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

Publication date: 17 January 2017
Source:Cell Reports, Volume 18, Issue 3
Author(s): Mukta Dutta, Shelly J. Robertson, 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. Best
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.

Graphical abstract

Teaser

Mitochondrial antiviral signaling protein (MAVS) is strongly implicated as critical to control the replication of Ebola virus, but the role of MAVS in vivo is not known. Dutta et al. show that MAVS signaling specifically in myeloid cells controls replication of Ebola virus through both IFN-I-dependent and -independent mechanisms.


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