Cell Rep. 2017 Jan 17;18(3):816-829. doi: 10.1016/j.celrep.2016.12.069.
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.
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.
The team at Ozgene has over two decades of experience creating customised knockout and knock-in mice for pivotal medical research globally. Over 400 scientific publications are based on research using Ozgene mice.