The intestinal crypt is a potential reservoir for hepatitis E virus infections

The hepatitis E virus (HEV) is a leading cause of acute hepatitis worldwide. Although most HEV infections are self-limiting, zoonotic genotypes can establish persistent infections in immunocompromised individuals. Transmitted via the fecal-oral route, HEV has been suggested to directly infect the intestinal epithelium, an organ composed of diverse cell types with high regenerative capacity. In this study, we demonstrate that HEV predominantly infects proliferative transit-amplifying and intestinal stem cells located within the crypts of human pluripotent stem cell-derived intestinal organoids (hIOs). Supporting this, we detected HEV RNA in the crypts of intestinal tissue from an HEV-infected patient. We further found that HEV can spread through cell division and establish persistent infection in hIOs for over 40 days, contrasting with acute hepatitis A virus, whose infections are rapidly cleared from hIOs. Given the self-renewal ability and metabolic constraints of proliferative intestinal progenitor cells, our findings suggest that intestinal crypts could serve as reservoirs for chronic HEV infection and highlight the crypt as a new primary target for viral infection in the gastrointestinal tract.