Hepatitis E virus replication is maintained in proliferative cells within the intestinal crypt
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.
Authors
- Patrick Behrendt (ORCID: https://orcid.org/0000-0001-5750-4259)
- Claudia Beisel (ORCID: https://orcid.org/0000-0002-4905-4646)
- Julien Marlet (ORCID: https://orcid.org/0000-0002-8645-8703)
- Sarah Prallet
- Michael T. Dill (ORCID: https://orcid.org/0000-0002-1926-4204)
- Philip Puchas
- Vibor Laketa (ORCID: https://orcid.org/0000-0002-9472-2738)
- Volker Lohmann (ORCID: https://orcid.org/0000-0001-8719-7608)
- Eike Steinmann (ORCID: https://orcid.org/0000-0002-3654-9965)
- Tobias Boettler (ORCID: https://orcid.org/0000-0002-1195-055X)
- Hao-En Huang
- Carolin Mogler (ORCID: https://orcid.org/0000-0003-3400-7254)
- Viet Loan Dao Thi (ORCID: https://orcid.org/0000-0003-2293-3592)
- Ombretta Colasanti
- Niclas Maier
- Deb Purna Keya
- Senjuti Saha
- C Hermann
- Jungen Hu
- Joachim Wittbrodt
- Cassian Afting
Institutions
- Université de Tours (FR)
- Inserm (FR)
- University of Freiburg (DE)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- University Medical Center Freiburg (DE)
- University Hospital Heidelberg (DE)
- Centre Hospitalier Universitaire de Tours (FR)
- German Center for Infection Research (DE)
- Child Health Research Foundation (BD)
- Center for Experimental and Clinical Infection Research (DE)
- Technical University of Munich (DE)
- Heidelberg University (US)
- Ruhr University Bochum (DE)
Publication Details
- Journal
- Science Advances
- Published
- 2026-04-01
- DOI
- https://doi.org/10.1126/sciadv.aeb2333
- Primary Topic
- Hepatitis Viruses Studies and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Baden-Württemberg Stiftung
- Deutsches Zentrum für Infektionsforschung
- Deutsche Forschungsgemeinschaft
- China Scholarship Council
- Deutsche Krebshilfe