Sarah Prallet, Niclas Maier, Albert Li, Cassian Afting, Hao-En Huang, Jungen Hu, Elif Toprak, Deb Purna Keya, Ombretta Colasanti, Nancy León-Janampa, Julien Marlet, Claudia Beisel, Carolin Mogler, Philip Puchas, Patrick Behrendt, Tobias Boettler, Eike Steinmann, Senjuti Saha, Vibor Laketa, Volker Lohmann, Joachim Wittbrodt, C Hermann, Michael T. Dill, Viet Loan Dao Thi
The hepatitis E virus (HEV) is a leading cause of acute hepatitis worldwide. Although most infections are self-limiting, zoonotic genotypes can persist in immunocompromised individuals. Transmitted via the fecal-oral route, HEV has been suggested to directly infect the intestinal epithelium, a tissue with high regenerative capacity. Here, we demonstrate that HEV predominantly infects proliferative transit-amplifying and intestinal stem cells within the crypts of human pluripotent stem cell-derived intestinal organoids (hIOs). Supporting this, we detected HEV RNA in the intestinal crypts of an HEV-infected patient. We further found that HEV infection spreads through cell division and is maintained in hIOs for more than 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 intestinal crypt as a primary target for viral infection in the gastrointestinal tract.