Clostridium difficile Toxin–Induced Inflammation and Intestinal Injury Are Mediated by the Inflammasome

Ng, Jeffrey; Hirota, Simon A.; Groß, Olaf; Li, Yan; Ulke‐Lemée, Annegret; Potentier, Mireille S.; Schenck, L. Patrick; Vilaysane, Akosua; Seamone, Mark E.; Feng, Hanping; Armstrong, Glen D.; Tschopp, Jürg; MacDonald, Justin A.; Muruve, Daniel A.; Beck, Paul L.

doi:10.1053/j.gastro.2010.04.005

Cited by 212 publications

(221 citation statements)

References 41 publications

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“…33 Both TcdA and TcdB are cytotoxic and trigger inflammatory responses, causing disruption of the actin cytoskeleton of intestinal epithelial cells and disrupting tight junctions. 34,35 In this study we confirmed the essential role of these toxins in mediating colitis as no clinical or histopathologic disease was seen in animals that were challenged with the non-toxigenic strain F200. However, the fact that this strain could colonize to a level equivalent of a fully toxigenic strain demonstrates that toxin A and toxin B are not required to establish C. difficile colonization.…”

Section: Discussionsupporting

confidence: 68%

Cefoperazone-treated mice as an experimental platform to assess differential virulence ofClostridium difficilestrains

et al. 2011

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The toxin-producing bacterium C. difficile is the leading cause of antibiotic-associated colitis, with an estimated 500,000 cases C. difficile infection (CDI) each year in the US with a cost approaching 3 billion dollars. Despite the significance of CDI, the pathogenesis of this infection is still being defined. The recent development of tractable murine models of CDI will help define the determinants of C. difficile pathogenesis in vivo. To determine if cefoperazone-treated mice could be utilized to reveal differential pathogenicity of C. difficile strains, 5-8 week old C57BL/6 mice were pretreated with a 10 d course of cefoperazone administered in the drinking water. Following a 2-d recovery period without antibiotics, the animals were orally challenged with C. difficile strains chosen to represent the potential range of virulence of this organism from rapidly fatal to nonpathogenic. Animals were monitored for loss of weight and clinical signs of colitis. At the time of harvest, C. difficile strains were isolated from cecal contents and the severity of colitis was determined by histopathologic examination of the cecum and colon. Cefoperazone treated mice challenged with C. difficile strains VPI 10463 and BI1 exhibited signs of severe colitis while infection with 630 and F200 was subclinical. This increased clinical severity was correlated with more severe histopathology with significantly more edema, inflammation and epithelial damage encountered in the colons of animals infected with VPI 10463 and BI1. Disease severity also correlated with levels of C. difficile cytotoxic activity in intestinal tissues and elevated blood neutrophil counts. Cefoperazone treated mice represent a useful model of C. difficile infection that will help us better understand the pathogenesis and virulence of this re-emerging pathogen.

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Section: Discussionsupporting

confidence: 68%

Cefoperazone-treated mice as an experimental platform to assess differential virulence ofClostridium difficilestrains

et al. 2011

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“…The most well characterised is the NLRP3 inflammasome that is activated in response to cell stress signals [31], whole bacteria and viruses, or their virulence factors [32][33][34][35], and is likely to play a key role in inflammatory periodontal disease [26]. NLRP2 is less well studied, but it is considered to inhibit the NLRP3-ASC interaction [36,37].…”

Section: Introductionmentioning

confidence: 99%

Aggregatibacter actinomycetemcomitans targets NLRP3 and NLRP6 inflammasome expression in human mononuclear leukocytes

Belibasakis

Johansson

2012

Cytokine

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Periodontitis is an inflammatory condition that destroys the tooth-supporting tissues, as a result of local bacterial infection. Aggregatibacter actinomycetemcomitans is a Gram-negative facultative anaerobic species, highly associated with aggressive periodontitis. Periodontal inflammation is dominated by cytokines of the Interleukin (IL)-1 family. Prior to their secretion by mononuclear cells, IL-1 cytokines are processed by intracellular protein complexes, known as "inflammasomes", which can sense the bacterial challenge. The aim of this study was to investigate which inflammasomes are regulated in mononuclear cells in response to A. actinomycetemcomitans. The D7SS strain and its derivative leukotoxin and cytolethal distending toxin knock-out mutant strains were used to infect human mononuclear cells at a 1:10 cell: bacteria ratio, for 3 h. The expression of various inflammasome components in the cells was investigated by TaqMan quantitative real-time polymerase chain reaction (qPCR). The expressions of NOD-like receptor protein (NLRP)1, NLRP2 and Absent In Melanoma (AIM)2 inflammasome sensors, as well as their effector Caspase-1 were not affected. However, NLRP3 was up-regulated, while NLRP6 was down-regulated. This effect was not dependent on the leukotoxin or the cytolethal distending toxin, as demonstrated by the use of specific gene knock-out mutant strains. IL-1 and IL-18 expressions were also up-regulated by the bacterial challenge. In conclusion, A. actinomycetemcomitans enhances NLRP3 and reduces NLRP6 inflammasome expression, irrespective of its major virulence factors, confirming the high pathogenic profile of this species, and providing further insights to the mechanisms of periodontal inflammation. actinomycetemcomitans enhances NLRP3 and reduces NLRP6 inflammasome expression, irrespective of its major virulence factors, confirming the high pathogenic profile of this species, and providing further insights to the mechanisms of periodontal inflammation.

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“…Оскільки Clostridium spp. проду-кує бутират, який посилює бар'єрні власти-вості слизової оболонки через підвищення експресії муцину, антимікробних пептидів та протеїнів щільних контактів [18].…”

Section: результати та їх обговоренняunclassified

Structural and functional features of small intestine mucous depending on quantitative and qualitative microbiota composition

Putnikov¹,

Vareniuk²,

Roslova³

et al. 2017

Fiziol Zh

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Clostridium difficile Toxin–Induced Inflammation and Intestinal Injury Are Mediated by the Inflammasome

Cited by 212 publications

References 41 publications

Cefoperazone-treated mice as an experimental platform to assess differential virulence ofClostridium difficilestrains

Cefoperazone-treated mice as an experimental platform to assess differential virulence ofClostridium difficilestrains

Aggregatibacter actinomycetemcomitans targets NLRP3 and NLRP6 inflammasome expression in human mononuclear leukocytes

Structural and functional features of small intestine mucous depending on quantitative and qualitative microbiota composition

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