A Major Role for Proteolytic Activity and Proteinase-Activated Receptor-2 in the Pathogenesis of Infectious Colitis

Citrobacter rodentium is a bacterial pathogen that causes a murine infectious colitis equivalent to enterohemorrhagic Escherichia coli infection in humans. Colonic luminal fluid from C. rodentium-infected mice, but not from sham-infected mice, contains active serine proteinases that can activate pro...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2005-06, Vol.102 (23), p.8363-8368
Main Authors: Hansen, Kristina K., Sherman, Philip M., Cellars, Laurie, Andrade-Gordon, Patricia, Pan, Zhengying, Baruch, Amos, Wallace, John L., Hollenberg, Morley D., Vergnolle, Nathalie, Cuatrecasas, Pedro M.
Format: Article
Language:English
Subjects:
Agonists
Anatomy & physiology
Animals
Biological Sciences
Calcium
Citrobacter rodentium - physiology
Colitis
Colitis - enzymology
Colitis - metabolism
Colitis - microbiology
Colitis - pathology
Endopeptidases - metabolism
Endopeptidases - secretion
Gastrointestinal diseases
Gels
Granulocytes
Granzymes
Infections
Inflammation
Kidney cells
Mass spectrometry
Medical research
Mice
Pathogens
Receptor, PAR-2 - metabolism
Rodents
Serine Endopeptidases - metabolism
Trypsin - metabolism
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Summary:Citrobacter rodentium is a bacterial pathogen that causes a murine infectious colitis equivalent to enterohemorrhagic Escherichia coli infection in humans. Colonic luminal fluid from C. rodentium-infected mice, but not from sham-infected mice, contains active serine proteinases that can activate proteinase-activated receptor-2 ( PAR2). We have identified granzyme A and murine trypsins to be present in C. rodentium-infected luminal fluid, as determined by mass spectrometry and Western blot analysis. Inflammatory indices (colonic mucosa macroscopic damage score, increased intestinal wall thickness, granulocyte infiltration, and bacterial translocation from the colonic lumen to peritoneal organs) were all increased in C. rodentium-infected mice, compared with sham-infected mice. Soybean trypsin inhibitor-treated wild-type mice and untreated PAR2-deficient ( PAR2 -/-) mice (compared with their wild-type littermates) both had substantially reduced levels of C. rodentium-induced inflammation. These data point to an important role for both pathogen-induced host serine proteinases and PAR2in the setting of infectious colitis.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0409535102