Rotavirus induces intercellular calcium waves through ADP signaling

Area of Science:

• Gastroenterology
• Virology
• Cell Biology

Background:

• Rotavirus infection causes severe diarrheal disease in children by disrupting intestinal homeostasis.
• The precise mechanisms underlying rotavirus-induced intestinal dysregulation are not fully understood.

Purpose of the Study:

• To elucidate the mechanism by which rotavirus disrupts intestinal homeostasis.
• To investigate the role of intercellular calcium waves (ICWs) in rotavirus pathogenesis.

Main Methods:

• Observation of ICWs in rotavirus-infected cell lines and human intestinal enteroids.
• Identification of extracellular adenosine 5"-diphosphate (ADP) as the signaling molecule.
• Utilized P2Y1 receptor antagonists and CRISPR-Cas9 gene editing to block purinergic signaling.
• Assessed the impact of blocking ADP signaling on rotavirus replication, host responses, and diarrhea severity in neonatal mice.

Main Results:

• Rotavirus infection induced ICWs mediated by extracellular ADP activating P2Y1 purinergic receptors.
• Inhibition of P2Y1 signaling blocked ICWs, reduced rotavirus replication, and decreased rotavirus-induced serotonin release and fluid secretion.
• Blocking the ADP-P2Y1 pathway significantly reduced diarrhea severity in a neonatal mouse model.

Conclusions:

• Rotavirus exploits paracrine purinergic signaling, specifically ADP acting on P2Y1 receptors, to generate ICWs.
• These ICWs amplify host cell dysregulation and alter gastrointestinal physiology, contributing to rotavirus-induced diarrhea.
• Targeting this purinergic signaling pathway presents a potential therapeutic strategy for managing rotavirus infections.