Entamoeba histolytica exacerbates epithelial tight junction permeability and proinflammatory responses in Muc2(-/-) mice.
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.
Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Gastrointestinal Research Group, University of Calgary Health Sciences Centre, Calgary, Alberta, Canada.
Vanessa
V
Kissoon-Singh
France
F
Moreau
Elizabeth
E
Trusevych
Kris
K
Chadee
D000818:Animals; D001773:Blood Cells / Q000378:metabolism; D003106:Colon / Q000469:parasitology / Q000473:pathology; D004748:Entamoeba histolytica / Q000472:pathogenicity / Q000502:physiology*; D004847:Epithelial Cells / Q000469:parasitology* / Q000473:pathology*; D005786:Gene Expression Regulation; D020397:Goblet Cells / Q000469:parasitology / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D007422:Intestines / Q000469:parasitology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D055262:Mucin-2 / Q000172:deficiency* / Q000378:metabolism; D010539:Permeability; D062725:Tight Junction Proteins / Q000235:genetics / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism / Q000469:parasitology*; D037521:Virulence Factors / Q000378:metabolism
D018836:Inflammation Mediators; D055262:Mucin-2; D062725:Tight Junction Proteins; D037521:Virulence Factors