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.
Highlights
Coxsackievirus B3 (CVB3) is a single stranded, positive sense RNA virus that is one of the major etiological viral agents of human myocarditis and dilated cardiomyopathy [1,2,3]
We examined this model in mice transgenically expressing c-FLIPS in T cells during infection with Coxsackievirus B3 (CVB3)
The percentage of CD4+IFN-c+ spleen cells was not different between the two groups. These results demonstrated that increased expression of c-FLIPS in T lymphocytes greatly enhanced myocarditis susceptibility in female mice, which may have resulted in part from a decreased proportion of immunosuppressive T cells
Summary
Coxsackievirus B3 (CVB3) is a single stranded, positive sense RNA virus that is one of the major etiological viral agents of human myocarditis and dilated cardiomyopathy [1,2,3]. Viral elimination depends upon several distinct host defense mechanisms including type I interferons (IFN-a and IFN-b) [5,6,7,8], T cell response to CVB3 [8], virus neutralizing antibody [9], and activated macrophages [10]. The type of immune cells involved in myocardial inflammation may lead to either the resolution or progression of disease. It was shown that IFN-b immunotherapy significantly reduces the principal CD8+ T cells that are found in the cardiac infiltrate during the chronic phase of autoimmune myocarditis following virus infection [15]. Better knowledge of the regulation of type I IFN production and its effects on myocardial infiltrates will assist in the development of therapeutic strategies to improve the prognosis of chronic inflammatory heart disease
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