4.6 Article

Human Intestinal Enteroids: a New Model To Study Human Rotavirus Infection, Host Restriction, and Pathophysiology

Journal

JOURNAL OF VIROLOGY
Volume 90, Issue 1, Pages 43-56

Publisher

AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.01930-15

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Funding

  1. HHS \ NIH \ National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  2. HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [R01-AI080656, U19-AI11497]
  3. HHS \ NIH \ National Center for Advancing Translational Sciences (NCATS) [U18-TR000552]
  4. Howard Hughes Medical Institute (HHMI) [570076890]
  5. EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [U54HD007495] Funding Source: NIH RePORTER
  6. NATIONAL CANCER INSTITUTE [P30CA125123] Funding Source: NIH RePORTER
  7. NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [U18TR000552] Funding Source: NIH RePORTER
  8. NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [U19AI116497, R01AI080656, P01AI057788] Funding Source: NIH RePORTER
  9. NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK026523, T32DK007632, P30DK089502, R24DK099803, P30DK056338] Funding Source: NIH RePORTER

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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.

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