Sex differences in TLR2 and TLR4 expression and their effect on coxsackievirus-induced autoimmune myocarditis

Abstract Coxsackievirus B3 (CVB3) infection of C57Bl/6 mice shows a sex bias with males developing more severe cardiac inflammation than females because males develop a Th1 inflammatory response, whereas females develop a Th2 response. Since their discovery, Toll-like receptors have been shown to play an important role in the development of the immune response against harmful pathogens. To assess the role of TLRs in coxsackievirus-induced myocarditis wild type and Toll-like receptor 2 −/− male and female mice were infected and assessed for viral replication, myocarditis, helper T-cell generation, and regulatory T-cell generation. TLR2 −/− mice show reduced Th1 expression compared to controls. Treatment of wild type mice with either Pam3CSK4 (TLR2) or LPS (TLR4) specific TLR agonists resulted in increased Th1 expression in male and female mice and a decrease in FoxP3 + regulatory T-cells in male mice. The suppression of T regulatory cells by TLR signaling in males but not females correlates with the increased myocarditis susceptibility of the males.