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1.
Vet Microbiol ; 247: 108785, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-827867

ABSTRACT

Porcine deltacoronavirus (PDCoV) is a novel swine enteropathogenic coronavirus that causes watery diarrhea, vomiting and mortality in nursing piglets. Type III interferons (IFN-λs) are the major antiviral cytokines in intestinal epithelial cells, the target cells in vivo for PDCoV. In this study, we found that PDCoV infection remarkably inhibited Sendai virus-induced IFN-λ1 production by suppressing transcription factors IRF and NF-κB in IPI-2I cells, a line of porcine intestinal mucosal epithelial cells. We also confirmed that PDCoV infection impeded the activation of IFN-λ1 promoter stimulated by RIG-I, MDA5 and MAVS, but not by TBK1 and IRF1. Although the expression levels of IRF1 and MAVS were not changed, PDCoV infection resulted in reduction of the number of peroxisomes, the platform for MAVS to activate IRF1, and subsequent type III IFN production. Taken together, our study demonstrates that PDCoV suppresses type III IFN responses to circumvent the host's antiviral immunity.


Subject(s)
Coronavirus Infections/veterinary , Epithelial Cells/immunology , Epithelial Cells/virology , Host-Pathogen Interactions/immunology , Interferons/antagonists & inhibitors , Animals , Cell Line , Coronavirus , Coronavirus Infections/immunology , Coronavirus Infections/virology , Interferon Regulatory Factor-1/antagonists & inhibitors , Interferon Regulatory Factor-1/immunology , Interferons/immunology , Intestines/cytology , Intestines/virology , Kidney/cytology , Kidney/virology , NF-kappa B/antagonists & inhibitors , NF-kappa B/immunology , Sendai virus/immunology , Signal Transduction/immunology , Swine/virology , Swine Diseases/immunology , Swine Diseases/virology
2.
Am J Respir Cell Mol Biol ; 63(6): 758-766, 2020 12.
Article in English | MEDLINE | ID: covidwho-733099

ABSTRACT

Viral pneumonias remain global health threats, as exemplified in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, requiring novel treatment strategies both early and late in the disease process. We have reported that mice treated before or soon after infection with a combination of inhaled Toll-like receptor (TLR) 2/6 and 9 agonists (Pam2-ODN) are broadly protected against microbial pathogens including respiratory viruses, but the mechanisms remain incompletely understood. The objective of this study was to validate strategies for immune modulation in a preclinical model of viral pneumonia and determine their mechanisms. Mice were challenged with the Sendai paramyxovirus in the presence or absence of Pam2-ODN treatment. Virus burden and host immune responses were assessed to elucidate Pam2-ODN mechanisms of action and to identify additional opportunities for therapeutic intervention. Enhanced survival of Sendai virus pneumonia with Pam2-ODN treatment was associated with reductions in lung virus burden and with virus inactivation before internalization. We noted that mortality in sham-treated mice corresponded with CD8+ T-cell lung inflammation on days 11-12 after virus challenge, after the viral burden had declined. Pam2-ODN blocked this injurious inflammation by minimizing virus burden. As an alternative intervention, depleting CD8+ T cells 8 days after viral challenge also decreased mortality. Stimulation of local innate immunity within the lungs by TLR agonists early in disease or suppression of adaptive immunity by systemic CD8+ T-cell depletion late in disease improves outcomes of viral pneumonia in mice. These data reveal opportunities for targeted immunomodulation to protect susceptible human subjects.


Subject(s)
Immunity, Innate/immunology , Lipopeptides/pharmacology , Pneumonia, Viral/drug therapy , Pneumonia/prevention & control , Respirovirus Infections/drug therapy , Sendai virus/drug effects , Viral Load/drug effects , Animals , Epithelial Cells/drug effects , Epithelial Cells/immunology , Epithelial Cells/virology , Female , Immunity, Innate/drug effects , Lung/drug effects , Lung/immunology , Lung/virology , Mice , Mice, Inbred C57BL , Pneumonia/immunology , Pneumonia/pathology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Respirovirus Infections/immunology , Respirovirus Infections/virology , Sendai virus/immunology
3.
Cytokine ; 136: 155221, 2020 12.
Article in English | MEDLINE | ID: covidwho-720486

ABSTRACT

ANCA-associated RPGN leads to renal failure through systemic vasculitis and diffuse crescentic glomerulonephritis. MPO-ANCA-RPGN patients are highly susceptible to infections. Our aim in this study was to uncover reasons why these patients were susceptible to infections. We analyzed various aspects of type I interferon system including HVJ-stimulated IFN-α producing capacity and plasmacytoid dendritic cell (pDC) number in whole blood in MPO-ANCA-RPGN patients. Compared with healthy subjects, MPO-ANCA-RPGN patients showed impaired HVJ-stimulated IFN-α producing capacity and lower pDC number with or without glucocorticoid treatment. Immuno-histological staining of MPO-ANCA-RPGN kidney samples revealed a few but apparent pDC in T cell infiltrating regions even in patients with low pDC number in their peripheral blood. Patients' low HVJ-stimulated IFN-α producing capacity and pDC numbers persisted even after patients underwent several years of treatment. Former infection was determined using patients' serum BPI, Lamp-2 and Calprotectin, since they are reflective of a history of infection. These markers were higher in MPO-ANCA-RPGN patients than in healthy subjects. These results indicate that impaired HVJ-stimulated IFN-α production as well as dysfunction of the IFN system might have resulted from a previous bout of infection and can be partially implicated in patients' long-term susceptibility and vulnerability to infection.


Subject(s)
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/immunology , Dendritic Cells/immunology , Interferon-alpha/immunology , Sendai virus/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/blood , Antibodies, Antineutrophil Cytoplasmic/blood , Antibodies, Antineutrophil Cytoplasmic/immunology , Dendritic Cells/metabolism , Disease Susceptibility , Female , Humans , Interferon-alpha/metabolism , Male , Middle Aged , Sendai virus/metabolism
4.
Virus Res ; 286: 198074, 2020 09.
Article in English | MEDLINE | ID: covidwho-611212

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human coronavirus causing the pandemic of severe pneumonia (Coronavirus Disease 2019, COVID-19). SARS-CoV-2 is highly pathogenic in human, having posed immeasurable public health challenges to the world. Innate immune response is critical for the host defense against viral infection and the dysregulation of the host innate immune responses probably aggravates SARS-CoV-2 infection, contributing to the high morbidity and lethality of COVID-19. It has been reported that some coronavirus proteins play an important role in modulating innate immunity of the host, but few studies have been conducted on SARS-CoV-2. In this study, we screened the viral proteins of SARS-CoV-2 and found that the viral ORF6, ORF8 and nucleocapsid proteins were potential inhibitors of type I interferon signaling pathway, a key component for antiviral response of host innate immune. All the three proteins showed strong inhibition on type I interferon (IFN-ß) and NF-κB-responsive promoter, further examination revealed that these proteins were able to inhibit the interferon-stimulated response element (ISRE) after infection with Sendai virus, while only ORF6 and ORF8 proteins were able to inhibit the ISRE after treatment with interferon beta. These findings would be helpful for the further study of the detailed signaling pathway and unveil the key molecular player that may be targeted.


Subject(s)
Betacoronavirus/genetics , Host-Pathogen Interactions/genetics , Interferon-beta/genetics , NF-kappa B/genetics , Nucleocapsid Proteins/genetics , Viral Proteins/genetics , Betacoronavirus/immunology , Coronavirus Nucleocapsid Proteins , Gene Expression Regulation , Genes, Reporter , HEK293 Cells , Host-Pathogen Interactions/immunology , Humans , Immunity, Innate , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H1N1 Subtype/immunology , Interferon-beta/immunology , Luciferases/genetics , Luciferases/metabolism , NF-kappa B/immunology , Nucleocapsid Proteins/immunology , Phosphoproteins , Plasmids/chemistry , Plasmids/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Response Elements , SARS-CoV-2 , Sendai virus/genetics , Sendai virus/immunology , Signal Transduction , Transfection/methods , Viral Proteins/immunology
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