Fig. 8.

Proposed model for GII.3 infection in HIEs supported by BA and ceramide. 1) Hydrophobic BAs, mainly conjugated BAs, may bind to BA receptor on the cell surface such as S1PR2 or interact with the cell in an undetermined manner and trigger rapid signals. The BA-mediated signals induce lysosomal exocytosis that releases lysosomal contents including ASM to apical surface. 2) The released ASM produces ceramide in the apical membrane that induces ceramide-rich microdomain formation. 3) The ceramide-rich microdomain likely cluster receptors, by which GII.3 can bind and subsequently enter into cells through BA-signaled uptake. 4) Concurrently, BAs increase endosomal acidification. 5) We hypothesize that virus or viral genome escape from the endosome is mediated by endosomal ASM activation and subsequent local ceramide formation, which increases the permeability of the endosomal membrane permitting release.