title: A Systems Approach Reveals MAVS Signaling in Myeloid Cells as Critical for Resistance to Ebola Virus in Murine Models of Infection.
abstract: 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.
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, WA 59105, USA.
authors.forename: Mukta
authors.initials: M
authors.lastname: Dutta
authors.affiliation: Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 59840, USA.
authors.forename: Shelly J
authors.initials: SJ
authors.lastname: Robertson
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, WA 59105, USA; Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 59840, USA; Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Okumura
authors.affiliation: Rocky Mountain Veterinary Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 59840, USA.
authors.forename: Dana P
authors.initials: DP
authors.lastname: Scott
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, WA 59105, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, WA 59105, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Weiss
authors.affiliation: Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 59840, USA.
authors.forename: Gail L
authors.initials: GL
authors.lastname: Sturdevant
authors.affiliation: Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 59840, USA.
authors.forename: Friederike
authors.initials: F
authors.lastname: Feldmann
authors.affiliation: Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 59840, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Haddock
authors.affiliation: Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 59840, USA.
authors.forename: Abhilash I
authors.initials: AI
authors.lastname: Chiramel
authors.affiliation: Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 59840, USA.
authors.forename: Sanket S
authors.initials: SS
authors.lastname: Ponia
authors.affiliation: Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 59840, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Dougherty
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, WA 59105, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, WA 59105, USA; Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.
authors.forename: Angela L
authors.initials: AL
authors.lastname: Rasmussen
authors.affiliation: Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 59840, USA. Electronic address: sbest@niaid.nih.gov.
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Best
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000071457:DEAD Box Protein 58 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D029043:Ebolavirus / Q000502:physiology*; D019142:Hemorrhagic Fever, Ebola / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism / Q000821:virology; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism / Q000473:pathology / Q000821:virology; D014779:Virus Replication
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007370:Interferon Type I; D000071457:DEAD Box Protein 58
keywords: Ebola virus; MAVS; RLR; conditional; interferon; knockout; macrophages; mouse adapted