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1.
Int J Biol Sci ; 16(14): 2479-2489, 2020.
Article in English | MEDLINE | ID: covidwho-721623

ABSTRACT

The emergence of SARS-CoV-2 virus and its associated disease COVID-19 have triggered significant threats to public health, in addition to political and social changes. An important number of studies have reported the onset of symptoms compatible with pneumonia accompanied by coagulopathy and lymphocytopenia during COVID-19. Increased cytokine levels, the emergence of acute phase reactants, platelet activation and immune checkpoint expression are some of the biomarkers postulated in this context. As previously observed in prolonged sepsis, T-cell exhaustion due to SARS-CoV-2 and even their reduction in numbers due to apoptosis hinder the response to the infection. In this review, we synthesized the immune changes observed during COVID-19, the role of immune molecules as severity markers for patient stratification and their associated therapeutic options.


Subject(s)
Coronavirus Infections/immunology , Coronavirus Infections/physiopathology , Pneumonia, Viral/immunology , Pneumonia, Viral/physiopathology , Sepsis/physiopathology , Adrenal Cortex Hormones/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus , Biomarkers , Blood Coagulation Disorders/immunology , Cytokines/metabolism , Humans , Immune System , Immunity, Innate , Interferons/metabolism , Lymphopenia/immunology , Pandemics , Phenotype , Platelet Activation
2.
Science ; 369(6504): 706-712, 2020 08 07.
Article in English | MEDLINE | ID: covidwho-717344

ABSTRACT

Viral infections of the lower respiratory tract are a leading cause of mortality. Mounting evidence indicates that most severe cases are characterized by aberrant immune responses and do not depend on viral burden. In this study, we assessed how type III interferons (IFN-λ) contribute to the pathogenesis induced by RNA viruses. We report that IFN-λ is present in the lower, but not upper, airways of patients with coronavirus disease 2019 (COVID-19). In mice, we demonstrate that IFN-λ produced by lung dendritic cells in response to a synthetic viral RNA induces barrier damage, causing susceptibility to lethal bacterial superinfections. These findings provide a strong rationale for rethinking the pathophysiological role of IFN-λ and its possible use in clinical practice against endemic viruses, such as influenza virus as well as the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.


Subject(s)
Betacoronavirus , Coronavirus Infections/immunology , Coronavirus Infections/metabolism , Dendritic Cells/metabolism , Interferons/physiology , Lung/metabolism , Lung/pathology , Pneumonia, Viral/immunology , Pneumonia, Viral/metabolism , Animals , Bronchoalveolar Lavage Fluid/immunology , Cell Proliferation , Cytokines/metabolism , Humans , Interferon Type I/metabolism , Interferons/metabolism , Lung/immunology , Mice , Mice, Inbred C57BL , Nasopharynx/immunology , Pandemics , Poly I-C/administration & dosage , Respiratory Mucosa/pathology , Signal Transduction , Staphylococcal Infections/metabolism , Superinfection , Toll-Like Receptor 3/metabolism
3.
Emerg Microbes Infect ; 9(1): 1514-1522, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-611844

ABSTRACT

We previously made the hypothesis that STING contributes to COVID-19. The present review detail new arguments for over-activation of STING pathways in COVID-19, following the description of hyper-coagulability and Kawasaki-like diseases in children. Indeed, Kawasaki disease is induced by overreaction of innate cells following exposition to various viruses, including herpes viruses which trigger STING. It predisposes to diffuse vasculitis and aneurysms, whereas STING is over-expressed in arterial aneurisms. The redness at the inoculation site of bacillus Calmette-Guérin, a specific feature of Kawasaki disease, is reproduced by activation of the STING pathway, which is inhibited upstream by aspirin, intravenous immunoglobulins, and Vitamin-D. SARS-CoV2 binding to ACE2 can lead to excessive angiotensin II signaling, which activates the STING pathway in mice. Over-activation of the STING-pathway promotes hyper-coagulability through release of interferon-ß and tissue factor by monocytes-macrophages. Aspirin and dipyridamole, besides their anti-platelet activity, also reduce tissue factor procoagulant activity, and aspirin inhibits the STING pathway upstream of STING. Aspirin and dipyridamole may be used, in combination with drugs blocking downstream the activation of the STING pathway, like inhibitors of IL-6R and JAK/STAT pathways. The risk of bleeding should be low as bleeding has not been reported in severe COVID-19 patients.


Subject(s)
Coronavirus Infections/complications , Membrane Proteins/metabolism , Mucocutaneous Lymph Node Syndrome/etiology , Pneumonia, Viral/complications , Angiotensin II/metabolism , Animals , Aspirin/therapeutic use , Blood Coagulation Disorders/drug therapy , Blood Coagulation Disorders/metabolism , Blood Coagulation Disorders/virology , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Dipyridamole/therapeutic use , Humans , Immunoglobulins, Intravenous/therapeutic use , Interferons/metabolism , Mice , Mucocutaneous Lymph Node Syndrome/metabolism , Pandemics , Platelet Aggregation Inhibitors/therapeutic use , Pneumonia, Viral/drug therapy , Pneumonia, Viral/metabolism , Signal Transduction , Thrombosis/drug therapy , Thrombosis/metabolism , Thrombosis/virology
4.
Emerg Microbes Infect ; 9(1): 1418-1428, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-595042

ABSTRACT

The Coronavirus disease 2019 (COVID-19), which is caused by the novel SARS-CoV-2 virus, is now causing a tremendous global health concern. Since its first appearance in December 2019, the outbreak has already caused over 5.8 million infections worldwide (till 29 May 2020), with more than 0.35 million deaths. Early virus-mediated immune suppression is believed to be one of the unique characteristics of SARS-CoV-2 infection and contributes at least partially to the viral pathogenesis. In this study, we identified the key viral interferon antagonists of SARS-CoV-2 and compared them with two well-characterized SARS-CoV interferon antagonists, PLpro and orf6. Here we demonstrated that the SARS-CoV-2 nsp13, nsp14, nsp15 and orf6, but not the unique orf8, could potently suppress primary interferon production and interferon signalling. Although SARS-CoV PLpro has been well-characterized for its potent interferon-antagonizing, deubiquitinase and protease activities, SARS-CoV-2 PLpro, despite sharing high amino acid sequence similarity with SARS-CoV, loses both interferon-antagonising and deubiquitinase activities. Among the 27 viral proteins, SARS-CoV-2 orf6 demonstrated the strongest suppression on both primary interferon production and interferon signalling. Orf6-deleted SARS-CoV-2 may be considered for the development of intranasal live-but-attenuated vaccine against COVID-19.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/metabolism , Endoribonucleases/metabolism , Exoribonucleases/metabolism , Interferons/antagonists & inhibitors , Interferons/metabolism , Methyltransferases/metabolism , Pneumonia, Viral/metabolism , RNA Helicases/metabolism , Viral Nonstructural Proteins/metabolism , Viral Proteins/metabolism , Betacoronavirus/genetics , Cell Line , Coronavirus Infections/genetics , Coronavirus Infections/virology , Endoribonucleases/genetics , Exoribonucleases/genetics , Host-Pathogen Interactions , Humans , Interferons/genetics , Methyltransferases/genetics , Pandemics , Pneumonia, Viral/genetics , Pneumonia, Viral/virology , RNA Helicases/genetics , Viral Nonstructural Proteins/genetics , Viral Proteins/genetics
5.
Science ; 369(6504): 712-717, 2020 08 07.
Article in English | MEDLINE | ID: covidwho-594812

ABSTRACT

Excessive cytokine signaling frequently exacerbates lung tissue damage during respiratory viral infection. Type I (IFN-α and IFN-ß) and III (IFN-λ) interferons are host-produced antiviral cytokines. Prolonged IFN-α and IFN-ß responses can lead to harmful proinflammatory effects, whereas IFN-λ mainly signals in epithelia, thereby inducing localized antiviral immunity. In this work, we show that IFN signaling interferes with lung repair during influenza recovery in mice, with IFN-λ driving these effects most potently. IFN-induced protein p53 directly reduces epithelial proliferation and differentiation, which increases disease severity and susceptibility to bacterial superinfections. Thus, excessive or prolonged IFN production aggravates viral infection by impairing lung epithelial regeneration. Timing and duration are therefore critical parameters of endogenous IFN action and should be considered carefully for IFN therapeutic strategies against viral infections such as influenza and coronavirus disease 2019 (COVID-19).


Subject(s)
Alveolar Epithelial Cells/pathology , Cytokines/metabolism , Interferon Type I/metabolism , Interferons/metabolism , Lung/pathology , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/pathology , Alveolar Epithelial Cells/immunology , Animals , Apoptosis , Bronchoalveolar Lavage Fluid/immunology , Cell Differentiation , Cell Proliferation , Cells, Cultured , Cytokines/administration & dosage , Cytokines/immunology , Female , Influenza A Virus, H3N2 Subtype , Interferon Type I/administration & dosage , Interferon Type I/pharmacology , Interferon-alpha/administration & dosage , Interferon-alpha/metabolism , Interferon-alpha/pharmacology , Interferon-beta/administration & dosage , Interferon-beta/metabolism , Interferon-beta/pharmacology , Interferons/administration & dosage , Interferons/pharmacology , Male , Mice , Orthomyxoviridae Infections/metabolism , Receptor, Interferon alpha-beta/genetics , Receptor, Interferon alpha-beta/metabolism , Receptors, Interferon/genetics , Receptors, Interferon/metabolism , Signal Transduction , Tumor Suppressor Protein p53/metabolism
6.
Viruses ; 12(6)2020 06 10.
Article in English | MEDLINE | ID: covidwho-592405

ABSTRACT

The ongoing Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) signals an urgent need for an expansion in treatment options. In this study, we investigated the anti-SARS-CoV-2 activities of 22 antiviral agents with known broad-spectrum antiviral activities against coronaviruses and/or other viruses. They were first evaluated in our primary screening in VeroE6 cells and then the most potent anti-SARS-CoV-2 antiviral agents were further evaluated using viral antigen expression, viral load reduction, and plaque reduction assays. In addition to remdesivir, lopinavir, and chloroquine, our primary screening additionally identified types I and II recombinant interferons, 25-hydroxycholesterol, and AM580 as the most potent anti-SARS-CoV-2 agents among the 22 antiviral agents. Betaferon (interferon-ß1b) exhibited the most potent anti-SARS-CoV-2 activity in viral antigen expression, viral load reduction, and plaque reduction assays among the recombinant interferons. The lipogenesis modulators 25-hydroxycholesterol and AM580 exhibited EC50 at low micromolar levels and selectivity indices of >10.0. Combinational use of these host-based antiviral agents with virus-based antivirals to target different processes of the SARS-CoV-2 replication cycle should be evaluated in animal models and/or clinical trials.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Animals , Antigens, Viral/immunology , Betacoronavirus/immunology , Betacoronavirus/metabolism , Chlorocebus aethiops , Coronavirus Infections/virology , Humans , Interferons/metabolism , Lipogenesis/drug effects , Pandemics , Pneumonia, Viral/virology , Signal Transduction/drug effects , Vero Cells , Viral Load/drug effects , Viral Plaque Assay , Virus Replication/drug effects
7.
Psychiatry Res ; 291: 113198, 2020 09.
Article in English | MEDLINE | ID: covidwho-548196

ABSTRACT

An option currently being explored for the treatment of COVID-19 is the use of interferons (INFs), either alone or in combination with other antiviral agents. INFs are known to shift the metabolism of tryptophan (TRP) away from its role as a precursor of serotonin. For some patients, reduction in TRP levels may either expose an underlying vulnerability to depression or trigger a de novo episode of depression. This Commentary discusses the pathway involved and recommends in-hospital augmentation with foods or supplements that increase TRP levels for COVID-19 patients treated with INFs. Selective serotonin reuptake inhibitors may also be tried if the depressive symptomatology is not short-lived.


Subject(s)
Betacoronavirus , Coronavirus Infections/metabolism , Coronavirus Infections/psychology , Depression/metabolism , Interferons/metabolism , Pneumonia, Viral/metabolism , Pneumonia, Viral/psychology , Depression/psychology , Humans , Pandemics , Serotonin/metabolism , Tryptophan/metabolism
8.
J Virol ; 94(15)2020 07 16.
Article in English | MEDLINE | ID: covidwho-382053

ABSTRACT

Porcine deltacoronavirus (PDCoV) is an emerging swine enteropathogenic coronavirus. The nonstructural protein nsp5, also called 3C-like protease, is responsible for processing viral polyprotein precursors in coronavirus (CoV) replication. Previous studies have shown that PDCoV nsp5 cleaves the NF-κB essential modulator and the signal transducer and activator of transcription 2 to disrupt interferon (IFN) production and signaling, respectively. Whether PDCoV nsp5 also cleaves IFN-stimulated genes (ISGs), IFN-induced antiviral effector molecules, remains unclear. In this study, we screened 14 classical ISGs and found that PDCoV nsp5 cleaved the porcine mRNA-decapping enzyme 1a (pDCP1A) through its protease activity. Similar cleavage of endogenous pDCP1A was also observed in PDCoV-infected cells. PDCoV nsp5 cleaved pDCP1A at glutamine 343 (Q343), and the cleaved pDCP1A fragments, pDCP1A1-343 and pDCP1A344-580, were unable to inhibit PDCoV infection. Mutant pDCP1A-Q343A, which resists nsp5-mediated cleavage, exhibited a stronger ability to inhibit PDCoV infection than wild-type pDCP1A. Interestingly, the Q343 cleavage site is highly conserved in DCP1A homologs from other mammalian species. Further analyses demonstrated that nsp5 encoded by seven tested CoVs that can infect human or pig also cleaved pDCP1A and human DCP1A, suggesting that DCP1A may be the common target for cleavage by nsp5 of mammalian CoVs.IMPORTANCE Interferon (IFN)-stimulated gene (ISG) induction through IFN signaling is important to create an antiviral state and usually directly inhibits virus infection. The present study first demonstrated that PDCoV nsp5 can cleave mRNA-decapping enzyme 1a (DCP1A) to attenuate its antiviral activity. Furthermore, cleaving DCP1A is a common characteristic of nsp5 proteins from different coronaviruses (CoVs), which represents a common immune evasion mechanism of CoVs. Previous evidence showed that CoV nsp5 cleaves the NF-κB essential modulator and signal transducer and activator of transcription 2. Taken together, CoV nsp5 is a potent IFN antagonist because it can simultaneously target different aspects of the host IFN system, including IFN production and signaling and effector molecules.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus/drug effects , Coronavirus/metabolism , Cysteine Endopeptidases/metabolism , Endoribonucleases/metabolism , Trans-Activators/metabolism , Viral Nonstructural Proteins/metabolism , Animals , Coronavirus Infections/veterinary , Coronavirus Infections/virology , Cysteine Endopeptidases/chemistry , Exoribonucleases/metabolism , HEK293 Cells , Host-Pathogen Interactions , Humans , Immune Evasion , Interferons/metabolism , STAT2 Transcription Factor/metabolism , Signal Transduction , Swine , Swine Diseases/virology
9.
Dev Cell ; 53(5): 514-529.e3, 2020 06 08.
Article in English | MEDLINE | ID: covidwho-276241

ABSTRACT

The factors mediating fatal SARS-CoV-2 infections are poorly understood. Here, we show that cigarette smoke causes a dose-dependent upregulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 receptor, in rodent and human lungs. Using single-cell sequencing data, we demonstrate that ACE2 is expressed in a subset of secretory cells in the respiratory tract. Chronic smoke exposure triggers the expansion of this cell population and a concomitant increase in ACE2 expression. In contrast, quitting smoking decreases the abundance of these secretory cells and reduces ACE2 levels. Finally, we demonstrate that ACE2 expression is responsive to inflammatory signaling and can be upregulated by viral infections or interferon treatment. Taken together, these results may partially explain why smokers are particularly susceptible to severe SARS-CoV-2 infections. Furthermore, our work identifies ACE2 as an interferon-stimulated gene in lung cells, suggesting that SARS-CoV-2 infections could create positive feedback loops that increase ACE2 levels and facilitate viral dissemination.


Subject(s)
Alveolar Epithelial Cells/metabolism , Coronavirus Infections/epidemiology , Interferons/metabolism , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/epidemiology , Respiratory Mucosa/metabolism , Tobacco Smoke Pollution/adverse effects , Tobacco Smoking/genetics , Adult , Aged , Animals , Caco-2 Cells , Cells, Cultured , Female , HCT116 Cells , Humans , Interferons/genetics , Male , Mice , Middle Aged , Pandemics , Peptidyl-Dipeptidase A/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA-Seq , Rats , Signal Transduction , Single-Cell Analysis , Tobacco Smoking/epidemiology , Tobacco Smoking/metabolism , Up-Regulation
10.
Cell Host Microbe ; 27(6): 883-890.e2, 2020 06 10.
Article in English | MEDLINE | ID: covidwho-165371

ABSTRACT

The outbreaks of 2019 novel coronavirus disease (COVID-19) caused by SARS-CoV-2 infection have posed a severe threat to global public health. It is unclear how the human immune system responds to this infection. Here, we used metatranscriptomic sequencing to profile immune signatures in the bronchoalveolar lavage fluid of eight COVID-19 cases. The expression of proinflammatory genes, especially chemokines, was markedly elevated in COVID-19 cases compared to community-acquired pneumonia patients and healthy controls, suggesting that SARS-CoV-2 infection causes hypercytokinemia. Compared to SARS-CoV, which is thought to induce inadequate interferon (IFN) responses, SARS-CoV-2 robustly triggered expression of numerous IFN-stimulated genes (ISGs). These ISGs exhibit immunopathogenic potential, with overrepresentation of genes involved in inflammation. The transcriptome data was also used to estimate immune cell populations, revealing increases in activated dendritic cells and neutrophils. Collectively, these host responses to SARS-CoV-2 infection could further our understanding of disease pathogenesis and point toward antiviral strategies.


Subject(s)
Bronchoalveolar Lavage Fluid/immunology , Coronavirus Infections/immunology , Immunity, Innate , Pneumonia, Viral/immunology , Respiratory System/immunology , Bronchoalveolar Lavage Fluid/cytology , Coronavirus Infections/pathology , Cytokine Release Syndrome , Cytokines/analysis , Host-Pathogen Interactions , Humans , Interferons/metabolism , Pandemics , Pneumonia, Viral/pathology , Respiratory System/pathology
11.
Cell Host Microbe ; 27(6): 883-890.e2, 2020 06 10.
Article in English | MEDLINE | ID: covidwho-125388

ABSTRACT

The outbreaks of 2019 novel coronavirus disease (COVID-19) caused by SARS-CoV-2 infection have posed a severe threat to global public health. It is unclear how the human immune system responds to this infection. Here, we used metatranscriptomic sequencing to profile immune signatures in the bronchoalveolar lavage fluid of eight COVID-19 cases. The expression of proinflammatory genes, especially chemokines, was markedly elevated in COVID-19 cases compared to community-acquired pneumonia patients and healthy controls, suggesting that SARS-CoV-2 infection causes hypercytokinemia. Compared to SARS-CoV, which is thought to induce inadequate interferon (IFN) responses, SARS-CoV-2 robustly triggered expression of numerous IFN-stimulated genes (ISGs). These ISGs exhibit immunopathogenic potential, with overrepresentation of genes involved in inflammation. The transcriptome data was also used to estimate immune cell populations, revealing increases in activated dendritic cells and neutrophils. Collectively, these host responses to SARS-CoV-2 infection could further our understanding of disease pathogenesis and point toward antiviral strategies.


Subject(s)
Bronchoalveolar Lavage Fluid/immunology , Coronavirus Infections/immunology , Immunity, Innate , Pneumonia, Viral/immunology , Respiratory System/immunology , Bronchoalveolar Lavage Fluid/cytology , Coronavirus Infections/pathology , Cytokine Release Syndrome , Cytokines/analysis , Host-Pathogen Interactions , Humans , Interferons/metabolism , Pandemics , Pneumonia, Viral/pathology , Respiratory System/pathology
12.
J Exp Med ; 217(5)2020 05 04.
Article in English | MEDLINE | ID: covidwho-60343

ABSTRACT

With the first reports on coronavirus disease 2019 (COVID-19), which is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the scientific community working in the field of type III IFNs (IFN-λ) realized that this class of IFNs could play an important role in this and other emerging viral infections. In this Viewpoint, we present our opinion on the benefits and potential limitations of using IFN-λ to prevent, limit, and treat these dangerous viral infections.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/metabolism , Interferons/metabolism , Pneumonia, Viral/metabolism , Humans , Pandemics , Virus Internalization
13.
J Virol ; 94(11)2020 05 18.
Article in English | MEDLINE | ID: covidwho-9937

ABSTRACT

Coronaviruses (CoVs) encode multiple interferon (IFN) antagonists that modulate the host response to virus replication. Here, we evaluated the host transcriptional response to infection with murine coronaviruses encoding independent mutations in one of two different viral antagonists, the deubiquitinase (DUB) within nonstructural protein 3 or the endoribonuclease (EndoU) within nonstructural protein 15. We used transcriptomics approaches to compare the scope and kinetics of the host response to the wild-type (WT), DUBmut, and EndoUmut viruses in infected macrophages. We found that the EndoUmut virus activates a focused response that predominantly involves type I interferons and interferon-related genes, whereas the WT and DUBmut viruses more broadly stimulate upregulation of over 2,800 genes, including networks associated with activating the unfolded protein response (UPR) and the proinflammatory response associated with viral pathogenesis. This study highlights the role of viral interferon antagonists in shaping the kinetics and magnitude of the host response during virus infection and demonstrates that inactivating a dominant viral antagonist, the coronavirus endoribonuclease, dramatically alters the host response in macrophages.IMPORTANCE Macrophages are an important cell type during coronavirus infections because they "notice" the infection and respond by inducing type I interferons, which limits virus replication. In turn, coronaviruses encode proteins that mitigate the cell's ability to signal an interferon response. Here, we evaluated the host macrophage response to two independent mutant coronaviruses, one with reduced deubiquitinating activity (DUBmut) and the other containing an inactivated endoribonuclease (EndoUmut). We observed a rapid, robust, and focused response to the EndoUmut virus, which was characterized by enhanced expression of interferon and interferon-related genes. In contrast, wild-type virus and the DUBmut virus elicited a more limited interferon response and ultimately activated over 2,800 genes, including players in the unfolded protein response and proinflammatory pathways associated with progression of significant disease. This study reveals that EndoU activity substantially contributes to the ability of coronaviruses to evade the host innate response and to replicate in macrophages.


Subject(s)
Coronavirus Infections/metabolism , Coronavirus Infections/virology , Coronavirus/physiology , Endoribonucleases/metabolism , Interferons/metabolism , Macrophages/metabolism , Macrophages/virology , Viral Nonstructural Proteins/metabolism , Virus Replication , Animals , Computational Biology , Coronavirus Infections/genetics , Coronavirus Infections/immunology , Cytokines/metabolism , Gene Expression Profiling , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Inflammation Mediators/metabolism , Macrophages/immunology , Mice , Models, Biological , Mutation , RNA, Viral , Unfolded Protein Response
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