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    Authors: Natalia G Sampaio; Lise Chauveau; Jonny Hertzog; Anne Bridgeman; Gerissa Fowler; Jurgen P Moonen; Maeva Dupont; Rebecca A Russel; Marko Noerenberg; Jan Rehwinkel

    doi:10.1101/2021.03.26.437180 Date: 2021-03-27 Source: bioRxiv

    Human cells respond to infection by SARS-CoV-2, the virus that causes COVID-19 MESHD, by producing cytokines including type I and III interferons (IFNs) and proinflammatory factors such as IL6 HGNC and TNF HGNC. IFNs can limit SARS-CoV-2 replication but cytokine imbalance contributes to severe COVID-19 MESHD. We studied how cells detect SARS-CoV-2 infection MESHD. We report that the cytosolic RNA sensor MDA5 HGNC was required for type I and III IFN induction in the lung cancer MESHD cell line Calu-3 upon SARS-CoV-2 infection MESHD. Type I and III IFN HGNC induction further required MAVS HGNC and IRF3 HGNC. In contrast, induction of IL6 HGNC and TNF HGNC was independent of the MDA5 HGNC- MAVS HGNC- IRF3 HGNC axis in this setting. We further found that SARS-CoV-2 infection MESHD inhibited the ability of cells to respond to IFNs. In sum, we identified MDA5 HGNC as a cellular sensor for SARS-CoV-2 infection MESHD that induced type I MESHD and III IFNs.

    Systematic analysis of SARS-CoV-2 infection MESHD of an ACE2 HGNC-negative human airway cell

    Authors: Maritza Puray-Chavez; Kyle M Lapak; Travis P. Schrank; Jennifer L Elliott; Dhaval P Bhatt; Megan J Agajanian; Ria Jasuja; Dana Q Lawson; Keanu Davis; Paul W Rothlauf; Heejoon Jo; Nakyung Lee; Kasyap Tenneti; Jenna E Eschbach; Christian Shema Mugisha; Hung R Vuong; Adam L Bailey; D. Neil Hayes; Sean P.J. Whelan; Amjad Horani; Steven L Brody; Dennis Goldfarb; M. Ben Major; Sebla B Kutluay

    doi:10.1101/2021.03.01.433431 Date: 2021-03-01 Source: bioRxiv

    Established in vitro models for SARS-CoV-2 infection MESHD are limited and include cell lines of non-human origin and those engineered to overexpress ACE2 HGNC, the cognate host cell receptor. We identified human H522 lung adenocarcinoma MESHD cells as naturally permissive to SARS-CoV-2 infection MESHD despite complete absence of ACE2 HGNC. Infection of H522 cells required the SARS-CoV-2 spike PROTEIN protein, though in contrast to ACE2 HGNC-dependent models, spike alone was not sufficient for H522 infection. Temporally resolved transcriptomic and proteomic profiling revealed alterations in cell cycle and the antiviral host cell response, including MDA5 HGNC-dependent activation of type-I interferon signaling. Focused chemical screens point to important roles for clathrin-mediated endocytosis and endosomal cathepsins in SARS-CoV-2 infection MESHD of H522 cells. These findings imply the utilization of an alternative SARS-CoV-2 host cell receptor which may impact tropism of SARS-CoV-2 MESHD and consequently human disease pathogenesis.

    Differential roles of RIG-I HGNC-like receptors in SARS-CoV-2 infection MESHD

    Authors: Duomeng Yang; Tingting Geng; Andrew G Harrison; PENGHUA WANG

    doi:10.1101/2021.02.10.430677 Date: 2021-02-11 Source: bioRxiv

    The retinoic acid-inducible gene I ( RIG-I HGNC) and melanoma MESHD melanoma HGNC differentiation-associated protein 5 ( MDA5 HGNC) are the major viral RNA sensors that are essential for activation of antiviral immune responses. However, their roles in severe acute respiratory syndrome MESHD (SARS)-causing coronavirus (CoV) infection MESHD are largely unknown. Herein we investigate their functions in human epithelial cells, the primary and initial target of SARS-CoV-2, and the first line of host defense. A deficiency in MDA5 HGNC ( MDA5 HGNC-/-), RIG-I HGNC or mitochondrial antiviral signaling protein HGNC ( MAVS HGNC) greatly enhanced viral replication. Expression of the type I/III interferons (IFN) HGNC was upregulated following infection in wild-type cells, while this upregulation was severely abolished in MDA5 HGNC-/- and MAVS HGNC-/-, but not in RIG-I HGNC-/- cells. Of note, ACE2 HGNC expression was ~2.5 fold higher in RIG-I HGNC-/- than WT cells. These data demonstrate a dominant role of MDA5 HGNC in activating the type I/III IFN response to SARS-CoV-2, and an IFN HGNC-independent anti-SARS-CoV-2 role of RIG-I HGNC.

    Suppression of MDA5 HGNC-mediated antiviral immune responses by NSP8 PROTEIN of SARS-CoV-2

    Authors: Ziwei Yang; Xiaolin Zhang; Fan Wang; Peihui Wang; Xiaojuan Li; Ersheng Kuang

    doi:10.1101/2020.08.12.247767 Date: 2020-08-12 Source: bioRxiv

    Melanoma differentiation-associated gene-5 HGNC ( MDA5 HGNC) acts as a cytoplasmic RNA sensor to detect viral dsRNA and mediates type I interferon ( IFN HGNC) signaling and antiviral innate immune responses to infection by RNA viruses. Upon recognition of viral dsRNA, MDA5 HGNC is activated with K63-linked polyubiquitination and then triggers the recruitment of MAVS HGNC and activation of TBK1 HGNC and IKK, subsequently leading to IRF3 HGNC and NF-{kappa}B HGNC phosphorylation. Great numbers of symptomatic and severe infections of SARS-CoV-2 MESHD are spreading worldwide, and the poor efficacy of treatment with type I interferon and antiviral agents indicates that SARS-CoV-2 escapes from antiviral immune responses via an unknown mechanism. Here, we report that SARS-CoV-2 nonstructural protein 8 ( NSP8 PROTEIN) acts as an innate immune suppressor and inhibits type I IFN signaling to promote infection of RNA viruses. It downregulates the expression of type I IFNs, IFN HGNC-stimulated genes and proinflammatory cytokines by binding to MDA5 HGNC and impairing its K63-linked polyubiquitination. Our findings reveal that NSP8 PROTEIN mediates innate immune evasion during SARS-CoV-2 infection MESHD and may serve as a potential target for future therapeutics for SARS-CoV-2 infectious diseases MESHD.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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