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 completely understood. Wild-type EBOV (WT-EBOV) is not lethal in immunocompetent mice, although virus adaptation to mice is associated with mutations that facilitate replication and increase virulence. The mechanisms by which these mutations confer host-specific virulence is also not clear. We applied a systems approach to MAVS-/- mice infected with either WT- or mouse-adapted EBOV. This work revealed tissue-specific MAVS-dependent transcriptional pathways associated with resistance to EBOV, and demonstrated that EBOV adaptation to cause disease in mice involves changes in two distinct events, increased RLR-MAVS antagonism and increased suppression of RLR-independent type I interferon responses. The findings from these ongoing studies revealing the interplay between host interferon responses and EBOV infection will be discussed.