Human Intestinal Enteroids: a New Model To Study Human Rotavirus Infection, Host Restriction, and Pathophysiology
Open accessAbstract
Human gastrointestinal tract research is limited by the paucity of in vitro intestinal cell models that recapitulate the cellular diversity and complex functions of human physiology and disease pathology. Human intestinal enteroid (HIE) cultures contain multiple intestinal epithelial cell types that comprise the intestinal epithelium (enterocytes and goblet, enteroendocrine, and Paneth cells) and are physiologically active based on responses to agonists. We evaluated these nontransformed, three-dimensional HIE cultures as models for pathogenic infections in the small intestine by examining whether HIEs from different regions of the small intestine from different patients are susceptible to human rotavirus (HRV) infection. Little is known about HRVs, as they generally replicate poorly in transformed cell lines, and host range restriction prevents their replication in many animal models, whereas many animal rotaviruses (ARVs) exhibit a broader host range and replicate in mice. Using HRVs, including the Rotarix RV1 vaccine strain, and ARVs, we evaluated host susceptibility, virus production, and cellular responses of HIEs. HRVs infect at higher rates and grow to higher titers than do ARVs. HRVs infect differentiated enterocytes and enteroendocrine cells, and viroplasms and lipid droplets are induced. Heterogeneity in replication was seen in HIEs from different patients. HRV infection and RV enterotoxin treatment of HIEs caused physiological lumenal expansion detected by time-lapse microscopy, recapitulating one of the hallmarks of rotavirus-induced diarrhea. These results demonstrate that HIEs are a novel pathophysiological model that will allow the study of HRV biology, including host restriction, cell type restriction, and virus-induced fluid secretion. IMPORTANCE Our research establishes HIEs as nontransformed cell culture models to understand human intestinal physiology and pathophysiology and the epithelial response, including host restriction of gastrointestinal infections such as HRV infection. HRVs remain a major worldwide cause of diarrhea-associated morbidity and mortality in children ≤5 years of age. Current in vitro models of rotavirus infection rely primarily on the use of animal rotaviruses because HRV growth is limited in most transformed cell lines and animal models. We demonstrate that HIEs are novel, cellularly diverse, and physiologically relevant epithelial cell cultures that recapitulate in vivo properties of HRV infection. HIEs will allow the study of HRV biology, including human host-pathogen and live, attenuated vaccine interactions; host and cell type restriction; virus-induced fluid secretion; cell-cell communication within the epithelium; and the epithelial response to infection in cultures from genetically diverse individuals. Finally, drug therapies to prevent/treat diarrheal disease can be tested in these physiologically active cultures.
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SARS-CoV-2 targets goblet cells rather than ciliate cells in distal lung organoids, in contrast to a previous study in a 2D air-liquid interface model.
“SARS-Cov-2 targets goblet cells rather than ciliate ones, in contrast to a previous study in a 2D air-liquid interface model183.”
From Organoids (2022) · cites this paper as [183]
Studies in intestinal organoids show that SARS-CoV-2 can infect enterocytes.
“Studies in intestinal organoids show that SARS-Cov-2 can also infect enterocytes183,184.”
From Organoids (2022) · cites this paper as [183]
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- Authors
- Saxena, K., Blutt, S. E., Ettayebi, K., Zeng, X.-L., Broughman, J. R., Crawford, S. E., Karandikar, U. C., Sastri, N. P., Conner, M. E., Opekun, A. R., Graham, D. Y., Qureshi, W., Sherman, V., Foulke-Abel, J., In, J., Kovbasnjuk, O., Zachos, N. C., Donowitz, M., & Estes, M. K.
- Affiliations
- Baylor College of Medicine (US)
- Houston Methodist (US)
- Johns Hopkins University (US)
- ORCID
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2016-01
- Volume
- 90
- Issue
- 1
- Pages
- 43-56
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC4702582
- OpenAlex
- W2300378039
- Cited by
- 375
- References
- 64
- Citations by year
- 2026: 25 · 2025: 25 · 2024: 35 · 2023: 23 · 2022: 40 · 2021: 52 · 2020: 44 · 2019: 51 · 2018: 40 · 2017: 24 · 2016: 15 · 2015: 1
- FWCI
- 20.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Virology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
- HHS | NIH | National Institute of Allergy and Infectious Diseases (RO1-AI080656, U19-AI11497)
- HHS | NIH | National Center for Advancing Translational Sciences (U18-TR000552)
- Howard Hughes Medical Institute (570076890)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Viral gastroenteritis research and epidemiology
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Immunology and Microbiology › Parasitology › Parasitic Infections and Diagnostics
- Keywords
- human intestinal enteroids, human rotavirus, host restriction, enterocytes, enteroendocrine cells, viroplasm, lipid droplets, small intestine, in vitro infection model, enterotoxin, fluid secretion, host-pathogen interaction
- MeSH terms
- Humans, Intestine, Small, Models, Theoretical, Organ Culture Techniques, Rotavirus Infections, Rotavirus, Virus Replication
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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