Rotavirus NSP4 mediates an increase in the pro-inflammatory eicosanoid, prostaglandin E2, during infection

Rotavirus (RV) type A is a leading cause of severe infantile gastroenteritis globally. Studies show that prostaglandin E 2 (PGE 2 ) levels increase during RV infection, enhancing viral attachment and internalisation. However, the underlying mechanism for the increased PGE 2 levels remains unclear. Using a plasmid-based reverse genetics system, we engineered a recombinant RV carrying mutations in the viroporin domain of NSP4 that decreased cytoplasmic calcium (Ca 2+ ) conductivity. This resulted in decreased cytoplasmic phospholipase A 2 (cPLA 2 ) activity, the rate-limiting enzyme in PGE 2 biosynthesis, and subsequently reduced PGE 2 levels and viral yield. These findings are consistent with RV-induced PGE 2 production occurring in a NSP4-cyto[Ca²⁺]-cPLA 2 -dependent manner.