Calcium signaling in Calicivirus infection and replication

项目总结/摘要 肠道病毒如人诺如病毒（HuNoV）和轮状病毒（RV）仍然是急性病毒性腹泻的主要原因。 胃肠炎，其中全世界每年有超过7亿例病例。尽管这些普遍存在， 肠道病原体，在这两种病毒如何破坏体内平衡的知识方面存在持续的空白 细胞过程来增强它们的复制。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细胞周期中失调钙信号传导。 通过病毒离子通道或病毒孔蛋白的功能来控制感染过程。RV病毒孔蛋白诱导的钙 已显示失调启动ADP介导的旁分泌信号级联， 在ER中，钙从邻近的未感染细胞释放，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病毒孔蛋白活性启动了细胞凋亡。 这一过程被称为钙库操作的钙进入（SOCE）。杜兰病毒系统的初步数据， 密切相关的人诺如病毒替代物，已经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。的目的 建议是表征Tulane和人诺如病毒感染的细胞的钙信号传导表型， 将这些观察结果扩展到近端未感染的细胞，并确定失调的细胞的作用。 病毒复制中的细胞钙信号。该项目的目标1提出了表征异常钙 Tulane和人诺如病毒感染后感染和近端未感染细胞中的信号传导。目标2将 确定钙库操作的钙进入途径对病毒复制的贡献， 宿主细胞钙信号动力学对病毒生长的影响。揭示这些感染特征将揭示 在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上， 可能提示了一种潜在的保守机制，即增强的复制和疾病进展， 肠道嗜性病毒因此，这一建议将为新型广谱抗病毒药物提供重要的见解， 目标的

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.