Open AccessRotavirus induces intercellular calcium waves through ADP signaling
Author(s) -
Alexandra L. ChangGraham,
Jacob L. Perry,
Melinda A. Engevik,
Kristen A. Engevik,
Francesca J. Scribano,
J. Thomas Gebert,
Heather A. Danhof,
Joel C. Nelson,
Joseph Kellen,
Alicia C. Strtak,
Narayan P. Sastri,
Mary K. Estes,
Robert A. Britton,
James Versalovic,
Joseph M. Hyser
Publication year - 2020
Publication title -
science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 12.556
H-Index - 1186
eISSN - 1095-9203
pISSN - 0036-8075
DOI - 10.1126/science.abc3621
Subject(s) - intracellular , calcium , rotavirus , calcium in biology , calcium signaling , microbiology and biotechnology , chemistry , virology , biology , virus , organic chemistry
Rotavirus causes severe diarrheal disease in children by broadly dysregulating intestinal homeostasis. However, the underlying mechanism(s) of rotavirus-induced dysregulation remains unclear. We found that rotavirus-infected cells produce paracrine signals that manifested as intercellular calcium waves (ICWs), observed in cell lines and human intestinal enteroids. Rotavirus ICWs were caused by the release of extracellular adenosine 5'-diphosphate (ADP) that activated P2Y1 purinergic receptors on neighboring cells. ICWs were blocked by P2Y1 antagonists or CRISPR-Cas9 knockout of the P2Y1 receptor. Blocking the ADP signal reduced rotavirus replication, inhibited rotavirus-induced serotonin release and fluid secretion, and reduced diarrhea severity in neonatal mice. Thus, rotavirus exploited paracrine purinergic signaling to generate ICWs that amplified the dysregulation of host cells and altered gastrointestinal physiology to cause diarrhea.