Publication in detail

Cell Rep. 2017 Jan 17;18(3):816-829. doi: 10.1016/j.celrep.2016.12.069.

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

Dutta, M; Robertson, SJ; Okumura, A; Scott, DP; Chang, J; Weiss, JM; Sturdevant, GL; Feldmann, F; Haddock, E; Chiramel, AL; Ponia, SS; Dougherty, JD; Katze, MG; Rasmussen, AL; Best, SM

School of Medicine, University of Washington, Seattle, WA 59105, USA. National Institute of Allergy and Infectious Diseases, Hamilton, MT 59840, USA. Columbia University, New York, NY 10032, USA.

Abstract:
The unprecedented 2013-2016 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.

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