Michael Eledge, Baylor College of Medicine

Michael R. Eledge*, Francesca Scribano*, and Joseph Hyser* *Balyor College of Medicine, Houston Texas

Cell Biology of Viral Infection

Rotavirus (RV) primarily infects small intestinal enterocytes, which mount an innate immune responses to establish an antiviral ‘firewall’ to limit virus replication. RV infection increases Ca2+ signaling in both infected cells and in uninfected cells through paracrine activation of P2Y1 purinergic receptors. P2Y1 signaling promotes multiple aspects of RV pathogenesis; however, extracellular purines are also Damage-associated Molecular Patterns (DAMPs) that can influence virus-induced activation of interferon (IFN) or downstream IFN-stimulated gene (ISG) responses. We confirmed this by showing that while P2Y1 signaling alone did not induce an IFN response, P2Y1 activation amplified PolyI:C-stimulated Type I and III IFN responses and downstream ISGs. Cells lacking P2Y1 or the use of P2Y1 antagonists suppressed the P2Y1-mediated IFN amplification. P2Y1-dependnet amplification of IFN responses were also seen during RV infection of MA104s and HIOs; however, this amplification was significantly greater in strains with mutant NSP1s that have diminished IFN antagonism. Finally, P2Y1 signaling also amplified IFN responses to Tulane virus (TV), an enteric calicivirus that also induces purinergic signaling. Following both RV and TV, P2Y1 signaling also promotes virus replication and spread, indicating an evolutionary arms race to overcome these antiviral responses. Thus, virus-induced purinergic signaling is a conserved host response that serves to amplify antiviral IFN responses, but it is also exploited by viruses to promote replication. Unraveling the myrid of cellular responses to these signals will unveil new insights into the virus host arms race.