be an impediment to the adaptive immune response against SARS-CoV-2 infection. An 85 year old male presenting in our hospital with COVID-19, whose condition was complicated by acute respiratory distress syndrome and cardiac and renal failure (with oliguria) after 25 days of hospitalization, was intubated and received canakinumab for compassionate use. The immune response, including the release of pro-inflammatory cytokines and activation of T cells, are essential for controlling the viral spread, inflammation, and tissue renewal (5, 6) .
cord-262673-j2ot35lt	2020	
cord-262944-9k64f0tw	2020	In this review, we describe mechanisms of pathogenicity of two such viral pathogens, Human cytomegalovirus (HCMV) and Zika virus (ZIKV) at the maternal-fetal interface. We will focus on the viruses human Cytomegalovirus (HCMV) and ZIKV, which are known causes of adverse pregnancy outcomes and delve into how they interact with various decidual immune cells to promote their survival and replication. We will explore further the role that NK cells play in specific viral infections in pregnancy TORCH PATHOGENS HCMV Human cytomegalovirus (HCMV) was first described in 1954 by Margaret Smith, who replicated a virus from two newborn babies who had died from cytomegalic inclusion disease (CID) (41) . A study performed using decidual and chorionic villous tissue from early and mid-gestation human pregnancy shows that ZIKV appears to elevate type I and III IFN expression, which does not occur in HCMV infection (131) .
cord-263141-n200x6z1	2016	Studies have clearly demonstrated that hostile inflammation is accompanied by dysfunctional coagulation in respiratory IFV disease, and our investigations have proved that some immunobiotic strains are able to reduce viral disease severity through their capacity to modulate the immune-coagulative responses in the respiratory tract. Studies have clearly demonstrated that hostile inflammation is accompanied by dysfunctional coagulation in respiratory IFV disease, and our investigations have proved that some immunobiotic strains are able to reduce viral disease severity through their capacity to modulate the immune-coagulative responses in the respiratory tract. Studies have clearly demonstrated that hostile inflammation is accompanied by dysfunctional coagulation in respiratory IFV disease, and our investigations have proved that some immunobiotic strains are able to reduce viral disease severity through their capacity to modulate the immune-coagulative responses in the respiratory tract. Then, our studies were the first in demonstrating a beneficial modulation of the immune-coagulative response during respiratory TRL3 activation and IFV infection induced by immunobiotic microorganisms (Figure 3) .
cord-263433-oldy0gta	2015	As the ISGs described to date are coding genes, we sought to determine whether IFN also regulates the expression of long non-coding ISGs. To this aim, we used RNA sequencing to analyze the transcriptome of control and HuH7 cells treated with IFNα2. To address the issue of whether IFN could also regulate expression of lncRNAs, which may play key roles in the antiviral response, we analyzed the transcriptome of cells treated or not with IFNα2 by RNA sequencing (RNASeq). The results showed that at later times post-infection with the influenza virus lacking NS1, there was increased expression of lncISG15, lncBST2/BISPR, and their neighboring coding transcripts (Figure 3A) . To discriminate whether lncISG15 and lncBST2/BISPR are induced directly by the JAK/STAT signaling pathway or by a secondary wave of the IFN response, we evaluated the expression of these lncRNAs and their coding neighboring genes in HuH7 or A549 cells incubated or not with the JAK/STAT inhibitor ruxolitinib.
cord-264814-v4wnmg03	2020	Herein, we review the current knowledge about the immune response to this novel virus as it pertains to the design of effective and safe SARS-CoV-2 vaccines and the range of novel and established approaches to vaccine development being taken. Herein, we review the current knowledge about the immune response to this novel virus as it pertains to the design of effective and safe SARS-CoV-2 vaccines and the range of novel and established approaches to vaccine development being taken. Comprehensive safety studies are particularly critical because some candidate vaccines use platform technologies that have not been examined extensively in human subjects to date, including some of the viral vectors, mRNA and nanoparticle constructs, and because of the potential for enhanced disease and adverse events related to aberrant immune responses to be seen upon infection pre-and post-licensure.
cord-265005-e6rpryrh	2014	
cord-265855-zf52vl11	2020	Zinc deficiency may increase ACE-2 receptor activity on type 2 pneumocytes and other cells that are infected by SARS-COV-2, mainly in the lower respiratory tract. Although there are no specific data regarding zinc in this pathway for SARS-CoV-2, zinc may limit infection through upregulation of IFN-alpha production and an increase in its antiviral activity (77, 78) . Thus, patients with IL-6-174 GG polymorphism (C-carriers) may be susceptible to developing a severe infection due to SARS-CoV-2, leading to an increase in IL-6 levels that produce a cytokine storm related to impaired zinc homeostasis. We believe there is enough evidence to further investigate how zinc status or homeostasis is involved in the pathogenesis of severe illness produced by SARS-CoV-2 infection, and its potential role as an active treatment should be assessed in clinical trials.
cord-266085-914y3je0	2018	To establish this, we selected Folate Receptor alpha (FRα) as a model antigen and a mouse B cell line, expressing both the soluble and the membrane-bound forms of a human/mouse chimeric antibody (MOv18 IgG1) specific for FRα, as test antibody-expressing cells. In our study, we present an antigen-conjugated fluorescent bead methodology designed to identify and isolate single antibody-expressing cells and to derive and clone matched heavy and light chain antibody variable regions into full length antibodies. The workflow features bead-based identification and isolation of specific B cells using direct fluorescent-activated cell sorting, sequencing, and cloning of matched heavy and light chain variable regions in a single full sequence antibody expression vector system, and expression and testing the antigenic reactivity of the antibody clone. Following flow sorting of single cells directly into lysis buffer, we confirmed that it is possible to extract matched H and L chain variable region sequences from single antibody-expressing cells selected by specific antigen-coated beads.
cord-267134-5gz2dotn	2020	The first anatomical/histological reports from the lungs of severely SARS-CoV-2-affected patients experiencing acute respiratory disease syndrome (ARDS) revealed excessive inflammatory activation and destruction of the bronchial and alveolar epithelium, features already observed during the first SARS pandemics in 2003 (3, 4). The following sections will give an overview of the molecular and cellular mechanisms underpinning SARS-CoV virus infections and how lung and systemic host innate immune responses affect survival either positively, through downregulating the initial viral load, or negatively, by triggering uncontrolled inflammation. Regarding the lung, the differentiated Calu-3 cell line [when cultured at the air-liquid interface (ALI)] is the model of choice: in that set-up, SARS-CoV infection triggered an inflammatory response characterized by increased production of interleukin (IL)-6, IL-8, gamma interferon (IFN-γ), inducible protein 10 (IP-10), and activation of the transcription factor NF-κB (56) . Innate immune response of human alveolar type II cells infected with severe acute respiratory syndrome-coronavirus
cord-267166-ecmayzr6	2018	
cord-267237-wbwlfx7q	2020	METHODS: Fifty-nine SARS-Cov-2 positive hospitalized patients, classified according to ICU or non-ICU admission requirement, were prospectively recruited and analyzed by ELISA for levels of sCD14 and sCD163, along with other laboratory parameters, and compared to a healthy control group. CONCLUSIONS: Monocyte-macrophage activation markers are increased and correlate with other inflammatory markers in SARS-Cov-2 infection, in association to hospital admission. In this paper, we analyze serum levels of soluble monocyte activation markers in COVID-19 patients and their correlation with severity and other inflammatory markers. We found significant correlations between sCD14 and sCD163 levels and several clinical laboratory parameters in infected patients (in these analysis, adjusted significance under Bonferrori correction is 0.01), but only in the non-ICU group, possibly reflecting an interference of the use of tocilizumab or corticoids in the ICU group. Our results thus suggest that monocyte-macrophage activation can act as driver cells of the cytokine storm and immunopathology associated to severe clinical course of COVID-19 patients.
cord-267567-w39f584z	2018	Upon flavivirus infections, these are significantly altered: on the one hand, these viruses can co-opt lipid metabolic pathways to generate ATP to facilitate replication, or to synthesize membrane components to generate replication sites; on the other hand, more recent evidence suggests counter strategies employed by host cells, which actively modulate several of these networks in response to infection, enhancing interferon signaling by doing so, and thus creating an antiviral environment. In this review, we discuss recent data on mechanisms of alteration of lipid metabolic pathways during infection by flaviviruses, with a focus on cholesterol and fatty acid biosynthesis, which can be manipulated by the invading viruses to support replication, but can also be modulated by the host immune system itself, as a means to fight infection.
cord-268438-bjs5oliw	2019	title: Zebrafish TRIM25 Promotes Innate Immune Response to RGNNV Infection by Targeting 2CARD and RD Regions of RIG-I for K63-Linked Ubiquitination Here, we found that zebrafish TRIM25 (zbTRIM25) functioned as a positive regulator of RLR signaling pathway during red spotted grouper nervous necrosis virus (RGNNV) infection. In the present study, zebrafish TRIM25 (zbTRIM25) was involved in RGNNV infection and was identified as a positive mediator of RLR signaling pathway by binding to and ubiquitinating the caspase activation and recruitment domain (2CARD) and repressor domain (RD) regions of RIG-I, which is different with the findings in mammals. In mammals, previous reports showed that TRIM25 enhanced RLRs antiviral pathway by binding viral RNA-activated RIG-I to induce its K63-linked polyubiquitination and subsequent IFNs and ISGs production (26) . Here, we found that zbTRIM25 positively regulated RLR signaling pathway and facilitated zbRIG-I-mediated IFN 1 promoter activation, and overexpression of zbTRIM25 inhibited RGNNV infection, indicating the conservative antiviral properties of TRIM25 in fish and mammals.
cord-268483-joiajgs4	2020	As there are no specific treatments available for this novel coronavirus, numerous small molecular drugs that are being used for the treatment of diseases like SARS, MERS, HIV, ebola, malaria, and tuberculosis are being given to COVID-19 patients, and clinical trials for many such drugs have already begun. An ELISA-based time kinetics study to detect the COVID-19 specific humoral immune response showed that the patients produced IgM and IgG antibodies that did not cross-react with other human coronaviruses except SARS-CoV. A case study on pediatric patients reports that 5 out of 6 children showed a protective humoral response, with neutralizing IgG and IgM antibodies targeting the N and S-RBD proteins of SARS-CoV-2 (65) . T cell responses are required for protection from clinical disease and for virus clearance in severe acute respiratory syndrome coronavirus-infected mice
cord-268501-z4oztgi0	2020	In fact, by May 11th, 2020 seven vaccines had already entered Phase I clinical trials: (1) encapsulated mRNA encoding protein S (Moderna and NIAID, USA); (2) Adenovirus expressing protein S (Cansino Biologics, China); (3) DCs modified with lentivirus expressing several proteins and CTLs (Shenzen Geno-Immune Medical, China); (4) an APC modified with lentivirus expressing several viral proteins (35); (5) Inno 4800, SARS CoV2 DNA Injection (Innovio, USA); (6) ChAdOx1 vaccine from the Jenner Institute, Oxford University, (UK) which is a genetically modified Adenovirus expressing Coronavirus proteins (39) , and is also being tested in a Phase II trial; and finally (7) the whole inactivated coronavirus with Alum by Sinovac, China (40) . Furthermore, in vaccinated monkeys, seven days after infection, the Sinovac inactivated vaccine at 6 µg/dose induced high titers of IgG antibodies directed against the S, RBD and lower levels of anti-N protein antibodies, high titers of virus neutralizing antibodies with no detected antibodydependent enhancement of disease (ADE) (40) .
cord-268511-dx2cqqt5	2020	We have previously described that human CD28, a crucial co-stimulatory receptor necessary for full T cell activation, is also able to act as a TCR independent signaling receptor and to induce the expression of IL-17A and inflammatory cytokines related to Th17 cells, which together with Th22 cells represent the main cellular source of IL-22. However, although IL-6 itself is able to prime IL-22 production in activated human CD4 + T cells (41) , stimulation of CD4 + T cells with IL-6 alone is not sufficient for up-regulating IL-22 gene expression ( Figure 1G ) but requires a second signal delivered by CD28. During CD28 stimulation, RelA/NF-kB and IL-6-associated STAT3 cooperate for inducing IL-22 expression and secretion ( Figure 3 ) that in turn acts on epithelial cells by promoting the up-regulation of MUC1 ( Figure 4) .
cord-268781-6l74rrlm	2020	Besides, our results from human PBMCs and three independent infectious animal models (MERS, influenza and malaria) further reveal that IFNγ expression by epitope-specific CD8 + T cells does not always correlate with their cell-killing potential, highlighting the need for using cytotoxicity assays in specific contexts (e.g., evaluating vaccine candidates). Besides, our results from human PBMCs and three independent infectious animal models (MERS, influenza and malaria) further reveal that IFNγ expression by epitope-specific CD8 + T cells does not always correlate with their cell-killing potential, highlighting the need for using cytotoxicity assays in specific contexts (e.g., evaluating vaccine candidates). Splenocytes from vaccinated mice challenged by a lethal PR8 infection were used to measure epitope-specific CD8 T cell effector functions through direct (in vivo cytotoxicity) and indirect (IFNγ-ICS) assays.
cord-269170-9f460xbq	2020	The disease seems to result from the interplay of genetic and environmental susceptibility factors with infectious triggers, followed by a subsequent abnormal immune response characterized by increased levels of inflammatory cytokines and chemokines during the acute phase. Recent advances in culture-independent techniques for detection and identification of intestinal commensal bacteria enabled the discovery that Th17 and Treg differentiation are regulated by short chain fatty acids (SCFAs), in particular butyrate, produced by the gut microbiota. This perspective is illustrated in Figure 1 and can be explained as follows: [1] various factors during the in utero and postnatal period drive dysbiosis in young children; [2] dysbiosis results in reduced intestinal production of SCFAs including butyrate; [3] reduced levels of SCFAs in the gut cause an imbalance of Th17s/Tregs; and [4] individuals with Th17/Treg imbalances develop hypercytokinemia triggered by ubiquitous infectious agents(s), followed by KD (Figure 1) .
cord-269222-g2ibmo75	2018	
cord-271419-v6dfel3l	2020	
cord-272491-a84pahdr	2020	
cord-273277-4ewvwg4o	2020	
cord-273505-pcsw3vmx	2020	
cord-274557-2071770h	2015	
cord-275779-ocbygkyb	2017	
cord-277529-z2r14w2k	2020	
cord-278081-tk7vn1v1	2017	Here is presented new details to the hypothesis, explaining how the disrupted chromatin can lead to subsequent disruption of the nucleolus, even nucleolar fragmentation, which results in ineffective nucleolar functioning, misfolded RNAs, misassembled or incompletely assembled ribonucleoprotein (RNP) complexes, and stabilization of nucleolar components in autoantigenic conformations. For now there is no direct connection between viruses and the "X chromosome-nucleolus nexus" hypothesis to the increased risk of cancers among autoimmune disease patients but we can consider the induction by viruses of increased polyamine levels and the possible reactivation of X-linked polyamine genes as means by which competition for the cellular methyl donor, SAM, could reduce DNA methylation and open oncogenes for overexpression in proliferation competent cells. A disrupted Barr body could generate an abundance of polyamines and Alu RNA from X-linked genes and elements that further stress and damage the nucleolus, making it very inefficient in its functions, even fragmenting it and possibly leading to cell death.
cord-278839-uu2wlpmp	2020	In 2009, during the H1N1 flu pandemic, an increased ratio of female to male cases was verified, in which pregnant women developed more complications, as severe acute respiratory syndrome, and higher mortality compared to the general population (30, 31) . Additionally, infection by the Lassa virus in pregnant women shows high levels of placental replication, and the risk of maternal-fetal mortality increases with the duration of pregnancy (38, 39) . At first, contagion occurred through contact with some infected animals but, soon there were the first reports of human-to-human transmission (93), The virus was identified as belonging to the coronaviridae family and was designated SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) (94). Chen and collaborators, verified alteration in calcium and albumin levels in the blood of pregnant women with SARS-CoV-2 infection (124) , which could potentially increase the severity in COVID-19 (125) .
cord-279105-e2zjxjox	2020	With the limitations of qRT-PCR, immunoassays may offer another FIGURE 2 | Schematic illustration on the window period of detection for either viral RNA or antibodies in SARS-CoV-2-infected individuals. However, interestingly, one study demonstrated that longitudinal profiling of both antibodies in a population of 63 COVID-19 patients showed no specific chronological order in terms of IgM and IgG seroconversion (10) , which was also observed in patients infected with SARS-CoV and another human coronavirus, Middle East Respiratory Syndrome coronavirus (MERS-CoV) (22, 23) . These findings on SARS-CoV-2-specific antibodies seroconversion against the S viral protein suggest the importance to test for both IgM and IgG antibodies to confirm a positive infection. With the availability of immunoassays utilizing various coronavirus structural proteins, the use of more than one different antigen-based serological approach may be essential to establish a true positive SARS-CoV-2 infection.
cord-280605-2i4gk7et	2020	
cord-280924-g6062fwk	2020	title: Interferon-Induced Transmembrane Protein (IFITM3) Is Upregulated Explicitly in SARS-CoV-2 Infected Lung Epithelial Cells We identified IFITM3 as an early upregulated gene, and valproic acid was found to enhance its mRNA expression as well as induce its antiviral action. To effectively address the ongoing COVID-19 pandemic, there is a recognized need for a framework for rapid identification of novel targets for diagnostic and therapeutic interventions as well as determine clinically approved drugs with high potential for repurposed use against SARS-CoV-2. In this study, we have applied this approach, and our findings have identified IFITM3 as an early upregulated gene and indicate that valproic acid enhances IFITM3 mRNA expression and antiviral action. Our toxicogenomic analysis showed that valproic acid increased the mRNA expression of IFITM3, supporting a new report that the SARS-CoV-2-human protein-protein interaction map showed that valproic acid might be a potential repurposing drug for COVID-19 (34) .
cord-280941-ds6x0yym	2018	
cord-282081-qaagup4d	2020	
cord-282336-zvc04s39	2020	In contrast, the lung injury in LPS-challenged TTP KO mice was characterized by severe consolidation (>90% of total area of lung section) (Figures 1F,G) that included infiltration of neutrophils, edema, fibrin, and airspace hemorrhage within the airway and alveolar lumen, multifocal loss of bronchiolar epithelium with infiltration of neutrophils and red blood cells within the bronchiolar lumen, and moderate to severe perivascular edema and inflammation (Figures 1F-H) . To determine the cell-specific role of TTP levels in ALI, we modulated TTP levels in hematopoietic progenitor cells (HPCs) and non-HPCs. In order to test whether donor HPCs repopulate the recipient mouse lungs, we first made bone marrow chimeras in which total body irradiated WT mice were transplanted with HPCs from a mouse expressing green fluorescent protein (GFP) in their somatic cells.
cord-283382-t890r7xp	2020	
cord-283505-ousbar6c	2020	To elucidate the cellular immune mechanisms associated with disease severity and progression, we used a ferret model to closely resemble disease outcomes in humans following influenza virus infection. In this study, we aimed to examine the ferret immune response to H7N9 influenza virus infection by analyzing leukocyte population variation associated with disease pathogenesis. While the day 6 ferret which showed worsened disease progression did exhibit the most severe lung pathology, the lack of viral antigen in and around these lesions (Supplementary Figure 1) means they cannot conclusively be classified as being caused by the influenza infection, and thus we are hesitant to classify disease presentation in this ferret as like a high pathogenicity infection based on the histopathology findings regardless of the increase in clinical signs. Highly pathogenic avian influenza virus infection in chickens but not ducks is associated with elevated host immune and pro-inflammatory responses
cord-284156-btb4oodz	2017	Retinoic acid-inducible gene-I (RIG-I) is critical in triggering antiviral and inflammatory responses for the control of viral replication in response to cytoplasmic virus-specific RNA structures. They function as cytoplasmic sensors for the recognition of a variety of RNA viruses and subsequent activation of downstream signaling to drive type I IFN production and antiviral gene expressions. (c) Interactions between RIG-I-TRIM25 complex and 14-3-3ϵ promote RIG-I translocation to mitochondrial mitochondrial antiviral signaling protein (MAVS) for downstream signaling, leading to interferon production. Protein purification and mass spectrometry analysis identified that phosphorylation of Thr170 in the CARDs antagonizes RIG-I signaling by inhibiting TRIM25-mediated Lys172 ubiquitination and MAVS binding (68) . Ebola virus VP35 protein binds double-stranded RNA and inhibits alpha/beta interferon production induced by RIG-I signaling Inhibition of dengue and chikungunya virus infections by RIG-I-mediated type I interferon-independent stimulation of the innate antiviral response
cord-284409-xiyeceib	2014	
cord-284867-p4jgyusp	2020	Altogether, the SARS-CoV-2 icELISA test allows rapid (<48 h in total, read-out in seconds) and automated quantification of virus infection in cell culture to evaluate the efficacy of NAbs and antiviral drugs using reagents and equipment present in most routine diagnostics departments. The fact that the infection and the resulting icELISA signal were neutralized by NAbs present in immune sera indicated that the fast and automated icELISA format is applicable for icNTs. Although most SARS-CoV-2 NTs have not been formally validated and certified, classic plaque reduction neutralization tests (PRNT) are currently considered to represent the gold standard for the detection of SARS-CoV-2-specific NAbs. Various commercially available IgM, IgA, and IgG ELISAs have been compared to PRNTs [e.g., (30) ]. Given the excellent signal-to-noise ratio between infected and uninfected cells, the test was applicable to quantify the efficacy of antiviral compounds, here shown for IFNb, and SARS-CoV-2-specific NAbs present in immune sera.
cord-285760-y37ji92k	2020	
cord-286337-qk90xb3a	2018	
cord-288496-7rrh2gg6	2020	
cord-291941-9a4tt4f7	2020	Herein, we discuss the current state of MAIT cell characterization in NHPs [which has focused on rhesus macaques (RM), pigtail macaques (PTM), and Mauritian cynomolgus macaques (MCM)] and the changes in MAIT cell populations that occur during simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) infection, which are the critical animal models for HIV infection. MAIT cells are consistently maintained at low frequencies in secondary lymphoid organs (lymph nodes and spleen) compared to the peripheral blood, in both humans and NHPs. This is attributed to the relative lack of CCR7 and CD62L expression, both required for lymphoid tissue homing, on peripheral MAIT cells [reviewed in Kurioka et al. The lack of MAIT cell depletion during acute infection is consistent with what has been observed in humans during initial HIV infection and emphasizes the importance of the NHP-SIV/SHIV model to study MAIT cell dynamics during peracute infection.
cord-293736-nyvwv31m	2020	
cord-295302-vwrxentv	2020	While studying the human public IgM igome as represented by a library of 224,087 linear mimotopes, three exact matches to peptides in the proteins of SARS-CoV-2 were found: two in the open reading frame 1ab and one in the spike protein. For the present study, the degrees of the vertices representing the natural SARS-CoV-2 epitopes, all of which belonged to the giant component, were used as the number of adjacent mimotopes parameter. A simple comparison for exact matches to peptides from the SARS-CoV-2 proteome yielded 3 heptapeptides-two in the open reading frame 1ab ( 3518 AQTGIAV 3524 and 5198 TKGPHEF 5204 ) and one in the spike protein ( 108 TTLDSKT 114 ). This loop is adjacent to the loop representing the epitope of the neutralizing antibody LCA60 on the SARS-CoV spike (8, 9) . Thus, it is quite possible that the SARS-CoV-2 spike epitope TTLDSKT is bound by B cells that will contribute to the induced immune response.
cord-295416-y3lvcjqd	2020	
cord-296585-yfh5d4io	2018	
cord-297790-tpjxt0w5	2018	
cord-297960-4x1j0iqg	2019	
cord-298458-p7rvupjo	2018	CD8 T cells play a critical role in mediating viral clearance following many respiratory virus infections including RSV, IAV, and HMPV (25) (26) (27) . In addition, recent murine studies utilizing CD8 T cell epitope-specific immunization strategies observed significantly reduced lung viral titers following IAV, RSV, or SARS challenges (28) (29) (30) . Prime-boosted mice exhibited significantly reduced lung viral titers following RSV, IAV, or SARS infections compared to controls lacking virus-specific memory CD8 T cells. In addition to causing disease in acute respiratory infections, IFN-γ produced by memory CD8 T cells mediated the severe and fatal immunopathology following RSV infection of DC-LM prime-boosted mice (30) . Additionally, robust memory CD8 T cell responses efficiently reduced lung viral titers in the absence of neutralizing antibodies following RSV, IAV, or SARS secondary infections. Despite their benefits in mediating viral clearance and providing protection against secondary infections, memory CD8 T cell responses have been associated with the induction of immunopathology following respiratory virus infections.
cord-298604-tn8hc6jv	2020	Finally, we observed NET-like structures in IPF lung sections and in the BAL from ILD patients, and quantification showed increased cell-free DNA content (+5.5-fold, p < 0.01) and MPO-citrullinated histone H3 complexes (+21.9-fold, p < 0.01) in BAL from ILD patients compared to non-ILD controls. Finally, we observed NET-like structures in IPF lung sections and in the BAL from ILD patients, and quantification showed increased cell-free DNA content (+5.5-fold, p < 0.01) and MPO-citrullinated histone H3 complexes (+21.9-fold, p < 0.01) in BAL from ILD patients compared to non-ILD controls. We measured neutrophil adhesion to primary human endothelial cells in the absence or presence of PMA (a general integrin activator) or LPS (to mimic infectious stimuli), stimuli that induce NETs via distinct pathways (42) . We report, for the first time, that neutrophils and endothelial cells in ILD lung biopsies display HIF-1α expression and provide evidence of the extracellular release of nuclear DNA, citrullinated histones and MPO, indicative of NET formation in the ILD lung.
cord-300429-b0zev8zb	2018	We highlight recent data on protein S-palmitoylation in pathogens and their hosts obtained owing to the development of methods based on click chemistry and acyl-biotin exchange allowing proteomic analysis of protein lipidation. Given the large variety of chemical reporters preferentially mimicking distinct fatty acids, recent years have witnessed a plethora of chemistry-based proteomic studies not only on palmitoylated but also myristoylated proteins and proteins bearing the GPI anchor, including those of pathogens and immune cells (10, 14, 85, 86, 114) The aBe Method Reveals Protein The envelope is rich in transmembrane, often S-palmitoylated, glycoproteins called spikes, which can bind to cognate receptors on the host cell plasma membrane triggering endocytosis of the virion, mediate subsequent fusion of the viral and cellular membranes allowing entry of the viral genome to the cytoplasm, and are also involved in the budding of newly formed virus particles from the cell.
cord-302295-nblmshni	2013	
cord-303017-4zx94rm6	2020	
cord-304619-tpv76833	2020	A complex, rapidly evolving biomedical field that is of critical relevance to human health and well-being, immunology provides important and substantive opportunities to practice and teach the central tenets of a liberal arts curriculum. Iteratively learning to read the often dense and technical immunological literature and synthesizing and communicating these findings in their own written and spoken words is both preparation for future work in biomedical fields and a core tenet of a liberal arts education-the importance of listening, reading, speaking, arguing, and writing. However, they also write white papers and reflective essays connecting their learning in immunology to other disciplines, prepare educational materials for community organizations, teach secondary school students and mentor younger peers and, in doing so, practice translating the technical jargon of scientific communication into information that their audiences need and can use. Teaching about our immune systems in integrative, socially relevant ways can help our students make meaningful connections between the content of their learning and the larger global context in which they live.
cord-304623-j9ay4jkf	2020	We review the past, present and future of the veterinary immunological toolbox with specific reference to recent developments discussed at the International Union of Immunological Societies (IUIS) Veterinary Immunology Committee (VIC) Immune Toolkit Workshop at the 12th International Veterinary Immunology Symposium (IVIS) in Seattle, USA, 16–19 August 2019. The success of the HLDA workshops was based on good co-ordination, high-quality work and collective effort by the veterinary immunology community, as well as results from past species-specific CD workshops supported by IUIS VIC. A barrier to formal international collaboration was lifted in 2013 when USDA/NIFA and BBSRC launched a pilot call to support animal disease research of strategic importance to both the US and UK which included the development of veterinary immunological reagents for agriculturally-relevant animal species. To date, the concept of the veterinary immunological toolbox has largely (but not exclusively) focused on reagent development for livestock species due to their strategic relevance for funders with a stake in livestock health, food safety and global food security.
cord-304626-ffao7vka	2020	A better understanding of this virus-host interplay and its contribution to pathogenesis has previously led to: the identification of genetic factors which influence viral infection and disease outcome, the development of novel antivirals, and the production of safer, more effective vaccines. Infected host cells which present viral antigens on the cell surface membrane can activate the classical pathway, as the antigens bind IgM/IgG to induce complement dependent cytotoxicity (CDC). Non-neutralizing antibodies can still bind the viral target with the potential to cross-link with Fc receptors, or activate complement and interact with complement receptors, to enhance viral infection of host cells (241) . Use of the non-neutralizing influenza virus M2 extracellular vaccine in mice required functional C3 to confer protection and induce effective humoral and cell-mediated immune responses (245) .
cord-305936-tdswzj7r	2018	Despite not controlling for comorbidities, climate, and vaccination, for the >70 years, ratio of respiratory diseases excess mortality rates between AH1N1 (2009) and severe year of H3N2 (2007) shows protection in the pandemic year and great vulnerability during AH3N2 virus predominance. We analyzed particularly the most predominant variants (AH1N1 and AH3N2) on excess of mortality in the adults and elderly of different age groups in a region with marked seasonality of respiratory diseases in Brazil. Among adults (24-59 years), we observe a large excess of deaths rates during the 2009 pandemic (953 obits), which correspond to 7.1 excess deaths from all causes, and 99 excess mortality from respiratory diseases associated with viral infection in every 100,000 individuals of the age group. Although the elderly are the most vulnerable group to viral respiratory infections, we found relative small excess of deaths in years of circulating AH1N1 pre pandemic (2002 and 2008) .
cord-306600-cxz8hf9q	2019	Previous studies of the TLR5 agonist flagellin in animal models showed that standalone TLR stimulation does not result in the effective treatment of pneumococcal respiratory infection but does significantly improve the therapeutic outcome of concomitant antibiotic treatment. Previous studies of the TLR5 agonist flagellin in animal models showed that standalone TLR stimulation does not result in the effective treatment of pneumococcal respiratory infection but does significantly improve the therapeutic outcome of concomitant antibiotic treatment. pneumoniae lung infection, we recently demonstrated that combination treatment with mucosally administered flagellin and an orally or intraperitoneally administered low-dose (i.e., subtherapeutic) antibiotic is more effective than the antibiotic alone (i.e., with a lower bacterial load in the lung, and a lower mortality rate). Our data showed that several antimicrobial peptides (S100A9), cytokines (IL-1β and TNF), and chemokines (CCL20, CXCL1, and CXCL2) that were associated to epithelial responses are also upregulated after the administration of the combination treatment in the post-flu superinfection model, suggesting that the epithelium is also an important flagellin-specific driving force in the lung damaged by viral and bacterial infections.
cord-307813-elom30nx	2018	Besides controlling virus replication, potential targets for drug development include controlling virus-induced host immune responses such as the recently suggested involvement of innate lymphoid cells and NADPH oxidases in influenza virus pathogenesis and immune cell metabolism. Besides controlling virus replication, potential targets for drug development include controlling virus-induced host immune responses such as the recently suggested involvement of innate lymphoid cells and NADPH oxidases in influenza virus pathogenesis and immune cell metabolism. A recent study using RNAi also demonstrated that cholesterol homeostasis can be regulated via acid phosphatase 2 (ACP2)-mediated Niemann-Pick C2 activity and impaired the membrane fusion of IAV and influenza B virus (IBV) (52) , further suggesting the importance of controlling cholesterol homeostasis in the release of viral genome to cytoplasm. Furthermore, FPR2 antagonists have been described to possess antiviral activity against not only IAV but also IBV infection (111) , promoting the idea that antagonizing FPR2 to suppress Raf/MEK/ERK signaling cascade could potentially be a novel approach for the treatment of a broad spectrum of influenza viruses.
cord-308433-vrkdtrfz	2017	Addition of the TNFi drug adalimumab to anti-CD3-stimulated human CD4 + T cell/monocyte cocultures led to increased percentages of IL-10 + cells in pro-inflammatory IL-17 + , IFNγ + , TNFα + , GM-CSF + , and IL-4 + CD4 + T cell subpopulations. Addition of the TNFi drug adalimumab to anti-CD3-stimulated human CD4 + T cell/monocyte cocultures led to increased percentages of IL-10 + cells in pro-inflammatory IL-17 + , IFNγ + , TNFα + , GM-CSF + , and IL-4 + CD4 + T cell subpopulations. To investigate whether TNF blockade regulates IL-10 expression in different pro-inflammatory cytokine-producing CD4 + T cells, we isolated CD4 + T cells from PB of healthy donors and cocultured the cells with CD14 + monocytes and anti-CD3 mAb (100 ng/ml) in the absence or presence of the anti-TNF mAb adalimumab (1 µg/ml), as previously described (20) .
cord-312074-0nqmjdek	2015	Liebler showed that DPP4 inhibition enhances SDF-1/CXCR4 axis and increased the retention of human bone marrow-derived cells in the injured lungs of immune deficient mice by 30% (71) . It has been shown that parathyroid hormone treatment after myocardial infarction improves DPP4 in chemotaxis and cardiovascular disease Frontiers in Immunology | www.frontiersin.org survival and myocardial function with potential involvement of enhanced homing of bone marrow-derived stem cells. demonstrated that parathyroid hormone serves as a DPP4 inhibitor and increases cardiac SDF-1 level, which in turn enhances CXCR4 + bone marrow-derived stem cell homing to ischemic heart and attenuates ischemic cardiomyopathy after infarction (91) . Suppression of DPP4 enzymatic activities by pharmacological inhibitors preserves SDF-1, which results in an enhanced homing of CXCR4 + progenitor cells from bone marrow to infarcted tissues.
cord-312075-asbt0mcj	2016	
cord-312438-zr9zx7pv	2020	
cord-312955-gs65c3fy	2020	Although SARS-CoV-2 inhibits the production of IFNβ and thus obstructs the innate immune response to this virus, it is sensitive to the antiviral activity of externally administrated IFN-Is. In this review I discuss the diverse modes of biological actions of IFN-Is and how these are related to biophysical parameters of IFN-I–receptor interaction and cell-type specificity in light of the large variety of binding affinities of the different IFN-I subtypes towards the common interferon receptor. Thereby, it inhibits the nuclear transport of phosphorylated STAT1, rendering cells refractory to IFN-Is. Another example of viral mechanisms that evolved to eliminate IFN-I functions in inducing innate immunity is given by the SARS corona virus, where both the production of IFNb and the IFN-I induced signaling are attenuated. This gene was found to preferentially cleave the ubiquitin-like modifier interferon-stimulated gene 15 (ISG15), FIGURE 4 | SARS-CoV-2 has multiple effects on the immune system, including inhibition of IFNb production, which results in ISGs not to be produced, CD4+ and CD8+ exhaustion and increased levels of pro-inflammatory proteins (TNFa, IL6, NF-kB).
cord-313117-0qur0isb	2020	To address such issues, recent studies have reported transcriptomic profiles of cells, tissues and fluids from COVID-19 patients that mainly demonstrated activation of humoral immunity, dysregulated type I and III interferon expression, intense innate immune responses and inflammatory signaling. To address such issues, recent studies have reported transcriptomic profiles of cells, tissues and fluids from COVID-19 patients that mainly demonstrated activation of humoral immunity, dysregulated type I and III interferon expression, intense innate immune responses and inflammatory signaling. In addition, our approach also detected increased signals of monocytes (Figure 1B) , dendritic cells ( Figure 1C ) and of the mitochondrial respiratory electron transport chain in SARS-CoV-2 infection (Figure 1A) , suggesting a critical role of metabolic pathways for the immune response of COVID-19 patients.
cord-313227-6zwkfzab	2020	Interestingly, in patients infected by SARS-COv-2, there is an increase in IL1β, IFNγ, IP10, and MCP1, probably leading to activated T-helper-1 (TH1) cell responses, and increased production of T-helper-2 (TH2) immunosuppressive cytokines, such as IL4 and IL10 (18) . Peripheral blood examinations on admission in the majority of patients with COVID-19 displayed lymphopenia, elevated infection-related biomarkers (i.e., procalcitonin, erythrocyte sedimentation rate, serum ferritin, and C-reactive protein) (20) and several elevated inflammatory cytokines (i.e., tumor necrosis factor (TNF)-α, interleukin (IL)-2R and IL-6). Despite markedly reducing virus titers, anti-S-IgG caused lung injury during the early stages of infection, impairing the wound-healing macrophage response and TGF-β production, while promoting pro inflammatory cytokine IL-8, MCP1 production, and inflammatory macrophage accumulation (22) . Another proteasome inhibitor, VR23, possess powerful antiinflammatory activity reducing IL-6 in synovial cells from RA patients, and improving LPS-induced acute lung injury by decreasing neutrophil migration, TNF-α secretion, and tissue inflammation in a mice model (52) .
cord-313431-swkcdvx8	2020	The opposite effects seen in different inflammatory contexts highlight the need for a deeper and broader study of the androgen/ARmediated modulation of monocytes and macrophages, as these cells participate in both the initial and late phases of immune responses in a variety of diseases. Studies of androgen receptor function in human monocytes and macrophages have focused primarily on the roles of male sex and sex hormones in promoting atherosclerotic foam cell formation (196) and inhibiting cutaneous wound healing (186, 215) . There is a paucity of literature regarding how introducing or depleting exogenous sex hormones (such as in female-to-male transgender individuals receiving testosterone supplementation or women with estrogen blockade) affects the function of blood monocytes and lung macrophages in men and women with asthma. Modulation of monocyte and macrophage function mediated by the interaction of androgen and AR has been examined mostly by correlative studies in humans following lifespan changes in sex hormones or using hormonal manipulation in mouse models of lung disease.
cord-316702-dj2fo8sn	2020	Since many studies from different geographical locations are documenting preexisting immunity to SARS-CoV-2, it will be important to define specificities of these T and B cell immune response carefully to assess their association with COVID-19 disease severity. This preexisting cross-reactive T and B cell immunity to SARS-CoV-2 may have wide implications as this could explain differential clinical outcomes in COVID-19 patients, disease severity, vaccine development, and important in accessing herd immunity for SARS-CoV-2 viral infection/COVID-19 disease. Several studies have provided strong evidence for the importance of SARS-CoV-2 specific CTLs, and T helper cells in mild and moderate patients compared to severe COVID-19 disease (27, 28, (31) (32) (33) . Several studies have provided strong evidence for the importance of SARS-CoV-2specific neutralizing antibodies in association with less disease severity in COVID-19 patients (38, 39) . A recent modelling study has estimated that about one in five individuals worldwide would be at increased risk of severe COVID-19, upon infection with SARS-CoV-2, owing to the underlying conditions.
cord-317797-h229skaq	2020	For example, thrombocytopenia in children following varicella zoster virus infection first described antigenic mimicry for some microbial pathogens that encompass host generation of crossreactive antibodies to certain glycoproteins (e.g., GPIIIa) on the platelet surface, resulting in accelerated platelet clearance (117) . In addition to the effects on platelet count and function, microbial pathogens impact the host auto-and alloimmune response to platelet antigens in several immune-mediated diseases, such as immune thrombocytopenia (ITP), and fetal and neonatal alloimmune thrombocytopenia (FNAIT) (99-101) (Figure 3) . C-reactive protein is markedly upregulated during acute infections and inflammation (178) , and it has been shown that C-reactive protein, via binding to platelet phosphorylcholine residues, enhanced the IgG-mediated phagocytic responses against platelets and thereby thrombocytopenia, which has implications in the pathogenesis of both ITP and FNAIT (123, 124) .
cord-318418-uqxzds6g	2017	title: Dietary Probiotic Compound Improves Reproductive Performance of Porcine Epidemic Diarrhea Virus-Infected Sows Reared in a Japanese Commercial Swine Farm under Vaccine Control Condition Hence, here we evaluated the efficacy of administration of a probiotic compound containing Bacillus mesentericus, Clostridium butyricum, and Enterococcus faecalis together with a commercial live-attenuated PED vaccine (Nisseiken PED Live Vaccine, Nisseiken, Tokyo, Japan) to improve the health and reproductive performance of PED-infected sows. The aim of the present study was to evaluate the efficacy of the aforementioned probiotic compound mixed with peptide-zinc to improve the health and reproductive performance of PEDinfected lactating sows when administered along with a PED vaccine injection in Japan. Nonetheless, in the present work, probiotics supplementation significantly improved the concentration of total IgA and IgG in the milk of sows than did PED vaccination alone, possibly resulting from stimulation of gut immunity by bacteria in the administered probiotic compound (Figures 5A,B) .
cord-318630-h6j7iqbm	2015	In our studies, we have shown that cytotoxic/suppressor CD8(+) T-cells are CNS antigen-specific, MHC class I-restricted, IFNγand perforin-dependent, and are able to inhibit disease. iNTRODUCTiON Studies addressing the immunobiology of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) have focused on CD4 + T-cells as the main orchestrators of pathogenesis and regulation. Interestingly, immune deviation can be elicited against myelin antigens (61, 62) , pointing to the potential role for Qa-1-restricted CD8 + T-cells in EAE disease. We have also demonstrated that GA treatment induces CD8 + Treg in mice, and that these CD8 + T-cells are required for GA to be therapeutically effective in ameliorating EAE disease (64) . Furthermore, relapses in MS are associated with significantly lower CNS-specific CD8 + T-cell suppressor ability, while this potential in MS patients during quiescence is similar to healthy donors, suggesting a role with disease activity (5) .
cord-319729-6lzjhn8j	2018	title: Lab-Attenuated Rabies Virus Causes Abortive Infection and Induces Cytokine Expression in Astrocytes by Activating Mitochondrial Antiviral-Signaling Protein Signaling Pathway Activation of mitochondrial antiviral-signaling protein (MAVS), the common adaptor molecule for RIG-I and MDA5, results in the production of type I interferon (IFN) and the expression of hundreds of IFN-stimulated genes, which suppress RABV replication and spread in astrocytes. Activation of mitochondrial antiviral-signaling protein (MAVS), the common adaptor molecule for RIG-I and MDA5, results in the production of type I interferon (IFN) and the expression of hundreds of IFN-stimulated genes, which suppress RABV replication and spread in astrocytes. To assess innate immune responses in astrocytes, cells were infected with DRV or B2c at an MOI of 0.1 and the expression of several proteins involved in the MAVS signaling pathway, namely, RIG-I, p-IRF7, STAT1 and IFIT1 (ISG56), was measured by Western blot.
cord-319774-mkz7z38o	2016	The selectivity of the adaptive immune response is based on the enormous diversity of T and B cell antigen-specific receptors. During the past two decades, however, technical advances in high-throughput sequencing (HTS), also known as next-generation sequencing (NGS), along with evolving bioinformatic and statistical tools, have provided a new approach capable of analyzing the immune repertoire at the single sequence level. The depth and comprehensiveness of high-throughput immune repertoire sequencing are greater than ever, and the enormous sequencing data of disease-specific TCR/BCR clones provide great potential for the revealing dynamic changes in clonality during infectious states. Decrease in the overall diversity of the immune repertoire have been observed after various antigen exposures, including HIV, influenza, and human herpes virus, which implies expansion of particular T/B cell clones (67, 88, 92, 93) . Pairing the heavy and light chains as an integrated antibody has been another challenge for HTS-based immune repertoire analysis.
cord-320431-0877trhh	2020	In case of asthma, all these functions are impaired by the already existing allergic immune response that per se weakens the barrier integrity and self-cleaning abilities of the airway epithelium making it more vulnerable to penetration of allergens as well as of infection by bacteria and viruses. Besides this innate "rapid response team, " the polarized epithelium of the human airways is also able to transport and apically release immunoglobulins that carry a J-chain (joining chain) by using its poly Ig receptor (pIgR) (145) (146) (147) that is expressed by all non-stratified epithelial cells (Figure 2) . After contact for example with HDM extracts, representing a major source of asthma associated allergens, TLR4 dependent activation of NFκB and protease induced injuries in airway epithelial cells lead to secretion of chemokines and cytokines like thymic stromal lymphopoietin (TSLP), GM-CSF, IL-25, and IL-33 (211) (212) (213) (214) (215) .
cord-320474-jyk7zphp	2020	Initial findings from patients with COVID-19 treated with a single intravenous dose of mavrilimumab, a monoclonal antibody binding GM-CSF receptor α, showed oxygenation improvement and shorter hospitalization. Data supporting the role of hyperinflammation in sepsisrelated acute respiratory distress syndrome (ARDS) are derived from a sub-group analysis of a phase 3 randomized controlled trial of IL-1 receptor antagonist (anakinra), which showed significant survival benefit in patients treated with anakinra compared to placebo (15) . APC, antigen presenting cell; DC, dendritic cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. A randomized, double-blind, placebo-controlled phase II study tested the effects of low-dose hrGM-CSF (molgramostim, 3 µg/kg daily) for 5 days in patients in addition to the standard of care in critically ill patients with severe sepsis and respiratory dysfunction (65) .
cord-320663-xypg6evo	2020	
cord-321401-w4ne60fn	2020	Evidence for this immunomodulatory and protective role is derived from observational studies showing an association between vitamin D deficiency, chronic airway diseases and respiratory infections, and is supported by a range of experimental studies using cell culture and animal models. Furthermore, recent intervention studies have now shown that vitamin D supplementation reduces exacerbation rates in vitamin D-deficient patients with chronic obstructive pulmonary disease (COPD) or asthma and decreases the incidence of acute respiratory tract infections. Increasing evidence has indicated that vitamin D deficiency is also associated with various other diseases such as cancer, cardiovascular disease, Alzheimer''s disease and muscle myopathy, as well as several immune-related diseases such as type 1 diabetes, multiple sclerosis, inflammatory bowel disease (IBD), psoriasis and chronic inflammatory lung diseases including asthma, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD) (6) (7) (8) (9) .
cord-321568-okvt1fg3	2020	
cord-323590-m4jsu1q5	2020	The COVID-19 pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has generated a significant repercussion on the administration of adoptive cell therapies, including chimeric antigen receptor (CAR) T-cells. The aim of this mini-review is to focus on how the COVID-19 pandemic has affected CAR T-cell therapy and taking into consideration the differences between the large-scale centralized productions for the pharmaceutical industry versus product manufacturing in the academic/hospital environment. Therefore, the aim of this mini-review is to focus on how the effects caused by the pandemic have affected this therapy taking into consideration the differences between the large-scale centralized production of CAR T-cells by the pharmaceutical industry versus the product manufacturing processes employed by the academic/hospital environment. We also review different aspects of CAR T-cell therapy, including patient selection and resource prioritization performed in our center during the COVID-19 pandemic.
cord-323756-atnrw9ew	2013	When Janeway formulated the theory of pattern recognition in 1989, he proposed that host cells could sense microbial infection owing to receptors able to recognize invariant molecular structures defined as pathogen-associated molecular patterns (PAMPs). They share a similar organization with three distinct domains: (i) a C-terminal repressor domain (RD) embedded within the C-terminal domain (CTD); (ii) a central ATPase containing DExD/H-box helicase domain able to bind RNA; and (iii) a N-terminal tandem CARD domain that mediates downstream signaling, and which is present in RIG-I and MDA5 but absent in LGP2. DDX60 has also been shown to enhance the IFN-I response to RNA and DNA stimulation through formation of complexes with Frontiers in Immunology | Molecular Innate Immunity RIG-I, MDA5, and LGP2 but not with MAVS. Structural basis for the activation of innate immune pattern-recognition receptor RIG-I by viral RNA Nonself RNA-sensing mechanism of RIG-I helicase and activation of antiviral immune responses
cord-325129-faptufak	2020	Autoactivation of FXII by contact with SARS-CoV-2 could lead to activation of intrinsic coagulation, with fibrin formation (microthrombosis), and fibrinolysis, resulting in increased D-dimer levels. In this review, we try to address the complex link between the pathophysiology of COVID-19 and the different proteolytic defense systems operating in human vasculature, investigating the role of the mediators involved and speculating on the possibility of pharmacological modulation. After binding through its B2R, BK activates signaling pathways resulting in increased vascular permeability, vasodilation, edema formation, hypotension, pain, fever (14) : all typical clinical features of COVID-19. (79) hypothesized that a kinin-dependent local lung angioedema via B1R and eventually B2R is an important feature of COVID-19 and proposed that blocking the B2R and inhibiting plasma KAL activity might be beneficial in early disease, preventing ARDS.
cord-325353-tx6s4ggu	2018	The goals of this review are (1) to outline the differences between the neonatal and adult immune systems and (2) to present murine and human data that support the hypothesis that early-life interactions between the immune system and respiratory viruses can create a lung environment conducive to the development of asthma. Because RSV, influenza, and RVs cause a large proportion of respiratorytract infections in neonates, we will focus primarily on these three pathogens as models to better understand how early-life infection and antiviral immune responses might contribute to the subsequent development of asthma. The addition of RSV infection of airway epithelial cells with production of the type-2 innate cytokines, IL-33 (138) , TSLP (123) , and IL-25 (128) , would, therefore, be predicted to create an even more exaggerated type-2-biased microenvironment in the lung with activation of other immune cells (e.g., M2 macrophages, DCs, and/or ILC2 cells) and the development of AHR.
cord-328003-yovp8squ	2020	Here, we provide a comprehensive overview of the wealth of research related to the SARS-CoV-2 S glycoprotein biosynthesis, structure, function, and antigenicity, aiming to provide useful insights into the design and development of the S protein-based vaccines as well as therapeutics to prevent or treat the ongoing global spread of SARS-CoV-2/COVID-19. Prefusion structures of human coronavirus HKU1 (HCoV-HKU1) and mouse hepatitis virus S protein ectodomains without two consecutive proline mutations reveal only fully closed conformation (37, 42) , similar to that observed for a full-length, wild-type prefusion form of the SARS-CoV-2 S glycoprotein (41) . Therefore, SARS-CoV-2 evades immune surveillance also through conformational masking, which is well-documented for HIV-1 (43, 44) ; while at the same time, the S protein could transiently sample the functional state to engage ACE2, consistent with the notion that the fusion glycoprotein of highly pathogenic viruses have evolved to perform its functions while evading host neutralizing antibody responses.
cord-328011-6lf3no6u	2020	title: Vaccine Development Against COVID-19 Prior to Pandemic Outbreaks, Using in vitro Evolution and Reverse Genetics Since coronaviruses are increasing alarmingly, there is an urgent need for a safe and effective vaccine to prevent the spread of the virus during pandemic outbreaks, and stop deaths associated with the virulent COVID-19. We now know that SARS-CoV-2 shares 88% identity with two SARS-like coronaviruses (bat-SL-CoVZXC21 and bat-SL-CoVZC45) that both originated in China, and use the same human angiotensin-converting enzyme 2 receptor for cell entry during the process of infection (3). In response to such forewarnings from scientists, a predictive vaccine could have been designed and developed for the potential virus pandemic. Thereafter, during the time of pandemic, suitable stored transgenic cell lines could be used, based on the Abbreviations: COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; VLP, virus-like particle; WHO, World Health Organization.
cord-328549-r56lih8j	2018	First, it was reported that TRIM25 ubiquitin ligase delivered K63-linked polyubiquitin moiety to the 2CARDs. The polyubiquitin chain stabilizes a structure called the 2CARD tetramer, in which four 2CARDs assemble and make a core that promotes the aggregation of the mitochondrial antiviral-signaling (MAVS) protein on mitochondria. First, it was reported that TRIM25 ubiquitin ligase delivered K63-linked polyubiquitin moiety to the 2CARDs. The polyubiquitin chain stabilizes a structure called the 2CARD tetramer, in which four 2CARDs assemble and make a core that promotes the aggregation of the mitochondrial antiviral-signaling (MAVS) protein on mitochondria. However, subsequent studies have reported that Riplet, MEX3C, and TRIM4 ubiquitin ligases are also involved in K63-linked polyubiquitination and the activation of RIG-I. However, recent studies have reported three other ubiquitin ligases, RING finger protein leading to RIG-I activation (Riplet), mex-3 RNA-binding family member C (MEX3C), and TRIM4, which are required for the polyubiquitination and activation of RIG-I (28-30).
cord-328763-hcbs20a0	2020	
cord-330417-8nnobx8g	2020	Following the hypothesis that T cells in COVID-19 might have a similar, dual function, we comprehensively characterized the differentiation (CCR7, CD45RO) and activation status (HLA-DR, CD38, CD69, CD226), the co-expression of co-inhibitory molecules (PD1, TIM-3, LAG-3, BTLA, TIGIT), as well as the expression pattern of the transcription factors T-bet and eomes of CD8 + and CD4 + T cells of PBMC of n = 20 SARS-CoV-2 patients compared to n = 10 P. Following the hypothesis that T cells in COVID-19 might have a similar, dual function, we comprehensively characterized the differentiation (CCR7, CD45RO) and activation status (HLA-DR, CD38, CD69, CD226), the co-expression of co-inhibitory molecules (PD1, TIM-3, LAG-3, BTLA, TIGIT), as well as the expression pattern of the transcription factors T-bet and eomes of CD8 + and CD4 + T cells of PBMC of n = 20 SARS-CoV-2 patients compared to n = 10 P.
cord-332150-j76726no	2020	The main challenge for effective administration of anti-cytokine therapy in COVID-19 will be therefore to better define a precise "window of therapeutic opportunity." Only considering a more specific set of criteria able to integrate information on direct viral damage, the cytokine burden, and the patient''s immune vulnerability, it will be possible to decide, carefully balancing both benefits and risks, the appropriateness of using immunosuppressive drugs even in patients affected primarily by an infectious disease. Discovery of virus and host genomic factors will undoubtedly support risk stratification and targeted treatment; however, as genomic studies require long times before entering clinical practice, it is urgent to integrate easily accessible information on the dynamics and pathogenicity of the immune response during the different phases of SARS-CoV-2 infection. Accordingly, longitudinal immune profiling of hospitalized COVID-19 cases with different outcomes has recently shown that, despite similar levels of inflammatory cytokines in the first 10 days from symptom onset, patients with less severe disease evolution also express mediators of wound healing and tissue repair (41) .
cord-333041-69n2wwn3	2020	Obesity is a major independent risk factor for increased morbidity and mortality upon infection with Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), which is responsible for the current coronavirus disease pandemic (COVID-19). We further discuss how the effects of obesity upon SARS-CoV-2 infection are likely exacerbated with environmental exposures that promote chronic pulmonary inflammation and augment SPM deficits. Obesity is an independent risk factor for increased morbidity and mortality upon infection with the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) responsible for the current COVID-19 pandemic. The SPM precursor 17-hydroxydocosahexaenoic acid (17-HDHA) increased antibody levels and improved survival upon pH1N1 influenza vaccination and infection in lean mice by promoting B cell differentiation toward the formation of CD138 + long-lived antibody secreting cells (18) . Taken together, these data suggest that the susceptibility of obese individuals to environmental lung diseases may drive an altered pulmonary immune response and a state of SPM deficiency that increases the morbidity and mortality to respiratory infections, including COVID-19.
cord-333670-qv1orlv5	2020	In Italy, the possibility of performing autopsies or post-mortem diagnostic studies on suspect, probable, or confirmed COVID-19 cases has been intensively debated (5, 6) ; however, postmortem pathological analysis of COVID-19 patients in China has shown findings consistent with Acute Respiratory Distress Syndrome (ARDS) (7-9) (Figure 1 ). Consistently, recent results indicate that a systemic immune dysregulation that triggers auto-sustaining inflammatory lung damage, causing fatal respiratory-failure and consequent multiorgan-failure, is the main virus-related-death cause in patients who develop SARS-CoV-2 (10). Overall, understanding the role of pro-inflammatory cytokines certainly unravels a new battleground against the lethal clinical effect of CODIV-19 infection; this, along with the identification of a high-risk autoimmune profile, including the genotyping of Class I and II HLA, which have a key role in shaping the anti-viral immune response and Th1/Th2 lymphocyte subset response (Figure 1) , and immune-profiling, could also help to prevent these dangerous evolutions of the disease (29) .
cord-333932-aqcllik0	2020	Methods: We retrospectively reviewed the counts of T cells and serum cytokine concentration from data of 522 patients with laboratory-confirmed COVID-19 and 40 healthy controls. Our results thus provide a preliminary demonstration of T cell exhaustion during COVID-19 infection and suggest that more urgent, early intervention may be required in patients with low T lymphocyte counts. The expression of angiotensin converting enzyme 2 (ACE2), the predicted receptor of SARS-CoV-2 viruses, is absent on T cells (11) , suggesting that the depressed T counts in COVID-19 patients mentioned above (Figure 1 ) were likely not caused by direct infection of T cells. We demonstrate here that COVID-19 patients have very high levels of serum IL-10 following SARS-CoV-2 infection, while also displaying high levels of the PD-1 and Tim-3 exhaustion markers on their T cells, suggesting that IL-10 might be mechanistically responsible.
cord-334564-bqh9jkds	2020	Since COVID-19 is associated with increased levels of pro-inflammatory cytokines (8) , an immune signature shared with several psychiatric disorders, we propose how the relationship between SARS-CoV-2/host can possibly impair interactions between the immune, nervous and endocrine systems, leading to psychiatric symptoms. Several studies have demonstrated psychiatric manifestations in patients with MERS or SARS during the acute phase, such as increased stress levels, impaired memory, symptoms of depression, anxiety, PTSD, psychoses, and suicidal behavior (28) (29) (30) (31) (32) (33) . If the increase in cytokine levels and the manifestation of psychiatric symptoms are related to the severity of the symptoms of SARS-CoV infection, the "cytokine storm" might also be related to the "mental health thunderstorms" seen in patients with COVID-19? Similar to possible mechanisms involved in the impacts of SARS-CoV-2 infection on mental health, social isolation may also be associated with dysfunctional psycho-neuroendocrine-immune interactions, which in turn can contribute to the development or the worsening of psychiatric disturbances (Figure 2) .
cord-336201-fl606l3b	2020	Obesity-related immune cell infiltration, inflammation, and increased oxidative stress promote metabolic impairments in the insulin-sensitive tissues and finally, insulin resistance, organ failure, and premature aging occur. T2DM, the most common form of diabetes (∼90%), is characterized by a systemic inflammatory disease accompanied by insulin resistance (IR) or decreased metabolic response to insulin in several tissues, including the adipose tissue, liver, and skeletal muscle, as well as by reduced insulin synthesis by pancreatic beta cells (4, 5) . During the progression of diabetes, hyperglycemia promotes mitochondrial dysfunction and induces the formation of reactive oxygen species (ROS) that cause oxidative stress in several tissues such as blood vessels and pancreatic beta cells (7) (8) (9) . In addition, the attachment of AGEs to their receptors [e.g., CD36, galectin-3, scavenger receptors types I (SR-A1), and II (SR-A2)] on the surfaces of immune cells in the circulation and tissues activates the expression of pro-inflammatory cytokines and increases free radical generation (18) .
cord-336924-7xcbtn3q	2020	OBJECTIVE: To evaluate the prevalence and the clinical association of aPL in a large cohort of COVID-19 patients, and to characterize the epitope specificity of anti-β(2)GPI antibodies. aPL in COVID-19 patients are mainly directed against β(2)GPI but display an epitope specificity different from antibodies in antiphospholipid syndrome. The prevalence of COVID-19 patients positive for aCL and anti-b 2 GPI IgG/IgA/ IgM detected by ELISA and CIA is summarized in Table 2 . Again, there was no association between prolonged aPTT and the presence of aPS/PT antibodies nor with thrombotic events in our COVID-19 cohort. Again, there was no association between prolonged aPTT and the presence of aPS/PT antibodies nor with thrombotic events in our COVID-19 cohort. In conclusion, while the medium/high aPL titers with D1 specificity are associated with vascular events in APS, low antibody titers with reactivity against b 2 GPI epitope(s) different from D1 or D4,5 can be found in COVID-19.
cord-338092-barmkkwx	2015	Upon viral infections, plasmacytoid DCs (pDCs) rapidly produce large amounts of IFN-α, which has potent antiviral functions and activates several other immune cells. BDCA-3(+) mDC2 are the human homologue of CD8α(+) mDCs, since they share the expression of several key molecules, the capacity to cross-present antigens to CD8(+) T-cells and to produce IFN-λ. Dendritic cells (DCs) can express very high levels of MHC and costimulatory molecules, and it is generally accepted that they are the relevant cells to induce the activation ("priming") of antigen-specific "naive" T cells (1, 2) and induce their differentiation into various types of effector T cells. Overall, these differences in pathogen sensing and T-cell activation between human and murine DCs are likely to have an important impact on their role in immune responses against specific pathogens. Dendritic cell subsets in humans and mice express not only different patterns of toll-like receptors, but they have also partially distinct cytokine profiles (Figure 1) .
cord-338261-tyimwctm	2020	title: Role of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair This mini review focuses on emerging literature on the role of the cytokine macrophage migration inhibitory factor (MIF) and its cell membrane receptor CD74, in protecting against injury and promoting healing in different parts of the body. This review focuses on the recent advances that have greatly contributed to our current understanding of the link between the signaling pathways activated upon binding of macrophage migration inhibitory factor cytokine to its membrane receptor CD74 and wound healing in different body parts (Figure 1 ). The complex pathological processes that result in disease combined with CD74''s expression on a variety of cell types, and its multiple co-receptors with diverse downstream signaling pathways contribute to these varied outcomes. Surface expression of CD74 by type II alveolar epithelial cells: a potential mechanism for macrophage migration inhibitory factor-induced epithelial repair
cord-338498-3238fz73	2020	Bacterial "new old friends" such as Bacille Calmette-Guérin (BCG) or Mycobacterium obuense have the ability to elevate basal systemic levels of type 1 cytokines and immune cells, correlating with increased protection against diverse and unrelated infectious agents, called "trained immunity." Here we describe dysfunctional immune responses induced by coronaviruses, representing potentially difficult to overcome obstacles to safe, effective vaccine development for COVID-19, and outline how trained immunity could help protect high risk populations through immunomodulation with BCG and other "new old friends." One recent example of the need for continued vigilance is a study using Chinese macaques indicating cause for concern by showing that vaccine-induced, S-specific immunity in the form of anti-spike IgG resulted in severe ALI by skewing macrophage responses during subsequent, acute infection with closely related SARS-CoV (139) .
cord-339152-wfakzb6w	2020	Ebola and Marburg hemorrhagic fevers, Lassa fever, Dengue fever, Yellow fever, West Nile fever, Zika, and Chikungunya vector-borne diseases, Swine flu, Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the recent Coronavirus disease 2019 (COVID-19) are examples of zoonoses that have spread throughout the globe with such a significant impact on public health that the scientific community has been called for a rapid intervention in preventing and treating emerging infections. The occurrence of significant disease outbreaks-such as SARS (severe acute respiratory syndrome) originating in China in 2002 (8) , the 2009 H1N1 swine flu pandemic from Mexico (9) , MERS (Middle East respiratory syndrome) that occurred in Saudi Arabia in 2012 (10) , the West African outbreak of Ebola virus (EBOV) in late 2013 (11) , the Zika virus (ZIKV) outbreak originating in Brazil in 2015 (12) , the 2018 health emergence in Nigeria caused by Lassa virus (13) , and the ongoing Coronavirus disease 2019 (COVID19) pandemic (14) -has renewed interests in developing strategies to faster prevent, treat, and/or control emerging and re-emerging viruses with high epidemic potential.
cord-340228-mvqoyror	2019	Results: A total of 274 PID children were registered in KNPIDR during the study period with predominance of immunodeficiencies affecting cellular and humoral immunity, followed by combined immunodeficiencies with associated syndromic features and diseases of immune dysregulation. CMV and parainfluenza infections were more common in the group of immunodeficiencies affecting cellular and humoral immunity while EBV and human papilloma virus (HPV) were more common in the immune dysregulation group and combined immunodeficiencies with associated syndromic features, respectively. The distribution of these patients according to PID categories is: immunodeficiencies affecting cellular and humoral immunity, 97 patients (35.4%); combined immunodeficiencies with associated syndromic features, 67 patients (24.5%); predominantly antibody deficiencies, 34 patients (12.4%); diseases of immune dysregulation, 47 patients (17.2%); congenital defects of phagocyte number or function, 17 patients (6.2%); autoinflammatory disorders, 1 patient (0.3%); and complement deficiencies, 11 patients (4%).
cord-340475-h0q1m3ed	2014	Further validation showed that ISR2, 8, and 12 expression mimics that of their neighboring genes GBP1, IRF1, and IL6, respectively, all related to the IFN response.These genes are induced in response to different doses of IFNα2 in different cell lines at early (ISR2 or 8) or later (ISR12) time points. HuH7 cells were treated for 6, 24, 48, or 72 h with increasing doses of IFNα2 up to 10,000 units/ml, and the expression levels of GBP1, IRF1, BST2, OAS, IL6, and ISG15 were evaluated by qRT-PCR (Figure 1) .
cord-340741-bhxm4zua	2019	title: P38 and JNK Mitogen-Activated Protein Kinases Interact With Chikungunya Virus Non-structural Protein-2 and Regulate TNF Induction During Viral Infection in Macrophages Additionally, it was noticed that the expressions of key transcription factors involved mainly in antiviral responses (p-IRF3) and TNF production (p-c-jun) were induced significantly in the CHIKV infected macrophages as compared to the corresponding mock cells. In summary, for the first time it has been shown that CHIKV triggers robust TNF production in the host macrophages via both p-p38 and p-JNK/p-c-jun pathways and the interaction of viral protein, nsP2 with these MAPKs during infection. In summary, for the first time it has been shown that CHIKV triggers robust TNF production (a key mediator of CHIKV induced inflammation) in the host macrophages via both p-p38 and p-JNK/p-c-jun pathways and viral protein nsP2 interacts with both the MAPKs during infection.
cord-341513-e6p3lrlf	2017	title: Microarray Analysis Identifies the Potential Role of Long Non-Coding RNA in Regulating Neuroinflammation during Japanese Encephalitis Virus Infection To determine the role of lncRNAs in inflammatory cytokine production, the cells were transfected with siE52329, siN54010 or non-specific control siRNA, and then infected with JEV. To examine the role of lncRNA E52329 and N54010 in regulating the kinase activity of MKK4/JNK pathway, BV2 cells were transfected with siE52329, siN54010 or non-specific control siRNA, and then infected with JEV. The results of our study reveal the first experimental evidence demonstrating the complex regulation of lncRNAs by JEV infection in mice brain and microglial cells. Third, the integration of microarray platform, quantitative real-time PCR, GO analysis, pathways analysis, and lncRNA-mRNA coexpression network analysis has allowed us to conduct an active comparative genomics and bioinformatics study to reveal host lncRNAs expression patterns associated with JEV infection.
cord-342776-hkjhqgie	2020	While studies on SARS-CoV-2 effects on immune cell function continue to progress, we know very little about the significance of depletion of key immune effectors by the virus in the mortality and morbidity of the disease. It also underscores the necessity for the future comprehensive studies of NK cells in SARS-CoV-2 infected individuals and animal models to better understand the role and significance of reported NK cell depletion and functional inactivation in disease morbidity and mortality, in hope to design effective therapeutic interventions for the disease. In particular, in the peripheral blood of patients that were infected with SARS, it was noted that there were significantly lower numbers of natural killer (NK) cells compared to healthy subjects (14) . As mentioned above the infectious agent of COVID-19 disease depletes NK cells in the peripheral blood, and potentially even in the lung tissues of patients, thereby, disabling and depleting the core immune effectors necessary to remove the virus and regulate uncontrolled immune activation.
cord-343824-00mqmpzw	2017	
cord-344093-3bniy5b5	2017	A prominent regulator of disease outcome, especially in-but not limited to-respiratory viral infection, is the IFN-dependent mediator TRAIL (TNF-related apoptosis-inducing ligand) produced by several cell types including immune cells such as macrophages or T cells. (73) Cell death induction, e.g., Bcl-2-associated X protein, caspase-8, Fas-associated protein with death domain, Fas ligand, and TNF-related apoptosis-inducing ligand (TRAIL) dsRNA, polyI:C (4, 110) IAV (4, 5, 10, 115) Sendai virus (110) TRAIL Virus control by apoptosis induction in infected cells IAV (6, 170, 171) Tissue injury by apoptosis of both infected and non-infected alveolar epithelial cells, lung macrophages IAV (5, 7, 10) RSV (137) Necrosis of fibroblasts, dendritic cells, and epithelial cells IAV (146, 147, 168) Increased cellular infiltration CoV (175) Decreased expression of Na,K-ATPase, impaired epithelial fluid reabsorption IAV (11) iNTRODUCTiON In 1957, Isaacs and Lindenmann (1) first recognized the potential of a soluble and probably cell-derived factor to combat influenza virus infection and named this factor interferon [(IFN) from latin interferre, to interfere].
cord-344610-mqq6fmsp	2015	Usually only four prolyl-specific peptidases are considered: DPPIV (EC 3.4.14.5), fibroblast activation protein α (FAP; EC 3.4.21.B28), and the more recently discovered DPP8 and DPP9 (EC 3.4.14). However, due to similarities in substrate specificity and structural homology, it is more relevant to consider a broader family that also includes prolyl oligopeptidase (PREP; EC 3.4.21.26), dipeptidyl peptidase II (DPPII) (EC 3.4.14.2), and prolyl carboxypeptidase (PRCP; EC 3.4.16.2). Three other studies also found no to low DPPIV expression or activity associated with human monocytes and/or macrophages (82, [136] [137] [138] . Dipeptidyl peptidase 4 is present in low amounts on freshly isolated human NK cells and its expression is only upregulated in a small subpopulation after IL-2 stimulation (158) . Dipeptidyl peptidase 8 and 9 have been found to be abundantly present in the macrophage-rich regions of human atherosclerotic plaques and considering DPP9''s role in macrophage activation, it might potentially be involved in atherogenesis (82). Expression and functional role of dipeptidyl peptidase IV (CD26) on human natural killer cells
cord-344829-adlp2rjy	2020	Here we review the literature regarding the mechanism of inflammasome activation by CoV infection, the role of the inflammasome in ARDS, ventilator-induced lung injury (VILI), and Disseminated Intravascular Coagulation (DIC) as well as the potential mechanism by which the inflammasome may contribute to the damaging effects of inflammation in the cardiac, renal, digestive, and nervous systems in COVID-19 patients. Here we review the literature on the role of the inflammasome in CoV infections, which includes how CoVs activate inflammasomes upon infection, the role of the inflammasome in acute respiratory distress syndrome (ARDS), how ventilator-induced lung injury (VILI) activates the inflammasome, how the inflammasome plays a role in the systemic complications associated with COVID-19, and how the inflammasome is involved in the process of Disseminated Intravascular Coagulation (DIC).
cord-346389-gbmnoo84	2020	
cord-348283-7xorq5ce	2020	The spike protein aids in receptor binding and viral entry within the host and therefore represents a potential target for vaccine and therapeutic development. In the current study, the spike protein of SARS-CoV-2 was explored for potential immunogenic epitopes to design multi-epitope vaccine constructs. We adapted a comprehensive predictive framework to provide novel insights into immunogenic epitopes of spike proteins, which can further be evaluated as potential vaccine candidates against COVID-19. Designed vaccines were then tested with different epitopes, including Truncated Ov-ASP-1 Protein (residues 10-153) and Beta defensin (45 residues long), and constructs having higher antigenicity and that are predicted to produce high antibody titers were added with the multi epitope vaccine construct to the enhance immune response (30) . For the interaction analysis of vaccine 3 and BCR (CD79), the HADDOCK server clustered 140 probable structures into 13 different clusters, which represented a total of 70% of the water-refined models.
cord-350041-b1vmnwv2	2020	There has been a gradual increase in studies exploring prevention and control measures, and we recommend paying close attention to nutrition, which may contribute to modulating some important consequences of COVID-19 infection, as such pro-inflammatory cytokine storm. Unfortunately, we do not yet have weight, height, and waist circumference data for all patients with laboratory-confirmed COVID-19, and, therefore, we cannot disentangle the effects of adiposity on lung function and immune response to viral infection. Recent data on patients with laboratory-confirmed COVID-19 treated at an academic health institution in New York City, the epicenter of the COVID-19 outbreak in the United States, between March 1, 2020, and April 2, 2020, with follow up through April 7, 2020 (13, 14) showed that obesity, after age, was linked to more severe coronavirus cases, with a substantially higher odds ratio than any cardiovascular or pulmonary disease.
cord-350492-1s6wtj25	2020	On these bases, we aimed to review the similarities between severe COVID-19 and diseases included in hyperferritinemic syndrome, from a pathogenic, clinical, and therapeutic point of view, thus proposing new insights to improve the management of those patients. In addition, it has been shown that increased amounts of pro-inflammatory cytokines, including IL-1β, IL-6, IL-12, IFN-γ, IP-10, and MCP1, were associated with pulmonary inflammation and extensive lung damage in SARS patients (25) , thus suggesting a further pathogenic loop in inducing the cytokine storm. The final result is the uncontrolled proliferation of activated immune cells, the massive production of pro-inflammatory mediators, and the development of cytokine storm syndrome, either in severe COVID-19 or SJIA. Considering the lack of efficacy of antiviral therapy for severe coronavirus infection, it is reasonable to postulate the clinical usefulness of specific immunomodulatory therapies (Figure 1) , as observed for other diseases included in hyperferritinemic syndrome such as intravenous immunoglobulins (IVIGs) and tocilizumab, the humanized monoclonal antibody against IL-6 receptor (7).
cord-350836-1enteev7	2019	
cord-351305-6vtv2xuh	2020	The current pandemic with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compels clinicians to develop recommendations for successful clinical management and surveillance of immunocompromised patients at high risk for severe disease progression. With only few case studies published on SARS-CoV-2 infection in patients with rheumatic diseases, we report a 25-year-old male who developed moderate coronavirus disease 2019 (COVID-19) with fever, mild dyspnea, and no major complications despite having received high-dose prednisolone, cyclophosphamide, and rituximab for the treatment of highly active, life-threatening eosinophilic granulomatosis with polyangiitis (EGPA). Thus, due to severity and refractory disease the previously healthy patient was continuously hospitalized from January to March 2020, receiving intravenous cyclophosphamide (CYCLOPS-protocol, cumulative dose 4.76 g), rituximab (4 × 375 mg/m 2 ), and a long-term, slowly tapered high-dose prednisolone treatment (up to 1 g/day). Long-term coexistence of SARS-CoV-2 with antibody response in COVID-19 patients
cord-351431-xcqz9d3t	2020	Increasing neutrophil counts paralleled lesion CT values (slope: 0.8 and 0.3–1.2), reflecting neutrophilia-induced lung injury in severe patients. Transcriptome analysis revealed that neutrophil activation was correlated with 17 neutrophil extracellular trap (NET)-associated genes in COVID-19 patients, which was related to innate immunity and interacted with T/NK/B cells, as supported by a protein–protein interaction network analysis. Principal component analysis was performed with R package "FactoMineR" to identify those clinical parameters that contribute most to distinguishing severe, moderate, and mild cases of COVID-19 (28) . For BALF, the most upregulated marker genes were similarly enriched in neutrophils, but more up-regulated genes in monocytes and B cells were observed in COVID-19 patients compared to healthy controls, which is different from the lung samples. Transcriptome analysis of lung specimens and BALF from COVID-19 patients also indicated the most up-regulated marker genes were neutrophil related. Neutrophil extracellular traps (NETs) as markers of disease severity in COVID-19
cord-352150-ey9kc7zj	2016	
cord-352230-8mazd3eu	2020	
cord-352737-3ttrx3lf	2020	Enhancing the efficacy of the adaptive immune response may be an important issue both for infection resolution as well as for the appropriate generation of immunity upon vaccination, while inhibiting inflamm-aging will likely emerge as a potential complementary therapeutic approach in the management of patients with severe COVID-19. Enhancing the efficacy of the adaptive immune response may be an important issue both for infection resolution as well as for the appropriate generation of immunity upon vaccination, while inhibiting inflamm-aging will likely emerge as a potential complementary therapeutic approach in the management of patients with severe COVID-19. Interestingly, polymorphonuclear leucocytes from the elderly are less capable of modulating the triggering receptor expressed on myeloid cell-1 (TREM-1)-induced oxidative bursts, suggesting that TREM-1 signal transduction altered with aging may be one of the mediators of the decrease in microbicidal potential of innate immune cells in older adults (41) .
cord-352960-pfccsgco	2017	Here, we report the case of a 1-year-old boy of Moroccan consanguineous parents, who was diagnosed at 4 months of age with ICF syndrome with a homozygous missense mutation in the DNMT3B gene. Here, we report the case of a 1-year-old boy of Moroccan consanguineous parents, who was diagnosed at 4 months of age with ICF syndrome with a homozygous missense mutation in the DNMT3B gene. Here, we report the case of a 1-year-old boy of Moroccan consanguineous descent diagnosed with ICF syndrome carrying a homozygous missense mutation in the DNMT3B gene (Ala603Thr) with hypogammagobulinemia, normal B cell count, facial anomaly, and failure to thrive. We report the successful allogeneic HSCT of a 1-year-old boy with ICF1 syndrome carrying a homozygous mutation in the DNMT3B gene after receipt of bone marrow cells from the 10/10 HLA-matched clinically healthy sister.
cord-353217-gmc3qrci	2020	Recent large observational studies indicate that hydroxychloroquine (HY) does not affect outcomes of patients hospitalized with COVID-19 (1, 2) and may even be harmful (3) . In view of this situation and of the importance of correct interpretation of antibody profiles for planning preventive measures for COVID-19, we would like to bring the attention of readers to studies that raise concerns about the possible impact of HY upon antibody responses to SARS-CoV-2. To the best of our knowledge, there are no new facts in the scientific and medical literature that indicate that the same mechanism could not operate in HY-treated patients suffering from COVID-19 and negatively impact their SARS-CoV-2-specific antibody responses. As more needs to be learned about the role of antibodies in recovery from and protection against infection with SARS-CoV-2, the impact of HY and other treatment regimens on antibody responses requires systematic evaluation.
cord-353594-z1vxamvp	2020	Since we observed similarities between COVID-19 and interstitial lung disease in connective tissue disease (CTD-ILD), we investigated features of autoimmunity in SARS-CoV-2-associated respiratory failure. Patients or their relatives had given written informed consent to routine diagnostic procedures (serology, bronchoscopy, radiology) as well as (partial) autopsy in the case of death, respectively, as well as to the scientific use of data and tissue samples in the present study. Our finding that significant ANA titers and/or detection of specific autoantibodies are found in most patients who develop ARDS raises the question if there is a comparable mechanism of lung damage between SARS-CoV-2 infection and exacerbating autoimmune disease. Our observation of CTD-associated autoantibodies together with the CTD-like radiologic and histopathologic lung findings in severe cases of COVID-19 point towards a possible dysregulation of the immune response upon SARS-CoV-2 infection that might fuel organizing pneumonia and trigger interstitial fibrosis, with deleterious effects on the functional outcome in long-term survivors.
cord-353887-f4yd7guj	2020	
cord-354030-8tfg881h	2020	The realm of immunoinformatics tools considers the mechanism of the host immune response to yield additional methodologies in the design of vaccine against diseases are cost-effective and convenient, as in silico predictions can reduce the number of experiments needed (13, 14) . In this present, we employed immunoinformatics to predict multiple immunogenic proteins from the SARS-CoV-2 proteome and thereby design a multi-epitope vaccine. developed a multi-epitope vaccine that was designed using immunoinformatics tools that potentially trigger both CD4+ and CD8+ T-cell immune responses (16) . developed a multi-epitope vaccine that was designed using immunoinformatics tools that potentially trigger both CD4+ and CD8+ T-cell immune responses (16) . A vaccine based on the spike protein could induce antibodies to block SARS-COV-2 binding and fusion or neutralize virus infection (18) , as well as induce harmful immune responses that cause liver damage (19) . To design an effective vaccine, we selected the SARS-CoV-2 protein through the above-mentioned methods for epitope prediction. Development of epitope-based peptide vaccine against novel coronavirus 2019 (SARS-COV-2): Immunoinformatics approach
cord-354353-hyz0gmpz	2020	While long-term exposure to air pollutants such as PM 2.5 and nitrous dioxide contributes to persistent inflammatory responses and cardiopulmonary diseases (7) , which might increase vulnerability to COVID-19, it is also plausible that depending on the environment SARS-CoV-2 "hitchhiking" on airborne PM pollutants might be an additional mechanism for spreading the infection. In summary, although long-term exposure to polluted air might increase vulnerability to COVID-19 through prior adverse cellular effects of settled PM (24), our proposed "hitchhiking" hypothesis offers an additional multi-mechanistic pathogenic process through delivery of low viral titres with diverse PM-virus composites and is applicable to both indoor and outdoor situations, where the pathogenic severity is dependent on PM concentration, composition, shape and size as well as the infectious viral load. Contrary to the suggestions that long-term exposure to PM might increase vulnerability to SAR-CoV-2 infection, inhaled PM might promote some forms of immunity to the virus in some individuals.
cord-354620-xf6glr2h	2020