Calcium signaling in Calicivirus infection and replication

项目摘要/摘要 肠道病毒，如人类诺如病毒(HuNov)和轮状病毒(RV)，仍然是急性病毒的主要原因 胃肠炎，全世界每年有超过7亿例胃肠炎。尽管这种情况很普遍 肠道病原体，关于这两种病毒如何破坏体内平衡的知识一直存在空白。 细胞过程以增强它们的复制。除了分享疾病的临床表现外， 呼肠孤病毒科和杯状病毒科的成员都知道在 通过病毒离子通道或病毒孔蛋白的功能而感染的过程。轮状病毒病毒素诱导的钙离子 已有研究表明，调节失调会启动ADP介导的旁分泌信号级联反应，最终导致 在内质网中，邻近未受感染的细胞释放钙，这种细胞现象称为细胞间 钙波。除了近端细胞调节失调外，RV nsp4病毒孔蛋白活性还启动了细胞 这一过程被称为储存操作钙离子进入(SOCE)。杜兰病毒系统的初步数据，a 密切相关的人类诺沃克病毒替代物，已经显示出类似的细胞间钙信号 表型和利用SOCE途径增强复制的潜力。这样做的目的是 建议表征杜兰和人诺如病毒感染细胞的钙信号表型， 将这些观察扩大到包括近端未感染的细胞，并确定调控失调的作用 病毒复制中的细胞钙信号。该项目的目标1建议描述异常钙的特征。 杜兰和人类诺如病毒感染后感染和近端未感染细胞中的信号。目标2将 确定储存操作的钙进入途径对病毒复制的贡献，关键链接 宿主细胞钙信号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递过程和 可能暗示了一种潜在的保守机制，即增强复制和疾病进展 嗜肠病毒。因此，这项提议将为新型广谱抗病毒药物提供重要的见解。 目标。

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.