Targeting transient receptor potential channels to suppress proviral mitochondrial fission and mitophagy in order to mitigate CVB pancreatitis

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PROJECT SUMMARY Coxsackievirus B (CVB) is a common human pathogen that can cause an array of inflammatory diseases such as meningo-encephalitis, myocarditis and pancreatitis. CVB has strong tropism to the pancreas and as such is a leading cause of viral pancreatitis. Acute pancreatitis can sometimes be severe, which leads to systemic inflammation, damage to other organs and death in 10-30% of patients. Children are at higher risk for lethal CVB pancreatitis. CVB can also cause chronic pancreatitis, which is a persistent inflammation of the pancreas that is a risk factor for pancreatic cancer. Treatments for severe viral pancreatitis generally aim to mitigate symptoms, however there is a lack of effective interventions that limit disease progression. In a recent study we had reported that CVB type 3 (CVB3) infection causes mitochondrial fission with subsequent activation of mitophagy in infected cells. We surmise that CVB3 triggers this in order to become engulfed in mitophagosomes which become expelled from the host cell as virus-laden extracellular vesicles. Specifically blocking mitochondrial fission or mitophagy pathways disrupts this process and attenuates infection. In recent reports, the transient receptor potential (TRP) ion channels have been shown to influence mitochondrial dynamics. The capsaicin and heat receptor TRPV1 can trigger mitochondrial depolarization which leads to mitochondrial fragmentation. We have found that inhibiting TRPV1 not only prevents CVB3-induced mitochondrial fission, but also significantly reduces infection in vitro. Similarly, activating the TRPV1 antagonist TRPM8 using menthol also greatly blunts infection. We tested the effects of oral menthol treatments in a mouse model of pancreatic CVB3 infection and saw that menthol blunts pancreatic damage and viral load. There is very limited data on how TRP channels influence viral infection. Understanding how these pathways influence CVB3 infection will allow us to establish novel antiviral treatments (such as menthol) to be used to suppress CVB3 pancreatitis as well as other CVB3- induced diseases.