Toll-like receptor signaling governs inflammatory phenotypes and progression in infectious myocarditisToll-like receptors shape severity of infectious myocarditis

Infectious myocarditis is a life-threatening cardiovascular inflammatory disorder characterized by high heterogeneity in clinical onset, progression and prognosis. Large-sample clinical data have demonstrated that the in-hospital mortality of COVID-19-associated myocarditis reaches 19.4%, significantly higher than that of influenza-associated myocarditis (10.5%). Additionally, the incidence of adeno-associated virus (AAV) gene therapy-related myocarditis is 6.2%, while the mortality of sepsis-associated myocarditis is as high as 70%–90%. Toll-like receptors (TLRs), the core pattern recognition receptors of innate immunity, dominate the entire pathological cascade, ranging from pathogen recognition and acute inflammatory burst to myocardial injury and chronic fibrous remodeling. Nevertheless, most current studies merely focus on the linear correlation between individual TLR activation and myocardial inflammation, failing to systematically clarify pathogen-TLR matching specificity and the spatiotemporal dynamic regulatory mechanisms of TLR signaling throughout disease progression. This review comprehensively combs the latest epidemiological profiles of infectious myocarditis, characterizes the expression patterns and signaling regulatory features of the TLR family within the cardiac immune microenvironment, analyzes pathogen-specific recognition modes mediated by common pathogens, elaborates the spatiotemporal regulatory rules of TLR signaling across acute inflammation, immune deviation and chronic fibrosis stages, and summarizes pathogen-oriented intervention strategies as well as relevant translational bottlenecks. Cumulative clinical evidence confirms that pathogen-TLR matching determines inflammatory phenotypes and severity of infectious myocarditis, and that the spatiotemporal dynamics of TLR signaling directly govern disease progression. Notably, TLR-targeted therapies must adhere to the core principles of pathogen specificity and staged precise regulation. This review provides a systematic theoretical basis for precise immunodiagnosis and individualized immunotherapy of infectious myocarditis.