title: c-FLIP-Short reduces type I interferon production and increases viremia with coxsackievirus B3.
abstract: Cellular FLIP (c-FLIP) is an enzymatically inactive paralogue of caspase-8 and as such can block death receptor-induced apoptosis. However, independent of death receptors, c-FLIP-Long (c-FLIPL) can heterodimerize with and activate caspase-8. This is critical for promoting the growth and survival of T lymphocytes as well as the regulation of the RIG-I helicase pathway for type I interferon production in response to viral infections. Truncated forms of FLIP also exist in mammalian cells (c-FLIPS) and certain viruses (v-FLIP), which lack the C-terminal domain that activates caspase-8. Thus, the ratio of c-FLIPL to these short forms of FLIP may greatly influence the outcome of an immune response. We examined this model in mice transgenically expressing c-FLIPS in T cells during infection with Coxsackievirus B3 (CVB3). In contrast to our earlier findings of reduced myocarditis and mortality with CVB3 infection of c-FLIPL-transgenic mice, c-FLIPS-transgenic mice were highly sensitive to CVB3 infection as manifested by increased cardiac virus titers, myocarditis score, and mortality compared to wild-type C57BL/6 mice. This observation was paralleled by a reduction in serum levels of IL-10 and IFN-α in CVB3-infected c-FLIPS mice. In vitro infection of c-FLIPS T cells with CVB3 confirmed these results. Furthermore, molecular studies revealed that following infection of cells with CVB3, c-FLIPL associates with mitochondrial antiviral signaling protein (MAVS), increases caspase-8 activity and type I IFN production, and reduces viral replication, whereas c-FLIPS promotes the opposite phenotype.
authors.affiliation: Department of Pathology, Vermont Center for Immunology and Infectious Diseases, University of Vermont, Burlington, Vermont, United States of America.
authors.forename: Iwona A
authors.initials: IA
authors.lastname: Buskiewicz
authors.affiliation: Department of Medicine, Vermont Center for Immunology and Infectious Diseases, University of Vermont, Burlington, Vermont, United States of America.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koenig
authors.affiliation: Department of Pathology, Vermont Center for Immunology and Infectious Diseases, University of Vermont, Burlington, Vermont, United States of America.
authors.forename: Brian
authors.initials: B
authors.lastname: Roberts
authors.affiliation: Department of Medicine, Vermont Center for Immunology and Infectious Diseases, University of Vermont, Burlington, Vermont, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Russell
authors.affiliation: Department of Medicine, Vermont Center for Immunology and Infectious Diseases, University of Vermont, Burlington, Vermont, United States of America.
authors.forename: Cuixia
authors.initials: C
authors.lastname: Shi
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Sun-Hwa
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Jae U
authors.initials: JU
authors.lastname: Jung
authors.affiliation: Department of Pathology, Vermont Center for Immunology and Infectious Diseases, University of Vermont, Burlington, Vermont, United States of America.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Huber
authors.affiliation: Department of Medicine, Vermont Center for Immunology and Infectious Diseases, University of Vermont, Burlington, Vermont, United States of America.
authors.forename: Ralph C
authors.initials: RC
authors.lastname: Budd
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D002478:Cells, Cultured; D003384:Coxsackievirus Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D004622:Embryo, Mammalian / Q000166:cytology; D004770:Enterovirus / Q000235:genetics / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D007370:Interferon Type I / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D016898:Interferon-alpha / Q000097:blood / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000097:blood / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000097:blood; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009205:Myocarditis / Q000235:genetics / Q000378:metabolism / Q000821:virology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology; D014766:Viremia / Q000235:genetics / Q000378:metabolism* / Q000821:virology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053181:Caspase 8; D007370:Interferon Type I; D016898:Interferon-alpha; D016899:Interferon-beta; D016753:Interleukin-10; C512612:MAVS protein, mouse