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1.
Cell Rep Med ; : 100230, 2021 Mar 18.
Article in English | MEDLINE | ID: covidwho-1147272

ABSTRACT

The deployment of a vaccine that limits transmission and disease likely will be required to end the Coronavirus Disease 2019 (COVID-19) pandemic. We recently described the protective activity of an intranasally-administered chimpanzee adenovirus-vectored vaccine encoding a pre-fusion stabilized spike (S) protein (ChAd-SARS-CoV-2-S) in the upper and lower respiratory tract of mice expressing the human angiotensin-converting enzyme 2 (ACE2) receptor. Here, we show the immunogenicity and protective efficacy of this vaccine in non-human primates. Rhesus macaques were immunized with ChAd-Control or ChAd-SARS-CoV-2-S and challenged one month later by combined intranasal and intrabronchial routes with SARS-CoV-2. A single intranasal dose of ChAd-SARS-CoV-2-S induces neutralizing antibodies and T cell responses and limits or prevents infection in the upper and lower respiratory tract after SARS-CoV-2 challenge. As this single intranasal dose vaccine confers protection against SARS-CoV-2 in non-human primates, it is a promising candidate for limiting SARS-CoV-2 infection and transmission in humans.

2.
Cell ; 184(9): 2316-2331.e15, 2021 04 29.
Article in English | MEDLINE | ID: covidwho-1135277

ABSTRACT

Most human monoclonal antibodies (mAbs) neutralizing SARS-CoV-2 recognize the spike (S) protein receptor-binding domain and block virus interactions with the cellular receptor angiotensin-converting enzyme 2. We describe a panel of human mAbs binding to diverse epitopes on the N-terminal domain (NTD) of S protein from SARS-CoV-2 convalescent donors and found a minority of these possessed neutralizing activity. Two mAbs (COV2-2676 and COV2-2489) inhibited infection of authentic SARS-CoV-2 and recombinant VSV/SARS-CoV-2 viruses. We mapped their binding epitopes by alanine-scanning mutagenesis and selection of functional SARS-CoV-2 S neutralization escape variants. Mechanistic studies showed that these antibodies neutralize in part by inhibiting a post-attachment step in the infection cycle. COV2-2676 and COV2-2489 offered protection either as prophylaxis or therapy, and Fc effector functions were required for optimal protection. Thus, natural infection induces a subset of potent NTD-specific mAbs that leverage neutralizing and Fc-mediated activities to protect against SARS-CoV-2 infection using multiple functional attributes.

4.
JACC Basic Transl Sci ; 2021 Feb 26.
Article in English | MEDLINE | ID: covidwho-1122096

ABSTRACT

There is ongoing debate as to whether cardiac complications of coronavirus disease 2019 (COVID-19) result from myocardial viral infection or are secondary to systemic inflammation and/or thrombosis. We provide evidence that cardiomyocytes are infected in patients with COVID-19 myocarditis and are susceptible to severe acute respiratory syndrome coronavirus 2. We establish an engineered heart tissue model of COVID-19 myocardial pathology, define mechanisms of viral pathogenesis, and demonstrate that cardiomyocyte severe acute respiratory syndrome coronavirus 2 infection results in contractile deficits, cytokine production, sarcomere disassembly, and cell death. These findings implicate direct infection of cardiomyocytes in the pathogenesis of COVID-19 myocardial pathology and provides a model system to study this emerging disease.

5.
Nat Med ; 27(4): 717-726, 2021 04.
Article in English | MEDLINE | ID: covidwho-1118812

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global COVID-19 pandemic. Rapidly spreading SARS-CoV-2 variants may jeopardize newly introduced antibody and vaccine countermeasures. Here, using monoclonal antibodies (mAbs), animal immune sera, human convalescent sera and human sera from recipients of the BNT162b2 mRNA vaccine, we report the impact on antibody neutralization of a panel of authentic SARS-CoV-2 variants including a B.1.1.7 isolate, chimeric strains with South African or Brazilian spike genes and isogenic recombinant viral variants. Many highly neutralizing mAbs engaging the receptor-binding domain or N-terminal domain and most convalescent sera and mRNA vaccine-induced immune sera showed reduced inhibitory activity against viruses containing an E484K spike mutation. As antibodies binding to spike receptor-binding domain and N-terminal domain demonstrate diminished neutralization potency in vitro against some emerging variants, updated mAb cocktails targeting highly conserved regions, enhancement of mAb potency or adjustments to the spike sequences of vaccines may be needed to prevent loss of protection in vivo.


Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , /immunology , Animals , /immunology , Chlorocebus aethiops , Cricetinae , Humans , Mice , Mutation , Neutralization Tests , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Vero Cells
6.
Virology ; 557: 70-85, 2021 05.
Article in English | MEDLINE | ID: covidwho-1108783

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged into the human population in late 2019 and caused the global COVID-19 pandemic. SARS-CoV-2 has spread to more than 215 countries and infected many millions of people. Despite the introduction of numerous governmental and public health measures to control disease spread, infections continue at an unabated pace, suggesting that effective vaccines and antiviral drugs will be required to curtail disease, end the pandemic, and restore societal norms. Here, we review the current developments in antibody and vaccine countermeasures to limit or prevent disease.


Subject(s)
Antibodies, Viral/biosynthesis , /prevention & control , Pandemics , /immunology , Animals , /immunology , /virology , /biosynthesis , Clinical Trials as Topic , Disease Models, Animal , Genetic Vectors/chemistry , Genetic Vectors/immunology , Humans , Immunity, Innate/drug effects , Immunization, Passive/methods , Immunogenicity, Vaccine , Patient Safety , /pathogenicity , Vaccines, Attenuated , Vaccines, DNA , Vaccines, Subunit , Vaccines, Virus-Like Particle/administration & dosage , Vaccines, Virus-Like Particle/biosynthesis , Vaccines, Virus-Like Particle/immunology
7.
Cell ; 184(8): 2229-2238.e13, 2021 04 15.
Article in English | MEDLINE | ID: covidwho-1095902

ABSTRACT

The biosafety level 3 (BSL-3) requirement to culture severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a bottleneck for research. Here, we report a trans-complementation system that produces single-round infectious SARS-CoV-2 that recapitulates authentic viral replication. We demonstrate that the single-round infectious SARS-CoV-2 can be used at BSL-2 laboratories for high-throughput neutralization and antiviral testing. The trans-complementation system consists of two components: a genomic viral RNA containing ORF3 and envelope gene deletions, as well as mutated transcriptional regulator sequences, and a producer cell line expressing the two deleted genes. Trans-complementation of the two components generates virions that can infect naive cells for only one round but does not produce wild-type SARS-CoV-2. Hamsters and K18-hACE2 transgenic mice inoculated with the complementation-derived virions exhibited no detectable disease, even after intracranial inoculation with the highest possible dose. Thus, the trans-complementation platform can be safely used at BSL-2 laboratories for research and countermeasure development.


Subject(s)
/virology , Containment of Biohazards/methods , A549 Cells , Animals , Chlorocebus aethiops , Cricetinae , Genetic Complementation Test/methods , Genome, Viral , HEK293 Cells , Humans , Male , Mice , Mice, Transgenic , RNA, Viral , /pathogenicity , Vero Cells , Virulence , Virus Replication
8.
Cell ; 184(8): 2183-2200.e22, 2021 04 15.
Article in English | MEDLINE | ID: covidwho-1086819

ABSTRACT

Antibodies are crucial to immune protection against SARS-CoV-2, with some in emergency use as therapeutics. Here, we identify 377 human monoclonal antibodies (mAbs) recognizing the virus spike and focus mainly on 80 that bind the receptor binding domain (RBD). We devise a competition data-driven method to map RBD binding sites. We find that although antibody binding sites are widely dispersed, neutralizing antibody binding is focused, with nearly all highly inhibitory mAbs (IC50 < 0.1 µg/mL) blocking receptor interaction, except for one that binds a unique epitope in the N-terminal domain. Many of these neutralizing mAbs use public V-genes and are close to germline. We dissect the structural basis of recognition for this large panel of antibodies through X-ray crystallography and cryoelectron microscopy of 19 Fab-antigen structures. We find novel binding modes for some potently inhibitory antibodies and demonstrate that strongly neutralizing mAbs protect, prophylactically or therapeutically, in animal models.


Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Spike Glycoprotein, Coronavirus/immunology , Animals , Binding Sites, Antibody , CHO Cells , Chlorocebus aethiops , Cricetulus , Epitopes , Female , HEK293 Cells , Humans , Male , Mice , Mice, Transgenic , Models, Molecular , Protein Binding , Protein Structure, Tertiary , Vero Cells
9.
Cell ; 184(7): 1804-1820.e16, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1084553

ABSTRACT

SARS-CoV-2 has caused the global COVID-19 pandemic. Although passively delivered neutralizing antibodies against SARS-CoV-2 show promise in clinical trials, their mechanism of action in vivo is incompletely understood. Here, we define correlates of protection of neutralizing human monoclonal antibodies (mAbs) in SARS-CoV-2-infected animals. Whereas Fc effector functions are dispensable when representative neutralizing mAbs are administered as prophylaxis, they are required for optimal protection as therapy. When given after infection, intact mAbs reduce SARS-CoV-2 burden and lung disease in mice and hamsters better than loss-of-function Fc variant mAbs. Fc engagement of neutralizing antibodies mitigates inflammation and improves respiratory mechanics, and transcriptional profiling suggests these phenotypes are associated with diminished innate immune signaling and preserved tissue repair. Immune cell depletions establish that neutralizing mAbs require monocytes and CD8+ T cells for optimal clinical and virological benefit. Thus, potently neutralizing mAbs utilize Fc effector functions during therapy to mitigate lung infection and disease.


Subject(s)
Antibodies, Monoclonal , Antibodies, Neutralizing , Antibodies, Viral , CD8-Positive T-Lymphocytes , Immunoglobulin Fc Fragments/immunology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/immunology , Antibodies, Viral/therapeutic use , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , CHO Cells , /therapy , Chlorocebus aethiops , Cricetulus , Disease Models, Animal , Female , Humans , Male , Mice , Mice, Inbred C57BL , Vero Cells , Viral Load
10.
Cell ; 184(1): 15-17, 2021 01 07.
Article in English | MEDLINE | ID: covidwho-1064912

ABSTRACT

Complementary genome-wide CRISPR-Cas9 screens performed by multiple groups reveal new insights into SARS-CoV-2 biology including aspects of viral entry, translation, replication, egress, and the genes regulating these processes. Comparisons with other coronaviruses enhances our understanding of the cellular life cycle of this medically important family of emerging viruses.

11.
Cell Host Microbe ; 29(3): 477-488.e4, 2021 03 10.
Article in English | MEDLINE | ID: covidwho-1053270

ABSTRACT

Neutralizing antibodies against the SARS-CoV-2 spike (S) protein are a goal of COVID-19 vaccines and have received emergency use authorization as therapeutics. However, viral escape mutants could compromise efficacy. To define immune-selected mutations in the S protein, we exposed a VSV-eGFP-SARS-CoV-2-S chimeric virus, in which the VSV glycoprotein is replaced with the S protein, to 19 neutralizing monoclonal antibodies (mAbs) against the receptor-binding domain (RBD) and generated 50 different escape mutants. Each mAb had a unique resistance profile, although many shared residues within an epitope of the RBD. Some variants (e.g., S477N) were resistant to neutralization by multiple mAbs, whereas others (e.g., E484K) escaped neutralization by convalescent sera. Additionally, sequential selection identified mutants that escape neutralization by antibody cocktails. Comparing these antibody-mediated mutations with sequence variation in circulating SARS-CoV-2 revealed substitutions that may attenuate neutralizing immune responses in some humans and thus warrant further investigation.


Subject(s)
Antibodies, Monoclonal/blood , Antibodies, Viral/blood , Mutation , Neutralization Tests/methods , Spike Glycoprotein, Coronavirus/genetics , Amino Acid Substitution , Animals , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/pharmacology , Antibodies, Viral/immunology , /immunology , Chlorocebus aethiops , Female , Humans , Mice , Mice, Inbred BALB C , Models, Molecular , Protein Binding , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus/immunology , Vero Cells
12.
Nature ; 591(7849): 293-299, 2021 03.
Article in English | MEDLINE | ID: covidwho-1046014

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-a new coronavirus that has led to a worldwide pandemic1-has a furin cleavage site (PRRAR) in its spike protein that is absent in other group-2B coronaviruses2. To explore whether the furin cleavage site contributes to infection and pathogenesis in this virus, we generated a mutant SARS-CoV-2 that lacks the furin cleavage site (ΔPRRA). Here we report that replicates of ΔPRRA SARS-CoV-2 had faster kinetics, improved fitness in Vero E6 cells and reduced spike protein processing, as compared to parental SARS-CoV-2. However, the ΔPRRA mutant had reduced replication in a human respiratory cell line and was attenuated in both hamster and K18-hACE2 transgenic mouse models of SARS-CoV-2 pathogenesis. Despite reduced disease, the ΔPRRA mutant conferred protection against rechallenge with the parental SARS-CoV-2. Importantly, the neutralization values of sera from patients with coronavirus disease 2019 (COVID-19) and monoclonal antibodies against the receptor-binding domain of SARS-CoV-2 were lower against the ΔPRRA mutant than against parental SARS-CoV-2, probably owing to an increased ratio of particles to plaque-forming units in infections with the former. Together, our results demonstrate a critical role for the furin cleavage site in infection with SARS-CoV-2 and highlight the importance of this site for evaluating the neutralization activities of antibodies.


Subject(s)
/virology , Furin/metabolism , Mutation , /pathogenicity , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Amino Acid Sequence , Animals , Antibodies, Neutralizing/immunology , /physiopathology , Cell Line , Chlorocebus aethiops , Cricetinae , Female , Humans , Lung Diseases/pathology , Lung Diseases/physiopathology , Lung Diseases/virology , Male , Mice , Mice, Transgenic , Models, Molecular , Mutant Proteins/chemistry , Mutant Proteins/genetics , Mutant Proteins/metabolism , Proteolysis , /metabolism , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells , Virus Replication/genetics
13.
Proc Natl Acad Sci U S A ; 2020 Nov 25.
Article in English | MEDLINE | ID: covidwho-947594

ABSTRACT

Cholesterol 25-hydroxylase (CH25H) is an interferon (IFN)-stimulated gene that shows broad antiviral activities against a wide range of enveloped viruses. Here, using an IFN-stimulated gene screen against vesicular stomatitis virus (VSV)-SARS-CoV and VSV-SARS-CoV-2 chimeric viruses, we identified CH25H and its enzymatic product 25-hydroxycholesterol (25HC) as potent inhibitors of SARS-CoV-2 replication. Internalized 25HC accumulates in the late endosomes and potentially restricts SARS-CoV-2 spike protein catalyzed membrane fusion via blockade of cholesterol export. Our results highlight one of the possible antiviral mechanisms of 25HC and provide the molecular basis for its therapeutic development.

14.
Science ; 370(6515): 426-431, 2020 10 23.
Article in English | MEDLINE | ID: covidwho-889834

ABSTRACT

Targeting the interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor is a promising therapeutic strategy. We designed inhibitors using two de novo design approaches. Computer-generated scaffolds were either built around an ACE2 helix that interacts with the spike receptor binding domain (RBD) or docked against the RBD to identify new binding modes, and their amino acid sequences were designed to optimize target binding, folding, and stability. Ten designs bound the RBD, with affinities ranging from 100 picomolar to 10 nanomolar, and blocked SARS-CoV-2 infection of Vero E6 cells with median inhibitory concentration (IC50) values between 24 picomolar and 35 nanomolar. The most potent, with new binding modes, are 56- and 64-residue proteins (IC50 ~ 0.16 nanograms per milliliter). Cryo-electron microscopy structures of these minibinders in complex with the SARS-CoV-2 spike ectodomain trimer with all three RBDs bound are nearly identical to the computational models. These hyperstable minibinders provide starting points for SARS-CoV-2 therapeutics.


Subject(s)
Antiviral Agents/chemistry , Betacoronavirus/drug effects , Drug Design , Peptidyl-Dipeptidase A/chemistry , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Amino Acid Sequence , Animals , Binding Sites , Chlorocebus aethiops , Coronavirus Infections , Cryoelectron Microscopy , Molecular Docking Simulation , Pandemics , Pneumonia, Viral , Protein Binding/drug effects , Spike Glycoprotein, Coronavirus/chemistry , Vero Cells
15.
Nat Immunol ; 21(12): 1506-1516, 2020 12.
Article in English | MEDLINE | ID: covidwho-840532

ABSTRACT

A wide spectrum of clinical manifestations has become a hallmark of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 pandemic, although the immunological underpinnings of diverse disease outcomes remain to be defined. We performed detailed characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation and shared B cell repertoire features previously described in autoimmune settings. Extrafollicular activation correlated strongly with large antibody-secreting cell expansion and early production of high concentrations of SARS-CoV-2-specific neutralizing antibodies. Yet, these patients had severe disease with elevated inflammatory biomarkers, multiorgan failure and death. Overall, these findings strongly suggest a pathogenic role for immune activation in subsets of patients with COVID-19. Our study provides further evidence that targeted immunomodulatory therapy may be beneficial in specific patient subpopulations and can be informed by careful immune profiling.

16.
bioRxiv ; 2020 Sep 25.
Article in English | MEDLINE | ID: covidwho-808504

ABSTRACT

Pathogenic coronaviruses represent a major threat to global public health. Here, using a recombinant reporter virus-based compound screening approach, we identified several small-molecule inhibitors that potently block the replication of the newly emerged severe acute respiratory syndrome virus 2 (SARS-CoV-2). Two compounds, nitazoxanide and JIB-04 inhibited SARS-CoV-2 replication in Vero E6 cells with an EC 50 of 4.90 µM and 0.69 µM, respectively, with specificity indices of greater than 150. Both inhibitors had in vitro antiviral activity in multiple cell types against some DNA and RNA viruses, including porcine transmissible gastroenteritis virus. In an in vivo porcine model of coronavirus infection, administration of JIB-04 reduced virus infection and associated tissue pathology, which resulted in improved body weight gain and survival. These results highlight the potential utility of nitazoxanide and JIB-04 as antiviral agents against SARS-CoV-2 and other viral pathogens.

17.
Cell Host Microbe ; 28(5): 638-645, 2020 11 11.
Article in English | MEDLINE | ID: covidwho-806959

ABSTRACT

When SARS-CoV-2 emerged at the end of 2019, no approved therapeutics or vaccines were available. An urgent need for countermeasures during this crisis challenges the current paradigm of traditional drug discovery and development, which usually takes years from start to finish. Approaches that accelerate this process need to be considered. Here we propose the minimum data package required to move a compound into clinical development safely. We further define the additional data that should be collected in parallel without impacting the rapid path to clinical development. Accelerated paths for antivirals, immunomodulators, anticoagulants, and other agents have been developed and can serve as "roadmaps" to support prioritization of compounds for clinical testing. These accelerated paths are fueled by a skewed risk-benefit ratio and are necessary to advance therapeutic agents into human trials rapidly and safely for COVID-19. Such paths are adaptable to other potential future pandemics.


Subject(s)
Antiviral Agents , Betacoronavirus , Coronavirus Infections , Pandemics , Pneumonia, Viral , Vaccines , Antiviral Agents/therapeutic use , Humans
18.
Clin Chem ; 2020 Sep 07.
Article in English | MEDLINE | ID: covidwho-745842

ABSTRACT

INTRODUCTION: Commercially available SARS-CoV-2 serological assays based on different viral antigens have been approved for the qualitative determination of anti-SARS-CoV-2 antibodies. However, there are limited published data associating the results from commercial assays with neutralizing antibodies. METHODS: 67 specimens from 48 patients with PCR-confirmed COVID-19 and a positive result by the Roche Elecsys Anti-SARS-CoV-2, Abbott SARS-CoV-2 IgG, or EUROIMMUN SARS-CoV-2 IgG assays and 5 control specimens were analyzed for the presence of neutralizing antibodies to SARS-CoV-2. Correlation, concordance, positive percent agreement (PPA), and negative percent agreement (NPA) were calculated at several cutoffs. Results were compared in patients categorized by clinical outcomes. RESULTS: The correlation between SARS-CoV-2 neutralizing titer (EC50) and the Roche, Abbott, and EUROIMMUN assays was 0.29, 0.47, and 0.46 respectively. At an EC50 of 1:32, the concordance kappa with Roche was 0.49 (95% CI; 0.23-0.75), with Abbott was 0.52 (0.28-0.77), and with EUROIMMUN was 0.61 (0.4-0.82). At the same neutralizing titer, the PPA and NPA for the Roche was 100% (94-100) & 56% (30-80); Abbott was 96% (88-99) & 69% (44-86); and EUROIMMUN was 91% (80-96) & 81% (57-93) for distinguishing neutralizing antibodies. Patients who were intubated, had cardiac injury, or acute kidney injury from COVID-19 infection had higher neutralizing titers relative to those with mild symptoms. CONCLUSION: COVID-19 patients generate an antibody response to multiple viral proteins such that the calibrator ratios on the Roche, Abbott, and EUROIMMUN assays are all associated with SARS-CoV-2 neutralization. Nevertheless, commercial serological assays have poor NPA for SARS-CoV-2 neutralization, making them imperfect proxies for neutralization.

20.
Nat Immunol ; 21(11): 1327-1335, 2020 11.
Article in English | MEDLINE | ID: covidwho-728991

ABSTRACT

Although animal models have been evaluated for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, none have fully recapitulated the lung disease phenotypes seen in humans who have been hospitalized. Here, we evaluate transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lungs, with spread to other organs. A decline in pulmonary function occurs 4 days after peak viral titer and correlates with infiltration of monocytes, neutrophils and activated T cells. SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with signatures of nuclear factor-κB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection shares many features of severe COVID-19 infection and can be used to define the basis of lung disease and test immune and antiviral-based countermeasures.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/pathology , Immunity, Innate/immunology , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/pathology , Pneumonia/pathology , Animals , Chlorocebus aethiops , Coronavirus Infections/immunology , Disease Models, Animal , Female , Humans , Interferon Type I/immunology , Interferon-gamma/immunology , Keratin-18/genetics , Leukocytes/immunology , Lymphocyte Activation/immunology , Male , Mice , Mice, Transgenic , Monocytes/immunology , NF-kappa B/immunology , Neutrophil Infiltration/immunology , Neutrophils/immunology , Pandemics , Pneumonia/genetics , Pneumonia/virology , Pneumonia, Viral/immunology , Promoter Regions, Genetic/genetics , T-Lymphocytes/immunology , Vero Cells , Virus Replication/immunology
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