Toll-like receptors in infectious myocarditis: pathogen-specific recognition, spatiotemporal dynamic regulation and clinical translation

Figures

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  Figure 1. Specific recognition of distinct pathogens by TLRs in cardiomyocytes and subsequent inflammatory activation pathways. This diagram illustrates the specific recognition of pathogen-associated molecular patterns (PAMPs) from five classes of pathogens (viruses, Gram-negative bacteria, Gram-positive bacteria, fungi, ERV/AAV) by distinct TLR subtypes localized on the plasma membrane and endosomes of cardiomyocytes. Membrane-localized TLRs recognize: TLR1/2 heterodimers for peptidoglycan (Gram-positive); TLR2/6 heterodimers for lipoteichoic acid (Gram-positive); TLR4 for LPS (Gram-negative); and TLR2/6 heterodimers for β-glucan (Fungi). Endosomal TLRs recognize: TLR3 for viral dsRNA; TLR7/8 for viral ssRNA; and TLR9 for viral CpG-DNA and unmethylated CpG sequences derived from ERVs/AAVs. Ligand recognition triggers MyD88- or TRIF-dependent signaling cascades, leading to the activation of NF-κB, IRF3, and the NLRP3 inflammasome, which ultimately results in the release of inflammatory cytokines, myocardial inflammation, cellular injury, and fibrosis.

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  Figure 2. Spatiotemporal dynamic regulation of TLR signaling and pathological outcomes. This figure depicts the spatiotemporal dynamics of TLR signaling throughout the three phases of infectious myocarditis, illustrating changes in TLR profiles, driving factors, cellular functional transitions, and pathological outcomes. Acute Phase (0–7 d): Pathogen PAMPs activate TLR3/4/7/9 on cardiomyocytes, triggering an inflammatory storm and acute myocardial injury; this phase is counterbalanced by negative regulators such as A20, SOCS1, SIGIRR, and miR-146a. Transitional Phase (7–28 d): Damage-associated molecular patterns (DAMPs, e.g., HMGB1, mitochondrial DNA) sustain TLR activation, breaking immune tolerance and driving immune deviation and autoimmunity transformation. Chronic Phase (>28 d): Sustained high expression of TLR2/4/9 in macrophages and fibroblasts drives myocardial fibrosis and heart failure. Spatially, the functional relay transitions from cardiomyocytes (acute) to immune cells (transitional) and finally to fibroblasts (chronic).

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  Figure 3. TLR-targeted intervention strategies and core therapeutic effects in infectious myocarditis. This diagram illustrates the hierarchical TLR-targeted intervention strategies from upstream receptors to downstream pathways and their clinical translation status in infectious myocarditis. Left-side intervention hierarchy: (1) Upstream targets: TLR subtype-specific small-molecule inhibitors (e.g., TAK-242/CLI-095 for TLR4; NSC4375/Hydroxychloroquine for TLR7/9); (2) Midstream targets: Downstream pathway-targeted interventions (e.g., JNK inhibitors, AKT2 activators, ferroptosis inhibitors, endothelial cell exosomes); (3) Etiological layer: Special etiology combined interventions (e.g., AAV9-TRIM28 gene therapy, perioperative immunosuppression regimens, Omega-3 polyunsaturated fatty acids). Therapeutic output: These three layers converge to achieve three core therapeutic effects: alleviating inflammation, inhibiting fibrosis, and improving cardiac function. Right-side bottlenecks: Current clinical translation faces three major challenges: unclear therapeutic time windows, lack of a standardized patient stratification system, and insufficient specific biomarkers.