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Cell Report: A Systems Approach Reveals MAVS Signaling in Myeloid Cells as Critical for Resistance to Ebola Virus in Murine Models of Infection

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  • Cell Report: A Systems Approach Reveals MAVS Signaling in Myeloid Cells as Critical for Resistance to Ebola Virus in Murine Models of Infection

    A Systems Approach Reveals MAVS Signaling in Myeloid Cells as Critical for Resistance to Ebola Virus in Murine Models of Infection

    Mukta Dutta5
    , Shelly J. Robertson5
    , Atsushi Okumura
    , Dana P. Scott
    , Jean Chang
    , Jeffrey M. Weiss
    , Gail L. Sturdevant
    , Friederike Feldmann
    , Elaine Haddock
    , Abhilash I. Chiramel
    , Sanket S. Ponia
    , Jonathan D. Dougherty
    , Michael G. Katze
    , Angela L. Rasmussen
    , Sonja M. Best6,Press enter key for correspondence informationPress enter key to Email the author
    5Co-first author
    6Lead Contact
    Highlights

    • MAVS determines early differences in replication between WT and MA Ebola virus in mice
    • MAVS controls expression of IFN-I, inflammatory responses, and cell death
    • MAVS signaling specifically in myeloid cells is required for control of EBOV replication
    • MAVS has both IFN-I-dependent and -independent roles in the control of EBOV


    Summary

    The unprecedented 20132016 outbreak of Ebola virus (EBOV) resulted in over 11,300 human deaths. Host resistance to RNA viruses requires RIG-I-like receptor (RLR) signaling through the adaptor protein, mitochondrial antiviral signaling protein (MAVS), but the role of RLR-MAVS in orchestrating anti-EBOV responses in vivo is not known. Here we apply a systems approach to MAVS−/− mice infected with either wild-type or mouse-adapted EBOV. MAVS controlled EBOV replication through the expression of IFNα, regulation of inflammatory responses in the spleen, and prevention of cell death in the liver, with macrophages implicated as a major cell type influencing host resistance. A dominant role for RLR signaling in macrophages was confirmed following conditional MAVS deletion in LysM+ myeloid cells. These findings reveal tissue-specific MAVS-dependent transcriptional pathways associated with resistance to EBOV, and they demonstrate that EBOV adaptation to cause disease in mice involves changes in two distinct events, RLR-MAVS antagonism and suppression of RLR-independent IFN-I responses.

    full article

    http://www.cell.com/cell-reports/ful...247(16)31776-4



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