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

项目总结 柯萨奇B组病毒(CVB)是一种常见的人类病原体，可导致一系列炎症性疾病，如 如脑膜脑炎、心肌炎和胰腺炎。CVB对胰腺有强烈的趋向性，因此也是如此 病毒性胰腺炎的主要原因。急性胰腺炎有时会很严重，这会导致全身性 10%-30%的患者会出现炎症、其他器官受损和死亡。儿童患致命性CVB的风险更高 胰腺炎。CVB还可导致慢性胰腺炎，这是一种持续性的胰腺炎症，即 胰腺癌的危险因素。重症病毒性胰腺炎的治疗通常旨在缓解症状， 然而，缺乏有效的干预措施来限制疾病的发展。在最近的一项研究中，我们报告了 柯萨奇病毒3型(CVB3)感染引起线粒体分裂，继而激活有丝分裂 被感染的细胞。我们推测，CVB3触发这一过程是为了吞噬线粒吞噬小体 以携带病毒的胞外小泡的形式从宿主细胞中排出。特异地阻断线粒体 分裂或有丝分裂途径扰乱了这一过程，并减轻了感染。在最近的报告中，瞬变的 受体电位(Trp)离子通道已被证明影响线粒体动力学。辣椒素和 热感受器TRPV1可触发线粒体去极化，导致线粒体碎裂。我们 发现抑制TRPV1不仅可以阻止CVB3诱导的线粒体分裂，而且显著 减少体外感染。同样，用薄荷醇激活TRPV1拮抗剂TRPM8也会大大钝化 感染。我们测试了口服薄荷醇对胰腺CVB3感染小鼠模型的影响。 看到薄荷醇可以减缓胰腺损伤和病毒载量。关于Trp通道的数据非常有限 影响病毒感染。了解这些途径如何影响CVB3感染将使我们能够建立 新的抗病毒治疗(如薄荷醇)将用于抑制CVB3胰腺炎以及其他CVB3- 诱发疾病。

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.