ROTAVIRUS INDUCES INTERCELLULAR CALCIUM WAVES THROUGH ADP SIGNALING

Rotavirus causes severe diarrheal disease in children worldwide. A hallmark of rotavirus infection is an increase in cytosolic calcium in infected small intestine epithelial cells. However, the underlying mechanism(s) of rotavirus-cell signaling remains incompletely characterized. Here we show that rotavirus-infected cells produce paracrine signals that manifest as intercellular calcium waves (ICWs); which are observed in both cell lines and human intestinal enteroids (HIEs). Rotavirus ICWs are caused by the release of extracellular adenosine diphosphate (ADP) that activates P2Y1 purinergic receptors on neighboring cells and are blocked by P2Y1 antagonists or CRISPR/Cas9 knockout of P2Y1. This paracrine purinergic signal is critical for rotavirus replication and diarrhea. Blocking the ICW signal reduces rotavirus replication; inhibits rotavirus-induced serotonin release and fluid secretion; and reduces diarrhea severity in neonatal mice. This is the first evidence that viruses exploit intercellular calcium waves to amplify diarrheal signaling; a finding which have broad implications for gastrointestinal physiology.