Calcium signaling in Calicivirus infection and replication

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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.