Host IPR channels are dispensable for rotavirus Ca signaling but critical for intercellular Ca waves that prime uninfected cells for rapid virus spread.

Many viruses exploit host Ca signaling to facilitate their replication; however, little is known about how Ca signals from different host and viral channels contribute to the overall dysregulation of Ca signaling or promote virus replication. Using cells lacking IPR, a host ER Ca channel, we delineated intracellular Ca signals within virus-infected cells and intercellular Ca waves (ICWs), which increased Ca signaling in neighboring, uninfected cells. In infected cells, IPR was dispensable for rotavirus-induced Ca signaling and replication, suggesting the rotavirus NSP4 viroporin supplies these signals. However, IPR-mediated ICWs increase rotavirus replication kinetics and spread, indicating that the Ca signals from the ICWs may prime nearby uninfected cells to better support virus replication upon eventual infection. This "pre-emptive priming" of uninfected cells by exploiting host intercellular pathways in the vicinity of virus-infected cells represents a novel mechanism for viral reprogramming of the host to gain a replication advantage.