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Stem Cell-Derived Intestinal Organoids Boost Norovirus Research

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Review of “Replication of human noroviruses in stem cell–derived human enteroids” from Science by Stuart P. Atkinson

While the sickness and diarrhea associated with gastroenteritis present uncomfortable problems to healthy patients, such symptoms can be dangerous for the very young, the very old, and the immunocompromised. The leading cause of gastroenteritis is infection by the highly contagious human noroviruses (HuNoVs); however, the lack of suitable in vitro cultivation methods has impeded Norovirus research for over 40 years!

So what has this to do with stem cells we hear you ask? For the answer, we look to a recent article from the laboratory of Mary K. Estes (Baylor College of Medicine, Texas, USA) which has utilized stem cell-derived intestinal organoids (or human enteric organoids [HIEs]) [1, 2] to successfully support HuNoV growth for the first time!

The researchers hope that this new strategy will enable the in-depth study of HuNoV replication and evolution in the hope of delineating strategies to inhibit transmission and/or treat infection [3]. My gut says this is going to be a good read!

Stem cell-derived intestinal organoids can grow in either 2D or 3D culture conditions and contain multiple intestinal epithelial cell types making them an excellent potential “host” for HuNoV culture. In this article, monolayer enteroids permitted the complete replication cycle of the common GII.4 HuNoV strain [4] so suggesting their suitability for further HuNoV study.

These subsequent studies identified bile as a requirement for the growth of certain strains and demonstrated that HuNoVs could infect organoids generated from cells derived from various parts of the small intestine (duodenal, jejunal and ileal HIEs). so highlighting the common enterocyte cell as the primary target for HuNoV infection and replication.

But can research employing stem cell-derived intestinal organoids provide a means to inhibit infection? To this end, Ettayebi et al demonstrated that gamma irradiation and heat treatment of HuNoVs inhibited their growth in organoids, so proving that this system can be employed to search for further anti-viral treatments in the near future.

Over 40 years after the first visualization of human noroviruses by Albert Kapikian [5], stem cell research may have provided an effective means to examine their biological characteristics and tease out a means of stopping them in their tracks through the development of new diagnostics, vaccines, and therapeutics. Where can stem cell-derived organoids take us next?!

References

  1. Sato T, Stange DE, Ferrante M, et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology 2011;141:1762-1772.
  2. Saxena K, Blutt SE, Ettayebi K, et al. Human Intestinal Enteroids: a New Model To Study Human Rotavirus Infection, Host Restriction, and Pathophysiology. J Virol 2016;90:43-56.
  3. Ettayebi K, Crawford SE, Murakami K, et al. Replication of human noroviruses in stem cell-derived human enteroids. Science 2016;
  4. Ramani S, Atmar RL, and Estes MK. Epidemiology of human noroviruses and updates on vaccine development. Curr Opin Gastroenterol 2014;30:25-33.
  5. Kapikian AZ, Wyatt RG, Dolin R, et al. Visualization by immune electron microscopy of a 27-nm particle associated with acute infectious nonbacterial gastroenteritis. J Virol 1972;10:1075-1081.