Targeting the Myocardial Microenvironment: Novel Antiviral Strategies and Therapeutic Perspectives for Coxsackievirus B–Induced Myocarditis

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  Figure 1. Intercellular communication and interaction mechanisms in the myocardial microenvironment. (1) Cardiac fibroblasts and mast cells interact to promote the release of inflammatory factors and chemokines. (2) Cardiac fibroblasts secrete chemokines to recruit Th17 cells. (3) Trem2+ reparative macrophages secrete paracrine factors to act on endothelial cells, which provide a reparative microenvironment for them. (4) NK cells secrete cytokines to regulate the polarization direction of macrophages. (5) B cells inhibit M2 polarization of macrophages through cell–cell contact or cytokine secretion. (6) Cardiomyocytes secrete chemokines to recruit NK cells, and NK cells kill infected cardiomyocytes. (7) Cardiomyocytes release damage‐associated molecules to activate macrophages. (8) Macrophages secrete factors to activate cardiac fibroblasts, which secrete chemokines to recruit monocytes. (9) Endothelial cells undergo pyroptosis to release viruses and inflammatory factors that spread to cardiomyocytes. (10) Dendritic cells present antigens to activate T cells and regulate the differentiation direction of T‐cell subsets. (11) Neutrophils secrete cytokines to recruit macrophages, which…

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  Figure 2. Key molecular mechanisms and pathologic progression of myocarditis induced by coxsackievirus B3. CVB3 invades host cells via DAF and CAR receptors, translates viral proteins through IRES elements, and inhibits host translation; viral dsRNA activates RIG‐I, TLR3/7, and other receptors as well as the NF‐κB pathway, inducing the expression of type I interferons and cytokines. Sustained NF‐κB activation promotes the release of proinflammatory cytokines, and NLRP3 inflammasome activates caspase‐1 to trigger pyroptosis and produce mature cytokines; Bax/Bcl‐2 imbalance initiates the mitochondrial apoptotic pathway, activating caspase‐3 to mediate cardiomyocyte apoptosis. CAR indicates coxsackievirus and adenovirus receptor; CVB3, coxsackievirus B3; DAF, decay‐accelerating factor; dsRNA, double‐stranded RNA; eIF4G, eukaryotic translation initiation factor 4G; GSDMD, gasdermin D; IRES, internal ribosome entry site; NF‐κB, nuclear factor‐κB; NLRP3, NOD‐like receptor family pyrin domain containing 3; RIG‐I, retinoic acid–inducible gene I; TLR, toll‐like receptor; and TNF‐α, tumor necrosis factor‐α.

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  Figure 3. Molecular mechanisms of CVB3 infection in cardiac fibroblasts. CVB3 enters cardiac fibroblasts and its 2B protein induces ER stress via Ca2+ dysregulation, promoting LC3‐I conversion to LC3‐II and autophagosome formation. Reduced STX17 expression blocks autophagosome‐lysosome fusion, leading to autophagic flux impairment. TGF‐β1 activates downstream signaling pathways, including p38 MAPK, ERK, and Smad2/3, whereas Fosl‐2 upregulates beclin‐1 and LC3B to enhance autophagy. These events synergistically drive the synthesis of collagen type I/III and CTGF expression, ultimately contributing to cardiac fibrosis. CTGF indicates connective tissue growth factor; CVB3, coxsackievirus B3; ER, endoplasmic reticulum; ERK, extracellular signal‐regulated kinase; LC3, microtubule‐associated protein 1 light chain 3; MAPK, mitogen‐activated protein kinase; STX17, syntaxin 17; and TGF‐β, transforming growth factor‐β.

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  Figure 4. Macrophage molecular mechanisms and dynamic changes during CVB3‐induced cardiac infection. CVB3 infects cardiomyocytes and induces MCP‐1 release, which recruits CCR2+ monocytes to cardiac tissue via the MCP‐1/CCR2 axis. Recruited monocytes differentiate into MoMFs that polarize to proinflammatory M1 phenotype, accompanied by reduced resident macrophages. CVB3 capsid proteins (VP1/VP2) and myocardial mtDNA activate NLRP3 inflammasome and STING–NF‐κB pathway, respectively, whereas transmissible ER stress enhances cytokine secretion. Macrophage M1/M2 polarization imbalance persists with gender differences: IFN‐γ drives M1 in males, and IL‐4 promotes M2 in females. CCR indicates C‐C chemokine receptor; CVB3, coxsackievirus B3; ER, endoplasmic reticulum; iNOS, inducible nitric oxide synthase; IFN‐γ, interferon‐γ; IL, interleukin; MCP‐1, monocyte chemoattractant protein‐1; MoMF, monocyte‐derived macrophage; mtDNA, mitochondrial DNA; NF‐κB, nuclear factor‐κB; NLRP3, NOD‐like receptor family pyrin domain containing 3; STING, stimulator of interferon genes; and TNF‐α, tumor necrosis factor‐α.

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  Figure 5. Neutrophil‐ and lymphocyte‐mediated immune mechanisms in CVB3‐induced myocarditis. This schematic integrates innate and adaptive immune responses in CVB3‐induced myocarditis, showing neutrophil‐driven inflammation (A) and lymphocyte‐mediated immune regulation (B). A, CVB3 activates cardiac neutrophils via TLR8/NF‐κB signaling to produce proinflammatory cytokines, with self‐recruitment via CXCL2/CXCL3‐CXCR2. Viral RNA induces mROS‐PAD4–dependent NET release to capture viruses and amplify inflammation. B, Antigen‐presenting cells activate CD4+/CD8+ T cells and B cells. CD4+ T cells differentiate into Th1/Th2/Th17/Treg subsets, secreting cytokines to regulate viral replication, inflammation, and immune balance. CVB3 indicates coxsackievirus B3; CXCL, chemokine (C‐X‐C motif) ligand; CXCR, chemokine (C‐X‐C motif) receptor; IFN‐γ, interferon‐γ; IL, interleukin; MHC, major histocompatibility complex; mROS‐PAD, mitochondrial reactive oxygen species‐peptidylarginine deiminase; NET, neutrophil extracellular trap; NF‐kB, nuclear factor‐kB; Th, T helper cell; TLR, toll‐like receptor; TNF‐α, tumor necrosis factor‐α; and Treg, regulatory T cell.

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  Figure 6. Stage‐specific pathogenesis and targeted interventions in CVB3‐induced myocarditis. This schematic timeline illustrates 3 consecutive pathologic phases of CVB3‐induced myocarditis, summarizing stage‐specific core features, preferential target cells, key signaling pathways, and therapeutic principles. The early infection phase (0–3 days) is marked by viral replication and cardiomyocyte injury, prioritizing antiviral and cardioprotective strategies via RIG‐I/TLR3, cGAS‐STING, and IFN‐I pathways. The acute inflammatory phase (3–14 days) features immune infiltration and cytokine storm, requiring targeted immunomodulation via NF‐κB, CCL2/CCR2, and β‐arrestin/cGAS‐STING pathways. The chronic fibrosis phase (>14 days) presents progressive fibrosis and remodeling, requiring antifibrotic interventions via TGF‐β1/Smad2/3 and EndMT pathways. CAR indicates coxsackievirus and adenovirus receptor; CCL, chemokine (C‐C motif) ligand; CCR, C‐C chemokine receptor 2; cGAS, cyclic GMP‐AMP synthase; CXCL, chemokine (C‐X‐C motif) ligand; CXCR, chemokine (C‐X‐C motif) receptor; DAF, decay‐accelerating factor; DC, dendritic cell; EndMT, endothelial‐to‐mesenchymal transition; IFN, interferon; IL‐21R,…