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Infect Immun. 2019 Mar 25;87(4). pii: e00740-18. doi: 10.1128/IAI.00740-18. Print 2019 Apr.

Evaluating Shigella flexneri Pathogenesis in the Human Enteroid Model.

Author information

1
Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.
2
Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
3
Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA embarry@som.umaryland.edu.

Abstract

The enteric pathogen Shigella is one of the leading causes of moderate-to-severe diarrhea and death in young children in developing countries. Transformed cell lines and animal models have been widely used to study Shigella pathogenesis. In addition to altered physiology, transformed cell lines are composed of a single cell type that does not sufficiently represent the complex multicellular environment of the human colon. Most available animal models do not accurately mimic human disease. The human intestinal enteroid model, derived from LGR5+ stem cell-containing intestinal crypts from healthy subjects, represents a technological leap in human gastrointestinal system modeling and provides a more physiologically relevant system that includes multiple cell types and features of the human intestine. We established the utility of this model for studying basic aspects of Shigella pathogenesis and host responses. In this study, we show that Shigella flexneri is capable of infecting and replicating intracellularly in human enteroids derived from different segments of the intestine. Apical invasion by S. flexneri is very limited but increases ∼10-fold when enteroids are differentiated to include M cells. Invasion via the basolateral surface was at least 2-log10 units more efficient than apical infection. Increased secretion of interleukin-8 and higher expression levels of the mucin glycoprotein Muc2 were observed in the enteroids following S. flexneri infection. The human enteroid model promises to bridge some of the gaps between traditional cell culture, animal models, and human infection.

KEYWORDS:

M cells; S. flexneri pathogenesis; colonoid; human intestinal enteroids

PMID:
30642900
PMCID:
PMC6434113
DOI:
10.1128/IAI.00740-18
[Indexed for MEDLINE]
Free PMC Article

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