Calcium signaling in Calicivirus infection and replication

杯状病毒感染和复制中的钙信号传导

基本信息

批准号：
10652400
负责人：
Francesca Jean Scribano
金额：
$ 4.77万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10652400
关键词：
Acute Animal Model Antidiarrheals Antiviral Therapy Biological Models Calcium Calcium Channel Calcium Oscillations Calcium Signaling Calicivirus Calicivirus Infections Cell Culture Techniques Cell Signaling Process Cell physiology Cells Cessation of life Clinical Communication Data Development Disease Disease Progression Dose Enteral Family Fluids and Secretions Functional disorder Gastroenteritis Genetic Growth Human Image Infection Innate Immune Response Intestines Ion Channel Knock-out Knowledge Link Liquid substance Measures Mediating Norovirus Organoids Paracrine Communication Pathway interactions Phenotype Play Prevalence Proteins Purinoceptor Reoviridae Reovirus Role Rotavirus Rotavirus Infections Serotonin Signal Pathway Signal Transduction System Testing Therapeutic Transfection Vaccines Viral Viral Gastroenteritis Viral Pathogenesis Virus Virus Diseases Virus Replication Work chelation cytokine diarrheal disease enteric pathogen experience extracellular global health insight member monolayer novel paracrine pharmacologic rational design response societal costs

项目摘要

PROJECT SUMMARY/ABSTRACT Enteric viruses such as human norovirus (HuNoV) and rotavirus (RV) remain the leading causes of acute viral gastroenteritis, of which there are over 700 million annual cases worldwide. Despite the prevalence of these enteric pathogens, there are persistent gaps in knowledge in how both viruses disrupt homeostatic cellular processes to enhance their replication. In addition to sharing clinical manifestations of disease, members of both Reoviridae and Caliciviridae families are known to dysregulate calcium signaling during the course of infection through the function of a viral ion channel, or viroporin. RV viroporin-induced calcium dysregulation has been shown to initiate an ADP-mediated paracrine signaling cascade that ultimately results in ER calcium release from neighboring uninfected cells, a cellular phenomenon known as intercellular calcium waves. In addition to proximal cell dysregulation, RV NSP4 viroporin activity initiates a cellular process known as store-operated calcium entry (SOCE). Preliminary data in the Tulane virus system, a closely related human norovirus surrogate, has shown both an analogous intercellular calcium signaling phenotype and the potential to exploit SOCE pathways for enhanced replication. The objective of this proposal is to characterize the calcium signaling phenotype of Tulane and human norovirus infected cells, extending these observations to include proximal, uninfected cells, and to determine the role of dysregulated cellular calcium signaling in viral replication. Aim 1 of this project proposes to characterize aberrant calcium signaling in infected and proximal, uninfected cells following Tulane and human norovirus infection. Aim 2 will determine the contributions of store operated calcium entry pathways to virus replication, critically linking host cell calcium signaling dynamics to viral growth. Unveiling these features of infection will reveal important parallels in the way that reoviruses and caliciviruses disrupt host cell signaling processes and may suggest a potentially conserved mechanism of enhanced replication and disease progression in gut-tropic viruses. Therefore, this proposal will provide critical insight into novel broad-spectrum antiviral targets.

项目概要/摘要人类诺如病毒（HuNoV）和轮状病毒（RV）等肠道病毒仍然是急性病毒的主要原因胃肠炎，全世界每年有超过 7 亿例病例。尽管这些现象普遍存在肠道病原体，关于这两种病毒如何破坏体内平衡的知识仍然存在差距细胞过程以增强其复制。除了分享疾病的临床表现外，已知呼肠孤病毒科和杯状病毒科的成员在通过病毒离子通道或病毒孔蛋白的功能进行感染的过程。 RV病毒孔蛋白诱导的钙失调已被证明会启动 ADP 介导的旁分泌信号级联反应，最终导致内质网钙从邻近未感染细胞释放，这是一种称为细胞间的细胞现象钙波。除了近端细胞失调外，RV NSP4 病毒孔蛋白活性还引发细胞这个过程被称为存储操作钙进入（SOCE）。杜兰病毒系统的初步数据密切相关的人类诺如病毒替代品，显示出类似的细胞间钙信号传导表型和利用 SOCE 途径增强复制的潜力。此举的目的提议是表征杜兰大学和人类诺如病毒感染细胞的钙信号传导表型，将这些观察扩展到包括近端未感染的细胞，并确定失调的作用病毒复制中的细胞钙信号传导。该项目的目标 1 提出表征异常钙杜兰大学和人类诺如病毒感染后，受感染细胞和近端未感染细胞中的信号传导。目标2将确定商店操作的钙进入途径对病毒复制的贡献，关键联系宿主细胞钙信号传导动力学对病毒生长的影响。揭示感染的这些特征将揭示呼肠孤病毒和杯状病毒破坏宿主细胞信号传导过程的方式有重要的相似之处可能表明增强复制和疾病进展的潜在保守机制嗜肠道病毒。因此，该提案将为新型广谱抗病毒药物提供重要见解目标。