Mechanisms and Therapeutic Strategies of Viral Myocarditis Targeting Autophagy

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  FIGURE 1. The CVB3 life cycle. The CVB3 life cycle mainly involves six different stages: viral attachment to the host cell, penetration, RNA genome replication, viral protein translation, assembly of virions, and exit from the host cell. Specifically, CVB3 infection begins by the coupling of decay-accelerating factor (DAF, primary attachment protein or coreceptor) and coxsackievirus and adenovirus receptor (CAR, internalization receptor) on host cells. Virus binding to CAR facilitates virus internalization. Following internalization and virus uncoating, the positive-sense RNA of CVB3 enters the cytoplasm and serves as a template for the translation of viral polyprotein. Subsequently, the newly synthesized polyprotein is cleaved into several structural and functional proteins. Together with the positive RNA strands, new virions are assembled and released as progeny viruses to initiate new rounds of infection.

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  FIGURE 2. The process of autophagy. The process of autophagy includes induction and phagophore nucleation, phagophore expansion, autophagosome maturation, autophagosome fusion with lysosomal membranes, degradation, and recirculation of autophagosomal contents. Induction and phagophore nucleation occur in the structure known as the “omegasome” on the endoplasmic reticulum membrane and are mainly mediated by the ULK1 complex and PI3KC3 complex I. Local activated PI3P and recruited Atg9 provide the raw materials required for membrane formation. Then, the ATG12-ATG5-ATG16L1 complex is recruited to the membrane of the phagophore, enhancing the conversion of LC3 and GABARAPs to membrane-resident PE, promoting phagophore expansion. During the formation of autophagosomes, p62 serves as a bridge connecting LC3 with the ubiquitinated substrate. Finally, the ATG12-ATG5 and ATG8/LC3 conjugation systems mediate the process by which the isolation membrane of the autophagosome forms a closed bilayer membrane structure and matures. Mediated by autophagosome-localized STX17, SNAP29, and lysosome-localized VAMP8, mature autophagosomes fuse with lysosomes to form autolysosomes, which degrade cytoplasmic…

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  FIGURE 3. Altered autophagy in viral myocarditis. In viral myocarditis, CVB3 exploits the double-membrane structure of autophagosomes to replicate. CVB3 promotes the formation of autophagosomes in host cells, which may be associated with enhanced eIF2α phosphorylation. CVB3 proteinase 2B also plays a significant role in this process. After CVB3 infection, autophagy is activated. In the early stage, CVB3 is sequestered by autophagosomes and delivered to lysosomes, activating the autophagy positive-feedback pathway. Autophagosomes are subsequently degraded. However, as infection worsens, CVB3 proteinase 3C contributes to the cleavage of autophagy receptors that play a vital role in autophagosome-lysosome fusion. Moreover, CVB3 also targets TFEB for proteolytic processing by CVB3 proteinase 3C to disrupt host lysosomal function. Autophagosome-lysosome fusion is impaired, which affects the degradation of autophagosomes, enhancing viral infection.

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  FIGURE 4. In viral myocarditis, CVB3 influences the process of autophagy in both cardiomyocytes and cardiac fibroblasts, which promotes disease progression through a variety of mechanisms. In H9C2 cells, mitochondrial structures are destroyed by CVB3, which induces mitochondrial autophagy in a Parkin-dependent manner. Additionally, iNOS inhibition attenuates CVB3-induced autophagy activation, increasing cell proliferation, and suppressing cell apoptosis. Moreover, in the early stage of CVB3 infection in H9C2 cells, calpain is beneficial for viral replication by promoting the formation of autophagosomes and inhibiting apoptosis. However, in a study of cardiomyocytes from CVB3-infected suckling mice, inhibiting calpain promoted the formation of autophagosomes and CVB3 replication. In fibroblasts, CVB3 promotes the formation of autophagosomes by inhibiting PAR1 and subsequently contributes to the replication of CVB3 and the release of inflammatory factors.