title: Extrinsic MAVS signaling is critical for Treg maintenance of Foxp3 expression following acute flavivirus infection.
abstract: Given the rapid spread of flaviviruses such as West Nile virus (WNV) and Zika virus, it is critical that we develop a complete understanding of the key mediators of an effective anti-viral response. We previously demonstrated that WNV infection of mice deficient in mitochondrial antiviral-signaling protein (MAVS), the signaling adaptor for RNA helicases such as RIG-I, resulted in increased death and dysregulated immunity, which correlated with a failure of Treg expansion following infection. Thus, we sought to determine if intrinsic MAVS signaling is required for participation of Tregs in anti-WNV immunity. Despite evidence of increased Treg cell division, Foxp3 expression was not stably maintained after WNV infection in MAVS-deficient mice. However, intrinsic MAVS signaling was dispensable for Treg proliferation and suppressive capacity. Further, we observed generation of an effective anti-WNV immune response when Tregs lacked MAVS, thereby demonstrating that Treg detection of the presence of WNV through the MAVS signaling pathway is not required for generation of effective immunity. Together, these data suggest that while MAVS signaling has a considerable impact on Treg identity, this effect is not mediated by intrinsic MAVS signaling but rather is likely an effect of the overproduction of pro-inflammatory cytokines generated in MAVS-deficient mice after WNV infection.
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Graduate Program in Pathobiology, Department of Global Health, University of Washington, Seattle, WA, USA.
authors.forename: Andreia
authors.initials: A
authors.lastname: Da Costa
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Esteban
authors.initials: E
authors.lastname: Garza
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Jessica B
authors.initials: JB
authors.lastname: Graham
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Swarts
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Graduate Program in Pathobiology, Department of Global Health, University of Washington, Seattle, WA, USA.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Soerens
authors.affiliation: Graduate Program in Pathobiology, Department of Global Health, University of Washington, Seattle, WA, USA.|Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Graduate Program in Pathobiology, Department of Global Health, University of Washington, Seattle, WA, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Lund
mesh_terms: D000208:Acute Disease; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D005416:Flavivirus / Q000502:physiology*; D018177:Flavivirus Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D014901:West Nile Fever; D014902:West Nile virus
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C512612:MAVS protein, mouse