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

UNLABELLED

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/ ) 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/ , mitochondrial protein TOM70/ , and fission protein phospho-DRP1/ (Ser 616). Moreover, these EVs exhibited increased levels of heat shock protein HSP70/ , suggesting a potential role of these chaperones in facilitating infectious EV release from cells. Furthermore, TRPV1 inhibition with capsazepine significantly reduced viral infection . We previously observed similar effects with another TRPV1 inhibitor SB-366791. Our current 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 and TRPV1 as potential exacerbating factors that facilitates CVB3 dissemination via mitophagy-derived EVs.

IMPORTANCE

CVB3 is a prevalent pathogen responsible for a range of severe diseases, including myocarditis, pericarditis, pancreatitis, and meningoencephalitis. Despite its clinical significance, factors that determine the severity of CVB3 infection and why some individuals experience life-threatening manifestations while others have mild, cold-like symptoms remain poorly understood. This study provides new insights into the molecular mechanisms underlying CVB3 dissemination and pathogenesis. By investigating the role of capsaicin, a common dietary component, in modulating viral spread, we demonstrate that activation of TRPV1 by capsaicin enhances release of infectious CVB3 via mitophagy-derived EVs. Our results offer novel evidence that modulating TRPV1 activity could influence the clinical outcomes of CVB3 infection, opening new avenues for therapeutic interventions. Given the widespread consumption of capsaicin, this study highlights an important dietary factor that could play a role in shaping CVB3 pathogenesis and its clinical manifestations, underscoring the potential for targeted strategies to mitigate severe disease outcomes.