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

• DOI: 10.1016/j.celrep.2016.12.069
• Publication Date: 2017-01-17T19:47:06Z
• Authors: 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. Dough...; Michael G. Katze; Angela L. Rasmussen; Sonja M. Best
• Keywords: 0301 basic medicine; QH301-705.5; knockout; Kaplan-Meier Estimate; RLR; Virus Replication; Ebola virus; Mice; 03 medical and health sciences; Animals; Humans; Myeloid Cells; Biology (General); Adaptor Proteins, Signal Transducing; Mice, Knockout; conditional; Macrophages; interferon; Hemorrhagic Fever, Ebola; MAVS; Ebolavirus; macrophages; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; Liver; Interferon Type I; DEAD Box Protein 58; mouse adapted; Spleen; Signal Transduction

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.