Investigating the potential role of capsaicin in facilitating the spread of coxsackievirus B3 via extracellular vesicles

Abstract

Coxsackievirus B3 (CVB3) is a non-enveloped picornavirus that can cause systemic inflammatory diseases including myocarditis, pericarditis, pancreatitis, and meningoencephalitis. We have previously reported that following infection, CVB3 localizes to mitochondria, inducing mitochondrial fission and mitophagy, while inhibiting lysosomal degradation by blocking autophagosome-lysosome fusion. This results in the release of virus-laden mitophagosomes from the host cell as infectious extracellular vesicles (EVs) which allow non-lytic viral egress. Transient receptor potential vanilloid 1 (TRPV1/TRPV1) is a heat and capsaicin-sensitive cation channel that regulates mitochondrial dynamics by inducing mitochondrial membrane depolarization and fission. In this study, we found that treating cells with the TRPV1 agonist capsaicin dramatically enhances CVB3 egress via EVs. Analysis of the released EVs revealed increased levels of viral capsid protein VP1/VP1, mitochondrial protein TOM70/TOMM70, and fission protein phospho-DRP1/DNM1L (Ser 616). Moreover, these EVs exhibited increased levels of heat shock protein HSP70/HSPA1A, suggesting a potential role of these chaperones in facilitating infectious EV release from cells. Furthermore, TRPV1 inhibition with capsazepine significantly reduced viral infection in vitro. We previously observed similar effects in vitro with another TRPV1 inhibitor SB-366791. Our current in vivo studies found that SB-366791 significantly mitigates pancreatic damage and reduces viral titers in mouse model of CVB3 pancreatitis. Given the lack of understanding regarding the factors that contribute to diverse clinical manifestations of CVB3, our study highlights capsaicin andTRPV1 as a potential exacerbating factors that facilitates CVB3 dissemination via mitophagy-derived EVs.