Open AccessCryptosporidium parvum disrupts intestinal epithelial barrier function via altering expression of key tight junction and adherens junction proteins
Author(s) -
Kumar Anoop,
Chatterjee Ishita,
Anbazhagan Arivarasu N.,
Jayawardena Dulari,
Priyamvada Shubha,
Alrefai Waddah A.,
Sun Jun,
Borthakur Alip,
Dudeja Pradeep K.
Publication year - 2018
Publication title -
cellular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.542
H-Index - 138
eISSN - 1462-5822
pISSN - 1462-5814
DOI - 10.1111/cmi.12830
Subject(s) - occludin , tight junction , adherens junction , paracellular transport , claudin , biology , barrier function , microbiology and biotechnology , cryptosporidium parvum , cell junction , intestinal permeability , cadherin , immunology , cell , biochemistry , permeability (electromagnetism) , membrane
Infection with the protozoan parasite Cryptosporidium parvum (CP) causes cryptosporidiosis, a widespread diarrhoeal disease. Impaired intestinal epithelial barrier function and increased permeability are most commonly associated with diarrhoeal diseases caused by enteric infections. However, studies on barrier disruption and underlying mechanisms in cryptosporidiosis are extremely limited. Epithelial tight junctions (TJs) and adherens junctions (AJs) are important in maintaining barrier integrity. Therefore, we examined the effects of CP infection on paracellular permeability and on the expression of the major TJ and AJ proteins utilising in vitro, ex vivo, and in vivo models. CP infection (0.5 × 10 6 oocysts/well in Transwell inserts, 24 hr) increased paracellular permeability (FITC‐dextran flux) in Caco‐2 cell monolayers and substantially decreased the protein levels of occludin, claudin 4, and E‐cadherin. Claudin 3, zonula occludens‐1 (ZO1) and α‐catenin were also significantly decreased, whereas claudins 1 and 2 and β‐catenin were not altered. Substantial downregulation of occludin, claudin 4, and E‐cadherin was also observed in response to CP infection ex vivo in mouse enteroid‐derived monolayers and in vivo in the ileal and jejunal mocosa of C57BL/6 mice. The mRNA levels of these proteins were also significantly decreased in CP‐infected mouse ileum and jejunum but were unaltered in Caco‐2 cells. Further, bafilomycin‐A, an inhibitor of lysosomal proton pump, partially abrogated CP effects on occludin expression in Caco‐2 cells, suggesting a potential role of posttranslational mechanisms, such as induction of protein degradation pathways, in mediating the effects of the parasite. Our studies suggest that disruption of barrier function via downregulation of specific key components of TJ and AJ could be a major mechanism underlying CP infection‐induced diarrhoea.