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Am J Pathol. 2013 Mar;182(3):852-65. doi: 10.1016/j.ajpath.2012.11.035. Epub 2013 Jan 26.

Entamoeba histolytica exacerbates epithelial tight junction permeability and proinflammatory responses in Muc2(-/-) mice.

Author information

1
Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Gastrointestinal Research Group, University of Calgary Health Sciences Centre, Calgary, Alberta, Canada.

Abstract

Human mucin-2 (MUC-2) is the first line of innate host defense in preventing pathogen-induced epithelial injury. Entamoeba histolytica (Eh) colonizes the mucus layer by binding of the parasite's surface galactose lectin to galactose and N-acetyl-d-galactosamine residues on colonic MUC-2, preventing parasite contact-dependent cytolysis of epithelial cells. We quantified early innate responses to Eh in wild-type and MUC-2-deficient mice (Muc2(-/-)) using closed colonic loops. Eh infection in wild-type but not Muc2(-/-) mice induced a time-dependent increase in (3)H-labeled mucin and nonmucin glycoprotein secretions. Immunohistochemical staining revealed intense MUC-2 secretion, which formed a thick, protective mucus plug overlying the surface epithelium, entrapping Eh. In Muc2(-/-) mice, Eh induced a pronounced time-dependent secretory exudate with increased gross pathology scores and serum albumin leakage. Colonic pathology, secretory responses, and increased proinflammatory cytokine secretions of TNF-α, IFN-γ, and IL-13 correlated with altered expression of the tight junction proteins claudin-2, occludin, and ZO-1. We identified the putative Eh virulence factor that elicits the proinflammatory responses and alters tight junction permeability as Eh cysteine protease A5 (EhCP-A5). The present findings demonstrate that colonic mucins confer both luminal and epithelial barrier functions and that, in the absence of MUC-2, mice are more susceptible to Eh-induced secretory and proinflammatory responses mediated by EhCP-A5.

PMID:
23357502
DOI:
10.1016/j.ajpath.2012.11.035
[Indexed for MEDLINE]

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