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1.
Blood Adv ; 4(13): 2967-2978, 2020 07 14.
Article in English | MEDLINE | ID: covidwho-625455

ABSTRACT

Thrombocytopenia is a common complication of influenza virus infection, and its severity predicts the clinical outcome of critically ill patients. The underlying cause(s) remain incompletely understood. In this study, in patients with an influenza A/H1N1 virus infection, viral load and platelet count correlated inversely during the acute infection phase. We confirmed this finding in a ferret model of influenza virus infection. In these animals, platelet count decreased with the degree of virus pathogenicity varying from 0% in animals infected with the influenza A/H3N2 virus, to 22% in those with the pandemic influenza A/H1N1 virus, up to 62% in animals with a highly pathogenic A/H5N1 virus infection. This thrombocytopenia is associated with virus-containing platelets that circulate in the blood. Uptake of influenza virus particles by platelets requires binding to sialoglycans and results in the removal of sialic acids by the virus neuraminidase, a trigger for hepatic clearance of platelets. We propose the clearance of influenza virus by platelets as a paradigm. These insights clarify the pathophysiology of influenza virus infection and show how severe respiratory infections, including COVID-19, may propagate thrombocytopenia and/or thromboembolic complications.


Subject(s)
Blood Platelets/virology , Influenza A virus/pathogenicity , Influenza, Human/complications , N-Acetylneuraminic Acid/metabolism , Polysaccharides/metabolism , Thrombocytopenia/etiology , Animals , Blood Platelets/metabolism , Blood Platelets/pathology , Disease Models, Animal , Ferrets , Host-Pathogen Interactions , Humans , Influenza A Virus, H1N1 Subtype/pathogenicity , Influenza A Virus, H1N1 Subtype/physiology , Influenza A Virus, H3N2 Subtype/pathogenicity , Influenza A Virus, H3N2 Subtype/physiology , Influenza A Virus, H5N1 Subtype/pathogenicity , Influenza A Virus, H5N1 Subtype/physiology , Influenza A virus/physiology , Influenza, Human/metabolism , Influenza, Human/pathology , Influenza, Human/virology , Orthomyxoviridae Infections/complications , Orthomyxoviridae Infections/metabolism , Orthomyxoviridae Infections/pathology , Orthomyxoviridae Infections/virology , Thrombocytopenia/metabolism , Thrombocytopenia/pathology , Thrombocytopenia/virology , Virus Internalization
2.
Int Immunopharmacol ; 86: 106760, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-634138

ABSTRACT

Due to the vastness of the science virology, it is no longer an offshoot solely of the microbiology. Viruses have become as the causative agents of major epidemics throughout history. Many therapeutic strategies have been used for these microorganisms, and in this way the recognizing of potential targets of viruses is of particular importance for success. For decades, antibodies and antibody fragments have occupied a significant body of the treatment approaches against infectious diseases. Because of their high affinity, they can be designed and engineered against a variety of purposes, mainly since antibody fragments such as scFv, nanobody, diabody, and bispecific antibody have emerged owing to their small size and interesting properties. In this review, we have discussed the antibody discovery and molecular and biological design of antibody fragments as inspiring therapeutic and diagnostic agents against viral targets.


Subject(s)
Antibodies, Viral/therapeutic use , Betacoronavirus/immunology , Biological Products/therapeutic use , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Animals , Antibodies, Bispecific/immunology , Antibodies, Bispecific/therapeutic use , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Viral/immunology , Biological Products/immunology , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Disease Models, Animal , Drug Design , Drug Discovery , Humans , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Single-Domain Antibodies/immunology , Single-Domain Antibodies/therapeutic use
3.
Biomed Res Int ; 2020: 1594726, 2020.
Article in English | MEDLINE | ID: covidwho-633800

ABSTRACT

Acute kidney injury (AKI) is a common complication of sepsis and has also been observed in some patients suffering from the new coronavirus pneumonia COVID-19, which is currently a major global concern. Thymoquinone (TQ) is one of the most active ingredients in Nigella sativa seeds. It has a variety of beneficial properties including anti-inflammatory and antioxidative activities. Here, we investigated the possible protective effects of TQ against kidney damage in septic BALB/c mice. Eight-week-old male BALB/c mice were divided into four groups: control, TQ, cecal ligation and puncture (CLP), and TQ+CLP. CLP was performed after 2 weeks of TQ gavage. After 48 h, we measured the histopathological alterations in the kidney tissue and the serum levels of creatinine (CRE) and blood urea nitrogen (BUN). We also evaluated pyroptosis (NLRP3, caspase-1), apoptosis (caspase-3, caspase-8), proinflammatory (TNF-α, IL-1ß, and IL-6)-related protein and gene expression levels. Our results demonstrated that TQ inhibited CLP-induced increased serum CRE and BUN levels. It also significantly inhibited the high levels of NLRP3, caspase-1, caspase-3, caspase-8, TNF-α, IL-1ß, and IL-6 induced by CLP. Furthermore, NF-κB protein level was significantly decreased in the TQ+CLP group than in the CLP group. Together, our results indicate that TQ may be a potential therapeutic agent for sepsis-induced AKI.


Subject(s)
Acute Kidney Injury/drug therapy , Acute Kidney Injury/etiology , Benzoquinones/therapeutic use , Sepsis/complications , Sepsis/drug therapy , Acute Kidney Injury/pathology , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antioxidants/therapeutic use , Apoptosis/drug effects , Betacoronavirus , Blood Urea Nitrogen , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Creatinine/blood , Cytokines/metabolism , Disease Models, Animal , Humans , Inflammation Mediators/metabolism , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Male , Mice , Mice, Inbred BALB C , NF-kappa B/metabolism , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy
4.
Virol Sin ; 35(3): 290-304, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-618224

ABSTRACT

The recent outbreak of coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has already affected a large population of the world. SARS-CoV-2 belongs to the same family of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). COVID-19 has a complex pathology involving severe acute respiratory infection, hyper-immune response, and coagulopathy. At present, there is no therapeutic drug or vaccine approved for the disease. There is an urgent need for an ideal animal model that can reflect clinical symptoms and underlying etiopathogenesis similar to COVID-19 patients which can be further used for evaluation of underlying mechanisms, potential vaccines, and therapeutic strategies. The current review provides a paramount insight into the available animal models of SARS-CoV-2, SARS-CoV, and MERS-CoV for the management of the diseases.


Subject(s)
Betacoronavirus , Coronavirus Infections/virology , Disease Models, Animal , Middle East Respiratory Syndrome Coronavirus , Pneumonia, Viral/virology , SARS Virus , Severe Acute Respiratory Syndrome/virology , Animals , Betacoronavirus/pathogenicity , Camelids, New World , Camelus , Coronavirus Infections/immunology , Coronavirus Infections/physiopathology , Coronavirus Infections/therapy , Mice , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/physiopathology , Pneumonia, Viral/therapy , SARS Virus/pathogenicity , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/physiopathology , Severe Acute Respiratory Syndrome/therapy , Swine
5.
J Virol ; 94(15)2020 07 16.
Article in English | MEDLINE | ID: covidwho-762192

ABSTRACT

Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe acute respiratory disease in humans. MERS-CoV strains from early epidemic clade A and contemporary epidemic clade B have not been phenotypically characterized to compare their abilities to infect cells and mice. We isolated the clade B MERS-CoV ChinaGD01 strain from a patient infected during the South Korean MERS outbreak in 2015 and compared the phylogenetics and pathogenicity of MERS-CoV EMC/2012 (clade A) and ChinaGD01 (clade B) in vitro and in vivo Genome alignment analysis showed that most clade-specific mutations occurred in the orf1ab gene, including mutations that were predicted to be potential glycosylation sites. Minor differences in viral growth but no significant differences in plaque size or sensitivity to beta interferon (IFN-ß) were detected between these two viruses in vitro ChinaGD01 virus infection induced more weight loss and inflammatory cytokine production in human DPP4-transduced mice. Viral titers were higher in the lungs of ChinaGD01-infected mice than with EMC/2012 infection. Decreased virus-specific CD4+ and CD8+ T cell numbers were detected in the lungs of ChinaGD01-infected mice. In conclusion, MERS-CoV evolution induced changes to reshape its pathogenicity and virulence in vitro and in vivo and to evade adaptive immune response to hinder viral clearance.IMPORTANCE MERS-CoV is an important emerging pathogen and causes severe respiratory infection in humans. MERS-CoV strains from early epidemic clade A and contemporary epidemic clade B have not been phenotypically characterized to compare their abilities to infect cells and mice. In this study, we showed that a clade B virus ChinaGD01 strain caused more severe disease in mice, with delayed viral clearance, increased inflammatory cytokines, and decreased antiviral T cell responses, than the early clade A virus EMC/2012. Given the differences in pathogenicity of different clades of MERS-CoV, periodic assessment of currently circulating MERS-CoV is needed to monitor potential severity of zoonotic disease.


Subject(s)
Coronavirus Infections/virology , Genotype , Host-Pathogen Interactions , Middle East Respiratory Syndrome Coronavirus/physiology , Adult , Animals , Disease Models, Animal , Genome, Viral , Host-Pathogen Interactions/immunology , Humans , Interferon Type I/pharmacology , Male , Mice , Middle East Respiratory Syndrome Coronavirus/classification , Middle East Respiratory Syndrome Coronavirus/isolation & purification , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Phylogeny , RNA, Viral , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Virulence , Virus Replication/drug effects , Virus Replication/genetics , Whole Genome Sequencing
6.
PLoS Pathog ; 16(8): e1008820, 2020 08.
Article in English | MEDLINE | ID: covidwho-731094

ABSTRACT

The COVID-19 pandemic has caused more than 575,000 deaths worldwide as of mid-July 2020 and still continues globally unabated. Immune dysfunction and cytokine storm complicate the disease, which in turn leads to the question of whether stimulation or suppression of the immune system would curb the disease. Given the varied antiviral and regulatory functions of natural killer (NK) cells, they could be potent and powerful immune allies in this global fight against COVID-19. Unfortunately, there is somewhat limited knowledge of the role of NK cells in SARS-CoV-2 infections and even in the related SARS-CoV-1 and MERS-CoV infections. Several NK cell therapeutic options already exist in the treatment of tumor and other viral diseases and could be repurposed against COVID-19. In this review, we describe the current understanding and potential roles of NK cells and other Fc receptor (FcR) effector cells in SARS-CoV-2 infection, advantages of using animals to model COVID-19, and NK cell-based therapeutics that are being investigated for COVID-19 therapy.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Killer Cells, Natural/immunology , Pneumonia, Viral/immunology , Animals , Coronavirus Infections/mortality , Coronavirus Infections/pathology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/mortality , Cytokines/immunology , Cytokines/metabolism , Disease Models, Animal , Humans , Pandemics , Pneumonia, Viral/mortality , Pneumonia, Viral/pathology
7.
J Exp Med ; 217(12)2020 12 07.
Article in English | MEDLINE | ID: covidwho-726090

ABSTRACT

Type I interferons (IFN-I) are a major antiviral defense and are critical for the activation of the adaptive immune system. However, early viral clearance by IFN-I could limit antigen availability, which could in turn impinge upon the priming of the adaptive immune system. In this study, we hypothesized that transient IFN-I blockade could increase antigen presentation after acute viral infection. To test this hypothesis, we infected mice with viruses coadministered with a single dose of IFN-I receptor-blocking antibody to induce a short-term blockade of the IFN-I pathway. This resulted in a transient "spike" in antigen levels, followed by rapid antigen clearance. Interestingly, short-term IFN-I blockade after coronavirus, flavivirus, rhabdovirus, or arenavirus infection induced a long-lasting enhancement of immunological memory that conferred improved protection upon subsequent reinfections. Short-term IFN-I blockade also improved the efficacy of viral vaccines. These findings demonstrate a novel mechanism by which IFN-I regulate immunological memory and provide insights for rational vaccine design.


Subject(s)
Immunogenicity, Vaccine/immunology , Interferon Type I/antagonists & inhibitors , Interferon-alpha/immunology , Receptor, Interferon alpha-beta/immunology , Viral Vaccines/immunology , Zika Virus Infection/immunology , Zika Virus/immunology , Animals , Antibodies, Blocking/immunology , Antibodies, Blocking/pharmacology , Antibodies, Viral/immunology , Antigen Presentation/immunology , CD8-Positive T-Lymphocytes/metabolism , Dendritic Cells/immunology , Disease Models, Animal , Gene Expression/immunology , HEK293 Cells , Humans , Immunologic Memory , Interferon-alpha/genetics , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Receptor, Interferon alpha-beta/genetics , Transfection , Zika Virus Infection/virology
8.
Signal Transduct Target Ther ; 5(1): 157, 2020 10 19.
Article in English | MEDLINE | ID: covidwho-724972

ABSTRACT

Identification of a suitable nonhuman primate (NHP) model of COVID-19 remains challenging. Here, we characterized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in three NHP species: Old World monkeys Macaca mulatta (M. mulatta) and Macaca fascicularis (M. fascicularis) and New World monkey Callithrix jacchus (C. jacchus). Infected M. mulatta and M. fascicularis showed abnormal chest radiographs, an increased body temperature and a decreased body weight. Viral genomes were detected in swab and blood samples from all animals. Viral load was detected in the pulmonary tissues of M. mulatta and M. fascicularis but not C. jacchus. Furthermore, among the three animal species, M. mulatta showed the strongest response to SARS-CoV-2, including increased inflammatory cytokine expression and pathological changes in the pulmonary tissues. Collectively, these data revealed the different susceptibilities of Old World and New World monkeys to SARS-CoV-2 and identified M. mulatta as the most suitable for modeling COVID-19.


Subject(s)
Betacoronavirus/pathogenicity , Callithrix/virology , Coronavirus Infections/epidemiology , Disease Models, Animal , Macaca fascicularis/virology , Macaca mulatta/virology , Pandemics , Pneumonia, Viral/epidemiology , Animals , Antibodies, Viral/biosynthesis , Betacoronavirus/immunology , Body Temperature , Body Weight , Callithrix/immunology , Coronavirus Infections/diagnostic imaging , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Cytokines/biosynthesis , Cytokines/classification , Cytokines/immunology , Disease Susceptibility , Female , Humans , Lung/diagnostic imaging , Lung/immunology , Lung/pathology , Lung/virology , Macaca fascicularis/immunology , Macaca mulatta/immunology , Male , Pneumonia, Viral/diagnostic imaging , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Species Specificity , Tomography, X-Ray Computed , Viral Load , Virus Replication
9.
J Immunol Res ; 2020: 8624963, 2020.
Article in English | MEDLINE | ID: covidwho-721226

ABSTRACT

Single-cell RNA sequencing allows highly detailed profiling of cellular immune responses from limited-volume samples, advancing prospects of a new era of systems immunology. The power of single-cell RNA sequencing offers various opportunities to decipher the immune response to infectious diseases and vaccines. Here, we describe the potential uses of single-cell RNA sequencing methods in prophylactic vaccine development, concentrating on infectious diseases including COVID-19. Using examples from several diseases, we review how single-cell RNA sequencing has been used to evaluate the immunological response to different vaccine platforms and regimens. By highlighting published and unpublished single-cell RNA sequencing studies relevant to vaccinology, we discuss some general considerations how the field could be enriched with the widespread adoption of this technology.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , RNA-Seq/methods , Single-Cell Analysis , Vaccinology/methods , Viral Vaccines/administration & dosage , Animals , Cell Line , Clinical Trials as Topic , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Disease Models, Animal , Drug Evaluation, Preclinical , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immunity, Cellular/genetics , Immunity, Innate/genetics , Immunogenicity, Vaccine , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , RNA, Viral/isolation & purification , Viral Vaccines/immunology
10.
Virol J ; 17(1): 125, 2020 08 18.
Article in English | MEDLINE | ID: covidwho-719595

ABSTRACT

We recently reported the development of the first African green monkey (AGM) model for COVID-19 based on a combined liquid intranasal (i.n.) and intratracheal (i.t.) exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we followed up on this work by assessing an i.n. particle only route of exposure using the LMA mucosal atomization device (MAD). Six AGMs were infected with SARS-CoV-2; three animals were euthanized near the peak stage of virus replication (day 5) and three animals were euthanized during the early convalescence period (day 34). All six AGMs supported robust SARS-CoV-2 replication and developed respiratory disease. Evidence of coagulation dysfunction as noted by a transient increases in aPTT and circulating levels of fibrinogen was observed in all AGMs. The level of SARS-CoV-2 replication and lung pathology was not quite as pronounced as previously reported with AGMs exposed by the combined i.n. and i.t. routes; however, SARS-CoV-2 RNA was detected in nasal swabs of some animals as late as day 15 and rectal swabs as late as day 28 after virus challenge. Of particular importance to this study, all three AGMs that were followed until the early convalescence stage of COVID-19 showed substantial lung pathology at necropsy as evidenced by multifocal chronic interstitial pneumonia and increased collagen deposition in alveolar walls despite the absence of detectable SARS-CoV-2 in any of the lungs of these animals. These findings are consistent with human COVID-19 further demonstrating that the AGM faithfully reproduces the human condition.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/pathology , Coronavirus Infections/virology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Animals , Betacoronavirus/immunology , Chlorocebus aethiops , Convalescence , Coronavirus Infections/blood , Disease Models, Animal , Female , Lung Injury/pathology , Lung Injury/virology , Nasal Mucosa/virology , Pandemics , Pneumonia, Viral/blood , Seroconversion , Viral Load , Virus Shedding
11.
Nat Commun ; 11(1): 4081, 2020 08 14.
Article in English | MEDLINE | ID: covidwho-717117

ABSTRACT

The unprecedented coronavirus disease 2019 (COVID-19) epidemic has created a worldwide public health emergency, and there is an urgent need to develop an effective vaccine to control this severe infectious disease. Here, we find that a single vaccination with a replication-defective human type 5 adenovirus encoding the SARS-CoV-2 spike protein (Ad5-nCoV) protect mice completely against mouse-adapted SARS-CoV-2 infection in the upper and lower respiratory tracts. Additionally, a single vaccination with Ad5-nCoV protects ferrets from wild-type SARS-CoV-2 infection in the upper respiratory tract. This study suggests that the mucosal vaccination may provide a desirable protective efficacy and this delivery mode is worth further investigation in human clinical trials.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Viral Vaccines/immunology , Animals , Antibodies, Viral/immunology , Coronavirus Infections/immunology , Disease Models, Animal , Drug Design , Female , Genetic Vectors , HEK293 Cells , Humans , Mice , Mice, Inbred BALB C , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Viral Vaccines/administration & dosage , Viral Vaccines/genetics
12.
Viruses ; 12(8)2020 08 12.
Article in English | MEDLINE | ID: covidwho-717762

ABSTRACT

The fatal acute respiratory coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since COVID-19 was declared a pandemic by the World Health Organization in March 2020, infection and mortality rates have been rising steadily worldwide. The lack of a vaccine, as well as preventive and therapeutic strategies, emphasize the need to develop new strategies to mitigate SARS-CoV-2 transmission and pathogenesis. Since mouse hepatitis virus (MHV), severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS-CoV-2 share a common genus, lessons learnt from MHV and SARS-CoV could offer mechanistic insights into SARS-CoV-2. This review provides a comprehensive review of MHV in mice and SARS-CoV-2 in humans, thereby highlighting further translational avenues in the development of innovative strategies in controlling the detrimental course of SARS-CoV-2. Specifically, we have focused on various aspects, including host species, organotropism, transmission, clinical disease, pathogenesis, control and therapy, MHV as a model for SARS-CoV and SARS-CoV-2 as well as mouse models for infection with SARS-CoV and SARS-CoV-2. While MHV in mice and SARS-CoV-2 in humans share various similarities, there are also differences that need to be addressed when studying murine models. Translational approaches, such as humanized mouse models are pivotal in studying the clinical course and pathology observed in COVID-19 patients. Lessons from prior murine studies on coronavirus, coupled with novel murine models could offer new promising avenues for treatment of COVID-19.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/virology , Murine hepatitis virus/physiology , Pneumonia, Viral/virology , Animals , Betacoronavirus/genetics , Betacoronavirus/pathogenicity , Coronavirus Infections/immunology , Coronavirus Infections/therapy , Coronavirus Infections/transmission , Disease Models, Animal , Host Specificity , Humans , Mice , Murine hepatitis virus/genetics , Murine hepatitis virus/pathogenicity , Pandemics , SARS Virus/genetics , SARS Virus/pathogenicity , SARS Virus/physiology , Virus Internalization , Virus Replication
13.
J Exp Med ; 217(12)2020 12 07.
Article in English | MEDLINE | ID: covidwho-709757

ABSTRACT

Severe acute respiratory syndrome-coronavirus 2 (SARS-Cov-2) has caused over 13,000,000 cases of coronavirus disease (COVID-19) with a significant fatality rate. Laboratory mice have been the stalwart of therapeutic and vaccine development; however, they do not support infection by SARS-CoV-2 due to the virus's inability to use the mouse orthologue of its human entry receptor angiotensin-converting enzyme 2 (hACE2). While hACE2 transgenic mice support infection and pathogenesis, these mice are currently limited in availability and are restricted to a single genetic background. Here we report the development of a mouse model of SARS-CoV-2 based on adeno-associated virus (AAV)-mediated expression of hACE2. These mice support viral replication and exhibit pathological findings found in COVID-19 patients. Moreover, we show that type I interferons do not control SARS-CoV-2 replication in vivo but are significant drivers of pathological responses. Thus, the AAV-hACE2 mouse model enables rapid deployment for in-depth analysis following robust SARS-CoV-2 infection with authentic patient-derived virus in mice of diverse genetic backgrounds.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/metabolism , Disease Models, Animal , Interferon Type I/metabolism , Mice/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Animals , Cell Line, Tumor , Coronavirus Infections/pathology , Coronavirus Infections/virology , Dependovirus/genetics , Female , Humans , Inflammation/metabolism , Lung/pathology , Lung/virology , Male , Mice, Inbred C57BL , Mice, Transgenic , Pandemics , Parvoviridae Infections/metabolism , Parvoviridae Infections/virology , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Signal Transduction/genetics , Virus Replication/genetics
14.
Front Immunol ; 11: 1817, 2020.
Article in English | MEDLINE | ID: covidwho-703802

ABSTRACT

There is an urgent need for effective countermeasures against the current emergence and accelerating expansion of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Induction of herd immunity by mass vaccination has been a very successful strategy for preventing the spread of many infectious diseases, hence protecting the most vulnerable population groups unable to develop immunity, for example individuals with immunodeficiencies or a weakened immune system due to underlying medical or debilitating conditions. Therefore, vaccination represents one of the most promising counter-pandemic measures to COVID-19. However, to date, no licensed vaccine exists, neither for SARS-CoV-2 nor for the closely related SARS-CoV or Middle East respiratory syndrome-CoV. In addition, a few vaccine candidates have only recently entered human clinical trials, which hampers the progress in tackling COVID-19 infection. Here, we discuss potential prophylactic interventions for SARS-CoV-2 with a focus on the challenges existing for vaccine development, and we review pre-clinical progress and ongoing human clinical trials of COVID-19 vaccine candidates. Although COVID-19 vaccine development is currently accelerated via so-called fast-track programs, vaccines may not be timely available to have an impact on the first wave of the ongoing COVID-19 pandemic. Nevertheless, COVID-19 vaccines will be essential in the future for reducing morbidity and mortality and inducing herd immunity, if SARS-CoV-2 becomes established in the population like for example influenza virus.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/prevention & control , Immunity, Herd/immunology , Mass Vaccination/methods , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Viral Vaccines/immunology , Animals , Coronavirus Infections/immunology , Coronavirus Infections/transmission , Disease Models, Animal , Humans , Pneumonia, Viral/immunology , Pneumonia, Viral/transmission , Vaccines, DNA/immunology , Viral Proteins/immunology
15.
Sci Transl Med ; 12(557)2020 08 19.
Article in English | MEDLINE | ID: covidwho-694565

ABSTRACT

Pathogenic coronaviruses are a major threat to global public health, as exemplified by severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and the newly emerged SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19). We describe herein the structure-guided optimization of a series of inhibitors of the coronavirus 3C-like protease (3CLpro), an enzyme essential for viral replication. The optimized compounds were effective against several human coronaviruses including MERS-CoV, SARS-CoV, and SARS-CoV-2 in an enzyme assay and in cell-based assays using Huh-7 and Vero E6 cell lines. Two selected compounds showed antiviral effects against SARS-CoV-2 in cultured primary human airway epithelial cells. In a mouse model of MERS-CoV infection, administration of a lead compound 1 day after virus infection increased survival from 0 to 100% and reduced lung viral titers and lung histopathology. These results suggest that this series of compounds has the potential to be developed further as antiviral drugs against human coronaviruses.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Middle East Respiratory Syndrome Coronavirus/drug effects , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Virus Replication/drug effects , Animals , Antiviral Agents/chemistry , Betacoronavirus/physiology , Cell Line , Chlorocebus aethiops , Coronavirus Infections/pathology , Crystallography, X-Ray , Cysteine Endopeptidases/chemistry , Disease Models, Animal , Humans , In Vitro Techniques , Lung/pathology , Lung/virology , Male , Mice , Mice, Transgenic , Microbial Sensitivity Tests , Middle East Respiratory Syndrome Coronavirus/physiology , Models, Molecular , Pandemics , Protease Inhibitors/chemistry , Small Molecule Libraries , Species Specificity , Static Electricity , Translational Medical Research , Vero Cells , Viral Load/drug effects , Viral Nonstructural Proteins/chemistry
16.
Front Immunol ; 11: 1625, 2020.
Article in English | MEDLINE | ID: covidwho-688729

ABSTRACT

COVID-19 is a clinical syndrome ranging from mild symptoms to severe pneumonia that often leads to respiratory failure, need for mechanical ventilation, and death. Most of the lung damage is driven by a surge in inflammatory cytokines [interleukin-6, interferon-γ, and granulocyte-monocyte stimulating factor (GM-CSF)]. Blunting this hyperinflammation with immunomodulation may lead to clinical improvement. GM-CSF is produced by many cells, including macrophages and T-cells. GM-CSF-derived signals are involved in differentiation of macrophages, including alveolar macrophages (AMs). In animal models of respiratory infections, the intranasal administration of GM-CSF increased the proliferation of AMs and improved outcomes. Increased levels of GM-CSF have been recently described in patients with COVID-19 compared to healthy controls. While GM-CSF might be beneficial in some circumstances as an appropriate response, in this case the inflammatory response is maladaptive by virtue of being later and disproportionate. The inhibition of GM-CSF signaling may be beneficial in improving the hyperinflammation-related lung damage in the most severe cases of COVID-19. This blockade can be achieved through antagonism of the GM-CSF receptor or the direct binding of circulating GM-CSF. 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. Prospective, randomized, placebo-controlled trials are ongoing. Anti-GM-CSF monoclonal antibodies, TJ003234 and gimsilumab, will be tested in clinical trials in patients with COVID-19, while lenzilumab received FDA approval for compassionate use. These trials will help inform whether blunting the inflammatory signaling provided by the GM-CSF axis in COVID-19 is beneficial.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus/immunology , Coronavirus Infections , Drug Delivery Systems , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Pandemics , Pneumonia, Viral , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Animals , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Disease Models, Animal , Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Humans , Inflammation/drug therapy , Inflammation/immunology , Inflammation/pathology , Macrophages, Alveolar/immunology , Macrophages, Alveolar/pathology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Signal Transduction/drug effects , Signal Transduction/immunology , T-Lymphocytes/immunology , T-Lymphocytes/pathology
18.
Zool Res ; 41(5): 517-526, 2020 Sep 18.
Article in English | MEDLINE | ID: covidwho-671953

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic continues to pose a global threat to the human population. Identifying animal species susceptible to infection with the SARS-CoV-2/ HCoV-19 pathogen is essential for controlling the outbreak and for testing valid prophylactics or therapeutics based on animal model studies. Here, different aged Chinese tree shrews (adult group, 1 year old; old group, 5-6 years old), which are close relatives to primates, were infected with SARS-CoV-2. X-ray, viral shedding, laboratory, and histological analyses were performed on different days post-inoculation (dpi). Results showed that Chinese tree shrews could be infected by SARS-CoV-2. Lung infiltrates were visible in X-ray radiographs in most infected animals. Viral RNA was consistently detected in lung tissues from infected animals at 3, 5, and 7 dpi, along with alterations in related parameters from routine blood tests and serum biochemistry, including increased levels of aspartate aminotransferase (AST) and blood urea nitrogen (BUN). Histological analysis of lung tissues from animals at 3 dpi (adult group) and 7 dpi (old group) showed thickened alveolar septa and interstitial hemorrhage. Several differences were found between the two different aged groups in regard to viral shedding peak. Our results indicate that Chinese tree shrews have the potential to be used as animal models for SARS-CoV-2 infection.


Subject(s)
Betacoronavirus/growth & development , Coronavirus Infections/diagnosis , Disease Models, Animal , Lung/pathology , Pneumonia, Viral/diagnosis , Tupaiidae/physiology , Age Factors , Animals , Betacoronavirus/physiology , Coronavirus Infections/transmission , Coronavirus Infections/virology , Female , Humans , Lung/virology , Male , Pandemics , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , Tupaiidae/virology , Virus Shedding/physiology
19.
Nature ; 584(7821): 450-456, 2020 08.
Article in English | MEDLINE | ID: covidwho-664494

ABSTRACT

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic continues, with devasting consequences for human lives and the global economy1,2. The discovery and development of virus-neutralizing monoclonal antibodies could be one approach to treat or prevent infection by this coronavirus. Here we report the isolation of sixty-one SARS-CoV-2-neutralizing monoclonal antibodies from five patients infected with SARS-CoV-2 and admitted to hospital with severe coronavirus disease 2019 (COVID-19). Among these are nineteen antibodies that potently neutralized authentic SARS-CoV-2 in vitro, nine of which exhibited very high potency, with 50% virus-inhibitory concentrations of 0.7 to 9 ng ml-1. Epitope mapping showed that this collection of nineteen antibodies was about equally divided between those directed against the receptor-binding domain (RBD) and those directed against the N-terminal domain (NTD), indicating that both of these regions at the top of the viral spike are immunogenic. In addition, two other powerful neutralizing antibodies recognized quaternary epitopes that overlap with the domains at the top of the spike. Cryo-electron microscopy reconstructions of one antibody that targets the RBD, a second that targets the NTD, and a third that bridges two separate RBDs showed that the antibodies recognize the closed, 'all RBD-down' conformation of the spike. Several of these monoclonal antibodies are promising candidates for clinical development as potential therapeutic and/or prophylactic agents against SARS-CoV-2.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Epitopes, B-Lymphocyte/immunology , Pneumonia, Viral/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Animals , Antibodies, Monoclonal/analysis , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/ultrastructure , Antibodies, Neutralizing/analysis , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/ultrastructure , Antibodies, Viral/analysis , Antibodies, Viral/chemistry , Antibodies, Viral/ultrastructure , Betacoronavirus/chemistry , Betacoronavirus/ultrastructure , Coronavirus Infections/prevention & control , Cryoelectron Microscopy , Disease Models, Animal , Epitope Mapping , Epitopes, B-Lymphocyte/chemistry , Epitopes, B-Lymphocyte/ultrastructure , Female , Humans , Immunoglobulin Fab Fragments/chemistry , Immunoglobulin Fab Fragments/immunology , Immunoglobulin Fab Fragments/ultrastructure , Lung/pathology , Lung/virology , Male , Mesocricetus , Models, Molecular , Neutralization Tests , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Spike Glycoprotein, Coronavirus/ultrastructure
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