Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 7 de 7
Filter
1.
Cytokine ; 153: 155849, 2022 May.
Article in English | MEDLINE | ID: covidwho-1783275

ABSTRACT

As a member of JAK family of non-receptor tyrosine kinases, TYK2 has a crucial role in regulation of immune responses. This protein has a crucial role in constant expression of IFNAR1 on surface of cells and initiation of type I IFN signaling. In the current study, we measured expression of IFNAR1 and TYK2 levels in venous blood samples of COVID-19 patients and matched controls. TYK2 was significantly down-regulated in male patients compared with male controls (RME = 0.34, P value = 0.03). Though, levels of TYK2 were not different between female cases and female controls, or between ICU-admitted and non-ICU-admitted cases. Expression of IFNAR1 was not different either between COVID-19 cases and controls or between patients required ICU admission and non-ICU-admitted cases. However, none of these transcripts can properly diffrentiate COVID-19 cases from controls or separate patients based on disease severity. The current study proposes down-regulation of TYK2 as a molecular mechanism for incapacity of SARS-CoV-2 in induction of a competent IFN response.


Subject(s)
COVID-19 , Female , Humans , Male , Proteins/metabolism , Receptor, Interferon alpha-beta/genetics , Receptor, Interferon alpha-beta/metabolism , SARS-CoV-2 , TYK2 Kinase/genetics , TYK2 Kinase/metabolism
2.
Nature ; 591(7848): 124-130, 2021 03.
Article in English | MEDLINE | ID: covidwho-1368933

ABSTRACT

Although infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has pleiotropic and systemic effects in some individuals1-3, many others experience milder symptoms. Here, to gain a more comprehensive understanding of the distinction between severe and mild phenotypes in the pathology of coronavirus disease 2019 (COVID-19) and its origins, we performed a whole-blood-preserving single-cell analysis protocol to integrate contributions from all major immune cell types of the blood-including neutrophils, monocytes, platelets, lymphocytes and the contents of the serum. Patients with mild COVID-19 exhibit a coordinated pattern of expression of interferon-stimulated genes (ISGs)3 across every cell population, whereas these ISG-expressing cells are systemically absent in patients with severe disease. Paradoxically, individuals with severe COVID-19 produce very high titres of anti-SARS-CoV-2 antibodies and have a lower viral load compared to individuals with mild disease. Examination of the serum from patients with severe COVID-19 shows that these patients uniquely produce antibodies that functionally block the production of the ISG-expressing cells associated with mild disease, by activating conserved signalling circuits that dampen cellular responses to interferons. Overzealous antibody responses pit the immune system against itself in many patients with COVID-19, and perhaps also in individuals with other viral infections. Our findings reveal potential targets for immunotherapies in patients with severe COVID-19 to re-engage viral defence.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/physiopathology , Interferons/antagonists & inhibitors , Interferons/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Antibodies, Viral/blood , Antibody Formation , Base Sequence , COVID-19/blood , COVID-19/virology , Female , Humans , Immunoglobulin G/immunology , Interferons/metabolism , Male , Neutrophils/immunology , Neutrophils/pathology , Protein Domains , Receptor, Interferon alpha-beta/antagonists & inhibitors , Receptor, Interferon alpha-beta/immunology , Receptor, Interferon alpha-beta/metabolism , Receptors, IgG/immunology , Single-Cell Analysis , Viral Load/immunology
3.
J Virol ; 95(19): e0086221, 2021 09 09.
Article in English | MEDLINE | ID: covidwho-1309804

ABSTRACT

SARS-CoV-2 can infect multiple organs, including lung, intestine, kidney, heart, liver, and brain. The molecular details of how the virus navigates through diverse cellular environments and establishes replication are poorly defined. Here, we generated a panel of phenotypically diverse, SARS-CoV-2-infectible human cell lines representing different body organs and performed longitudinal survey of cellular proteins and pathways broadly affected by the virus. This revealed universal inhibition of interferon signaling across cell types following SARS-CoV-2 infection. We performed systematic analyses of the JAK-STAT pathway in a broad range of cellular systems, including immortalized cells and primary-like cardiomyocytes, and found that SARS-CoV-2 targeted the proximal pathway components, including Janus kinase 1 (JAK1), tyrosine kinase 2 (Tyk2), and the interferon receptor subunit 1 (IFNAR1), resulting in cellular desensitization to type I IFN. Detailed mechanistic investigation of IFNAR1 showed that the protein underwent ubiquitination upon SARS-CoV-2 infection. Furthermore, chemical inhibition of JAK kinases enhanced infection of stem cell-derived cultures, indicating that the virus benefits from inhibiting the JAK-STAT pathway. These findings suggest that the suppression of interferon signaling is a mechanism widely used by the virus to evade antiviral innate immunity, and that targeting the viral mediators of immune evasion may help block virus replication in patients with COVID-19. IMPORTANCE SARS-CoV-2 can infect various organs in the human body, but the molecular interface between the virus and these organs remains unexplored. In this study, we generated a panel of highly infectible human cell lines originating from various body organs and employed these cells to identify cellular processes commonly or distinctly disrupted by SARS-CoV-2 in different cell types. One among the universally impaired processes was interferon signaling. Systematic analysis of this pathway in diverse culture systems showed that SARS-CoV-2 targets the proximal JAK-STAT pathway components, destabilizes the type I interferon receptor though ubiquitination, and consequently renders the infected cells resistant to type I interferon. These findings illuminate how SARS-CoV-2 can continue to propagate in different tissues even in the presence of a disseminated innate immune response.


Subject(s)
COVID-19/metabolism , Host Microbial Interactions/physiology , Janus Kinases/metabolism , SARS-CoV-2/metabolism , Cell Line , Gene Expression Regulation , Humans , Immune Evasion , Immunity, Innate , Interferon Type I/metabolism , Janus Kinase 1/metabolism , Myocytes, Cardiac , Receptor, Interferon alpha-beta/metabolism , STAT1 Transcription Factor/metabolism , Signal Transduction , TYK2 Kinase/metabolism , Virus Replication
4.
J Interferon Cytokine Res ; 40(12): 549-554, 2020 12.
Article in English | MEDLINE | ID: covidwho-990532

ABSTRACT

Coronavirus disease 2019 (COVID-19) has spread rapidly and become a pandemic. Caused by a novel human coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), severe COVID-19 is characterized by cytokine storm syndromes due to innate immune activation. Primary immunodeficiency (PID) cases represent a special patient population whose impaired immune system might make them susceptible to severe infections, posing a higher risk to COVID-19, but this could also lead to suppressed inflammatory responses and cytokine storm. It remains an open question as to whether the impaired immune system constitutes a predisposing or protective factor for PID patients when facing SARS-CoV-2 infection. After literature review, it was found that, similar to other patient populations with different comorbidities, PID patients may be susceptible to SARS-CoV-2 infection. Their varied immune status, however, may lead to different disease severity and outcomes after SARS-CoV-2 infection. PID patients with deficiency in antiviral innate immune signaling [eg, Toll-like receptor (TLR)3, TLR7, or interferon regulatory factor 7 (IRF7)] or interferon signaling (IFNAR2) may be linked to severe COVID-19. Because of its anti-infection, anti-inflammatory, and immunomodulatory effects, routine intravenous immunoglobulin therapy may provide some protective effects to the PID patients.


Subject(s)
COVID-19/complications , COVID-19/immunology , Immune System , Inflammation , Primary Immunodeficiency Diseases/complications , Primary Immunodeficiency Diseases/immunology , Comorbidity , Disease Susceptibility , Humans , Immunity, Innate , Immunoglobulins, Intravenous/metabolism , Interferon Regulatory Factor-7/metabolism , Pandemics , Receptor, Interferon alpha-beta/metabolism , Risk , Toll-Like Receptor 3/metabolism , Toll-Like Receptor 7/metabolism
5.
J Virol ; 94(20)2020 09 29.
Article in English | MEDLINE | ID: covidwho-840609

ABSTRACT

Alpha/beta interferon (IFN-α/ß) signaling through the IFN-α/ß receptor (IFNAR) is essential to limit virus dissemination throughout the central nervous system (CNS) following many neurotropic virus infections. However, the distinct expression patterns of factors associated with the IFN-α/ß pathway in different CNS resident cell populations implicate complex cooperative pathways in IFN-α/ß induction and responsiveness. Here we show that mice devoid of IFNAR1 signaling in calcium/calmodulin-dependent protein kinase II alpha (CaMKIIα) expressing neurons (CaMKIIcre:IFNARfl/fl mice) infected with a mildly pathogenic neurotropic coronavirus (mouse hepatitis virus A59 strain [MHV-A59]) developed severe encephalomyelitis with hind-limb paralysis and succumbed within 7 days. Increased virus spread in CaMKIIcre:IFNARfl/fl mice compared to IFNARfl/fl mice affected neurons not only in the forebrain but also in the mid-hind brain and spinal cords but excluded the cerebellum. Infection was also increased in glia. The lack of viral control in CaMKIIcre:IFNARfl/fl relative to control mice coincided with sustained Cxcl1 and Ccl2 mRNAs but a decrease in mRNA levels of IFNα/ß pathway genes as well as Il6, Tnf, and Il1ß between days 4 and 6 postinfection (p.i.). T cell accumulation and IFN-γ production, an essential component of virus control, were not altered. However, IFN-γ responsiveness was impaired in microglia/macrophages irrespective of similar pSTAT1 nuclear translocation as in infected controls. The results reveal how perturbation of IFN-α/ß signaling in neurons can worsen disease course and disrupt complex interactions between the IFN-α/ß and IFN-γ pathways in achieving optimal antiviral responses.IMPORTANCE IFN-α/ß induction limits CNS viral spread by establishing an antiviral state, but also promotes blood brain barrier integrity, adaptive immunity, and activation of microglia/macrophages. However, the extent to which glial or neuronal signaling contributes to these diverse IFN-α/ß functions is poorly understood. Using a neurotropic mouse hepatitis virus encephalomyelitis model, this study demonstrated an essential role of IFN-α/ß receptor 1 (IFNAR1) specifically in neurons to control virus spread, regulate IFN-γ signaling, and prevent acute mortality. The results support the notion that effective neuronal IFNAR1 signaling compensates for their low basal expression of genes in the IFN-α/ß pathway compared to glia. The data further highlight the importance of tightly regulated communication between the IFN-α/ß and IFN-γ signaling pathways to optimize antiviral IFN-γ activity.


Subject(s)
Central Nervous System/virology , Interferon Type I/metabolism , Interferon-gamma/metabolism , Macrophages/metabolism , Microglia/metabolism , Neurons/metabolism , Signal Transduction , Animals , Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Central Nervous System/immunology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Disease Models, Animal , Encephalomyelitis/immunology , Encephalomyelitis/virology , Macrophages/virology , Mice , Mice, Mutant Strains , Microglia/virology , Murine hepatitis virus/physiology , Neurons/virology , Neutrophil Infiltration , Receptor, Interferon alpha-beta/deficiency , Receptor, Interferon alpha-beta/genetics , Receptor, Interferon alpha-beta/metabolism , Virus Replication
6.
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
7.
Cell ; 182(3): 734-743.e5, 2020 08 06.
Article in English | MEDLINE | ID: covidwho-592236

ABSTRACT

COVID-19, caused by SARS-CoV-2, is a virulent pneumonia, with >4,000,000 confirmed cases worldwide and >290,000 deaths as of May 15, 2020. It is critical that vaccines and therapeutics be developed very rapidly. Mice, the ideal animal for assessing such interventions, are resistant to SARS-CoV-2. Here, we overcome this difficulty by exogenous delivery of human ACE2 with a replication-deficient adenovirus (Ad5-hACE2). Ad5-hACE2-sensitized mice developed pneumonia characterized by weight loss, severe pulmonary pathology, and high-titer virus replication in lungs. Type I interferon, T cells, and, most importantly, signal transducer and activator of transcription 1 (STAT1) are critical for virus clearance and disease resolution in these mice. Ad5-hACE2-transduced mice enabled rapid assessments of a vaccine candidate, of human convalescent plasma, and of two antiviral therapies (poly I:C and remdesivir). In summary, we describe a murine model of broad and immediate utility to investigate COVID-19 pathogenesis and to evaluate new therapies and vaccines.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/pathology , Coronavirus Infections/prevention & control , Disease Models, Animal , Pandemics/prevention & control , Pneumonia, Viral/pathology , Pneumonia, Viral/prevention & control , Vaccination , Angiotensin-Converting Enzyme 2 , Animals , COVID-19 , Chlorocebus aethiops , Coronavirus Infections/virology , Drug Evaluation, Preclinical/methods , Female , Humans , Interferon-gamma/genetics , Interferon-gamma/metabolism , Lung/pathology , Lung/virology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Receptor, Interferon alpha-beta/genetics , Receptor, Interferon alpha-beta/metabolism , SARS-CoV-2 , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/metabolism , Specific Pathogen-Free Organisms , Transduction, Genetic , Vero Cells , Viral Load , Virus Replication
SELECTION OF CITATIONS
SEARCH DETAIL