Interferon regulatory factor 3 attenuates reovirus myocarditis and contributes to viral clearance.
Apoptosis is a pathological hallmark of encephalitis and myocarditis caused by reovirus in newborn mice. In cell culture models, the antiviral transcription factor interferon regulatory factor 3 (IRF-3) enhances reovirus-induced apoptosis following activation via retinoic acid inducible gene I and interferon promoter-stimulating factor 1. To determine the role of IRF-3 in reovirus disease, we infected newborn IRF-3(+/+) and IRF-3(-/-) mice perorally with mildly virulent strain type 1 Lang (T1L) and fully virulent strain type 3 SA+ (T3SA+) and monitored infected animals for survival. Both wild-type and IRF-3(-/-) mice succumbed with equivalent frequencies to infection with T3SA+. However, the absence of IRF-3 was associated with significantly decreased survival rates following infection with T1L. The two virus strains achieved similar peak titers in IRF-3(+/+) and IRF-3(-/-) mice in the intestine, brain, heart, liver, and spleen. However, by day 12 postinoculation, titers in all organs examined were 10- to 100-fold higher in IRF-3(-/-) mice than those in wild-type mice. Increased titers were associated with marked pathological changes in all organs examined, especially in the heart, where absence of IRF-3 resulted in severe myocarditis. Cellular and humoral immune responses were equivalent in wild-type and IRF-3(-/-) animals, suggesting that IRF-3 functions independently of the adaptive immune response to enhance reovirus clearance. Thus, IRF-3 serves to facilitate virus clearance and prevent tissue injury in response to reovirus infection.
Holm
Geoffrey H
GH
Lamb Center for Pediatric Research, D7235 MCN, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. terry.dermody@vanderbilt.edu
Pruijssers
Andrea J
AJ
Li
Lianna
L
Danthi
Pranav
P
Sherry
Barbara
B
Dermody
Terence S
TS
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D006801:Humans; D007109:Immunity; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000276:immunology / Q000473:pathology / Q000821:virology*; D032383:Myocytes, Cardiac / Q000473:pathology / Q000821:virology; D012087:Reoviridae / Q000378:metabolism* / Q000472:pathogenicity; D012088:Reoviridae Infections / Q000276:immunology / Q000473:pathology / Q000821:virology*; D013154:Spleen / Q000473:pathology / Q000821:virology; D015996:Survival Rate; D014018:Tissue Distribution
D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta
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