A systems approach reveals MAVS signaling in myeloid cells as critical in resistance to Ebola virus in murine models of infection. Mus musculus

The unprecedented 2013-16 outbreak of Ebola virus (EBOV) in West Africa resulted in over 11,300 human deaths. Host resistance to EBOV is thought to involve RIG-I-like receptor (RLR) signaling through the adaptor protein, mitochondrial antiviral signaling (MAVS), but role of RLR-MAVS in orchestrating anti-EBOV responses in vivo is not known. Here, we apply a systems approach to MAVS-deficient mice infected with either wild-type or mouse-adapted EBOV. MAVS controlled EBOV replication through expression of IFNα, IFN-stimulated genes, and regulation of inflammatory responses in the spleen, and prevented 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 deletion of MAVS in LysM+ myeloid cells. These findings reveal tissue-specific transcriptional pathways controlled by RLR signaling in resistance to EBOV, and suggest that EBOV adaptation to cause disease in mice is linked in part to increased antagonism of RLR-dependent signaling. Overall design: RNA was isolated from the liver and spleen of mice (C57BL/6 or MAVS-/-) that were either mock-infected or infected with mouse-adapted Ebola virus (MA-EBOV). These were run on Agilent microarrays to assess differences in gene expression related to MAVS signaling during the course of MA-EBOV infection.