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

Area of Science:

• Immunology
• Virology
• Cardiovascular Research

Background:

• Coxsackievirus B3 (CVB3) causes myocarditis with a sex bias, males exhibit more severe cardiac inflammation.
• Males develop a Th1 immune response, while females develop a Th2 response.
• Toll-like receptors (TLRs) are crucial in pathogen immune response development.

Purpose of the Study:

• To investigate the role of TLRs, specifically TLR2, in coxsackievirus-induced myocarditis.
• To assess the impact of TLR signaling on T-cell responses and myocarditis severity in a sex-dependent manner.

Main Methods:

• Infection of wild-type and Toll-like receptor 2 knockout (TLR2-/-) male and female mice with CVB3.
• Assessment of viral replication, myocarditis, helper T-cell (Th1/Th2) generation, and regulatory T-cell (Treg) generation.
• Treatment of wild-type mice with TLR2 and TLR4 agonists (Pam3CSK4 and LPS) to evaluate immune modulation.

Main Results:

• TLR2-/- mice exhibited reduced Th1 immune responses compared to controls.
• TLR agonist treatment increased Th1 responses in both male and female mice.
• TLR signaling decreased FoxP3+ regulatory T-cells in male mice but not females, correlating with increased myocarditis.

Conclusions:

• TLR2 signaling plays a significant role in the sex bias of CVB3-induced myocarditis.
• Suppression of regulatory T-cells by TLRs in males contributes to their heightened susceptibility to severe cardiac inflammation.
• Targeting TLRs may offer therapeutic strategies for managing viral myocarditis, considering sex-specific immune responses.