Recent insights into Clostridium difficile pathogenesis

Peniche, Alex G.; Savidge, Tor; Dann, Sara M.

doi:10.1097/01.qco.0000433318.82618.c6

Cited by 49 publications

(37 citation statements)

References 56 publications

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“…TcdA and TcdB cause CDAD and its more severe form, PMC, in humans and horses [5][6][7]. Thereby, either TcdA or TcdB alone seems to be sufficient to cause fulminant disease, as it can be deduced from mouse and hamster models of infection [116][117][118].…”

Section: Large Clostridial Glycosylating Toxins In Pathogenesismentioning

confidence: 93%

Large clostridial glycosylating toxins modifying small GTPases

Genth

Just

2015

The Comprehensive Sourcebook of Bacterial Protein Toxins

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Section: Large Clostridial Glycosylating Toxins In Pathogenesismentioning

confidence: 93%

Large clostridial glycosylating toxins modifying small GTPases

Genth

Just

2015

The Comprehensive Sourcebook of Bacterial Protein Toxins

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“…The interplay between Clostridium difficile ( C. difficile ) and the intestinal metabolome is believed to influence the severity of infection (1, 2). For example, the host's bile acid metabolites deoxycholate and taurocholate potently stimulate germination of C. difficile spores (3), while chenodeoxycholate inhibits it (3).…”

Section: Introductionmentioning

confidence: 99%

Tryptophan Catabolism Restricts IFN-γ–Expressing Neutrophils and Clostridium difficile Immunopathology

El–Zaatari

Chang

Zhang

et al. 2014

The Journal of Immunology

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The interplay between Clostridium difficile and the host's metabolome is believed to influence the severity of infection. However, the mechanism for this phenomenon remains unclear. In this study we model one of these metabolic pathways by focussing on tryptophan metabolism in the host. We found that inhibition of tryptophan catabolism in indoleamine 2,3-dioxygenase (IDO1) knockout mice led to increased mucosal destruction and cecal haemorrhage, increased production of IFNγ in response to C. difficile infection, but no significant change in mucosal effector or regulatory T cell numbers or IL-10 mRNA expression. The increased immunopathology in infected IDO1 knockout mice was associated with a lower Clostridium difficile burden and an increased percentage of IFNγ-expressing neutrophils. We further demonstrated the ability of kynurenine to induce apoptosis in bone marrow-derived neutrophils while the presence of tryptophan reversed this effect, providing a possible mechanism for the increased neutrophil accumulation in IDO1-/- mice. We conclude that Clostridium difficile induces tryptophan catabolism in cecal lamina propria cells, which restricts Clostridium difficile-associated immunopathology and the accumulation of IFNγ-expressing neutrophils. This might represent a self-regulatory mechanism for neutrophils, via the IFNγ-IDO1 pathway, to restrict their own accumulation during infection. These findings have important clinical implications as IDO inhibitors are currently used to treat cancer in clinical trials (in patients particularly susceptible to getting Clostridium difficile infection) and treatment with IDO1 inhibitors may exacerbate the severity of Clostridium difficile colitis.

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“…The pathogenesis of C. difficile infection largely depends on the altered balance of the intestinal microbiota, allowing pathogenic strains of C. difficile to infect the intestine [21].…”

Section: Clostridium Difficilementioning

confidence: 99%