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

靶向瞬时受体电位通道抑制原病毒线粒体裂变和线粒体自噬以减轻 CVB 胰腺炎

• 批准号: 10578775
• 负责人: Jon Sin
• 金额: $ 31.38万
• 依托单位: UNIVERSITY OF ALABAMA IN TUSCALOOSA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-07 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578775
• 关键词: Acute; Affect; Antibody titer measurement; Antiviral Therapy; Area; Attenuated; Capsaicin; Cardiac Myocytes; Cells; Cessation of life; Child; Coxsackie B Viruses; Coxsackie Viruses; Cytoplasm; Data; Diagnosis; Disease; Disease Progression; Enterovirus; Enzymes; Exocrine pancreas; Hela Cells; Human; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Ion Channel; Malignant neoplasm of cervix uteri; Malignant neoplasm of pancreas; Mediating; Meningoencephalitis; Menthol; Mitochondria; Mitochondrial RNA; Mus; Myocarditis; Nonlytic; Oral; Organ; Pancreas; Pancreatitis; Pathway interactions; Patients; Peptide Hydrolases; Play; Predisposition; Process; Production; Reporting; Ribosomes; Risk Factors; Role; Severities; Signal Transduction; Symptoms; TRP channel; TRPV1 gene; Testing; Translating; Translations; Tropism; Viral; Viral Load result; Viral Pathogenesis; Viral Proteins; Virus; Virus Diseases; Virus Replication; acute pancreatitis; antagonist; antiviral immunity; cancer cell; chronic pancreatitis; effective intervention; extracellular vesicles; high risk; human pathogen; insight; mortality; mouse model; neutralizing antibody; novel; novel therapeutics; premature; prevent; promoter; receptor; systemic inflammatory response; viral RNA

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.

项目概要 柯萨奇病毒 B (CVB) 是一种常见的人类病原体，可引起一系列炎症性疾病，例如 如脑膜脑炎、心肌炎和胰腺炎。 CVB 对胰腺有很强的趋向性，因此 病毒性胰腺炎的主要原因。急性胰腺炎有时可能很严重，导致全身性胰腺炎 10-30% 的患者出现炎症、其他器官损伤和死亡。儿童患致命 CVB 的风险更高 胰腺炎。 CVB 还可引起慢性胰腺炎，这是一种持续性的胰腺炎症， 胰腺癌的危险因素。严重病毒性胰腺炎的治疗通常旨在减轻症状， 然而，缺乏限制疾病进展的有效干预措施。在最近的一项研究中，我们报告了 CVB 3 型 (CVB3) 感染导致线粒体裂变，随后激活线粒体自噬 被感染的细胞。我们推测 CVB3 会触发这一点，以便被线粒体吞噬体吞噬，从而吞噬线粒体。 作为载有病毒的细胞外囊泡从宿主细胞中排出。特异性阻断线粒体 裂变或线粒体自噬途径会破坏这一过程并减弱感染。在最近的报告中，瞬态 受体电位 (TRP) 离子通道已被证明会影响线粒体动力学。辣椒素和 热受体 TRPV1 可以触发线粒体去极化，从而导致线粒体碎片。我们 研究发现，抑制 TRPV1 不仅可以阻止 CVB3 诱导的线粒体裂变，而且还可以显着抑制 减少体外感染。同样，使用薄荷醇激活 TRPV1 拮抗剂 TRPM8 也会大大削弱 感染。我们在胰腺 CVB3 感染小鼠模型中测试了口服薄荷醇治疗的效果， 发现薄荷醇可以减轻胰腺损伤和病毒载量。关于 TRP 如何传播的数据非常有限 影响病毒感染。了解这些途径如何影响 CVB3 感染将使我们能够确定 用于抑制 CVB3 胰腺炎以及其他 CVB3- 的新型抗病毒治疗（例如薄荷醇） 诱发疾病。