Antiviral innate immunity in myocarditis: mechanisms and emerging therapeutics

Figures

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  Fig. 1. Timeline of discovery of major cardiotropic viruses causing VM. Schematic timeline illustrating the approximate decades in which key viruses relevant to VM were identified. Influenza viruses and enteroviruses were recognized in the 1950s; cytomegalovirus in the 1970s; human immunodeficiency viruses in the 1980s; adenoviruses in the 1990s; human parvovirus and human herpesvirus 6 in the 2000s; hepatitis C virus and Epstein–Barr virus in the 2010s; SARS-CoV-2 in 2020; and thogotovirus most recently in 2025.

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  Fig. 2. Direct and indirect antiviral effector mechanisms of NK cells. Schematic illustration of the direct and indirect pathways by which NK cells contribute to antiviral immunity. Direct mechanisms include cytotoxic degranulation (perforin and granulysin), receptor-mediated killing of virus-infected cardiomyocytes or other target cells (for example, via NKG2D and Fas ligand) and production of antiviral cytokines such as IFN-γ and TNF. Indirect mechanisms involve NK cell-derived cytokines and chemokines that recruit and activate other immune cells, including neutrophils, monocytes and T cells, and promote adaptive immune responses through polarization of Th1 cells and activation of CD8+ T cells.

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  Fig. 3. TLR signaling pathways in antiviral innate immunity during VM. Schematic representation of TLR-mediated innate immune signaling in response to viral and microbial PAMPs during VM. Endosomal TLR3 senses viral dsRNA and signals through the adaptor TRIF, whereas TLR7 and TLR8 detect single-stranded RNA (ssRNA) and TLR9 recognizes CpG-containing single-stranded DNA (ssDNA), all primarily via the adaptor MyD88. Cell-surface TLR4 responds to lipopolysaccharide (LPS) and signals through both TRIF- and MyD88-dependent pathways. Engagement of these TLRs converges on activation of the adaptor proteins TRAF3 and TRAF6, leading to phosphorylation and activation of the transcription factors IRF3 and IRF7. Activated IRF3 and IRF7 translocate to the nucleus to induce type I IFN gene expression, promoting antiviral immune responses in the heart.

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  Fig. 4. RNA-sensing pathways in antiviral innate immunity during VM. Schematic overview of RLR-mediated and noncanonical RNA-sensing pathways activated by cardiotropic RNA viruses during VM. Viral RNA is recognized by RIG-I or MDA5 through binding to their C-terminal domains (CTDs), inducing conformational changes that expose the caspase activation and recruitment domains (CARDs). CARD–CARD interactions promote activation of the mitochondrial adaptor MAVS, leading to downstream signaling through TBK1 and IKK complexes, activation of IRF3 and IRF7, and induction of type I IFN, as well as activation of NF-κB and production of proinflammatory cytokines. In parallel, viral dsRNA can be sensed by the noncanonical RNA sensor PARP9, which activates a PI3K–AKT3 signaling axis to induce IRF3/7 activation independently of MAVS, further contributing to antiviral immune responses in the heart. Activating signals are shown with blue arrows; type I IFN transcription, which restricts VM, is indicated by a bold blue arrow, whereas transcription of proinflammatory cytokines, which promotes VM, is indicated by a bold red arrow.

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  Fig. 5. Regulation of the JAK–STAT signaling pathway during VM. Schematic illustration of SOCS-mediated feedback inhibition of the JAK–STAT pathway. Cytokine engagement of cell-surface receptors activates associated Janus kinases (JAKs), leading to phosphorylation and activation of STAT1 and STAT3, which translocate to the nucleus to induce target gene expression, including SOCS1 and SOCS3. SOCS1 directly binds phosphorylated JAK proteins to inhibit kinase activity, whereas SOCS3 associates with phosphorylated tyrosine residues within the cytoplasmic domain of cytokine receptors, thereby blocking further STAT activation. Together, SOCS1 and SOCS3 function as inducible negative regulators that terminate JAK–STAT signaling. Activating signals are shown with blue arrows, whereas negative feedback signals are shown with red arrows.

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  Fig. 6. DNA-sensing pathways in antiviral innate immunity during VM. Schematic overview of cytosolic DNA-sensing pathways that drive antiviral innate immune activation in response to cardiotropic DNA viruses. Viral dsDNA is recognized by cyclic GMP–AMP synthase (cGAS), leading to the production of the second messenger cyclic GMP–AMP (cGAMP), which binds and activates the adaptor protein STING. Activated STING recruits and activates TBK1 and the IKK complex, resulting in phosphorylation and activation of IRF3 and IRF7, as well as activation of NF-κB, thereby inducing transcription of type I IFN and proinflammatory cytokines. In parallel, the DNA sensors DDX41 and IFI16 also detect viral dsDNA and signal through STING to engage the same downstream TBK1–IRF and IKK–NF-κB pathways. In addition to STING-dependent signaling, AIM2 functions as an inflammasome-forming DNA sensor: upon binding cytosolic dsDNA, AIM2 recruits the adaptor ASC to assemble the AIM2 inflammasome and activate pro-caspase-1 (proCasp-1). Active caspase-1 (Casp-1) then processes proIL-1β and proIL-18 into mature IL-1β and IL-18 and cleaves gasdermin D (GSDMD) to generate the pore-forming N-terminal fragment (GSDMD-N),…