Monocytes Are Highly Sensitive to<i>Clostridium difficile</i>Toxin A-Induced Apoptotic and Nonapoptotic Cell Death

Solomon, Katie; Webb, J. N.; Ali, Nermin; Robins, R. A.; Mahida, Yashwant R.

doi:10.1128/iai.73.3.1625-1634.2005

Cited by 40 publications

(39 citation statements)

References 53 publications

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“…TcdA has also been shown to directly bind and induce apoptosis in monocytes, thereby inactivating key effector cells and directly influencing the host protective immune response [Modi et al 2011;Solomon et al 2005].…”

Section: Clostridium Difficile Virulence Factorsmentioning

confidence: 99%

The host immune response to Clostridium difficile infection

Solomon

2013

Therapeutic Advances in Infection

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Clostridium difficile infection (CDI) is the most common infectious cause of healthcare-acquired diarrhoea. Outcomes of C. difficile colonization are varied, from asymptomatic carriage to fulminant colitis and death, due in part to the interplay between the pathogenic virulence factors of the bacterium and the counteractive immune responses of the host.Secreted toxins A and B are the major virulence factors of C. difficile and induce a profound inflammatory response by intoxicating intestinal epithelial cells causing proinflammatory cytokine release. Host cell necrosis, vascular permeability and neutrophil infiltration lead to an elevated white cell count, profuse diarrhoea and in severe cases, dehydration, hypoalbuminaemia and toxic megacolon. Other bacterial virulence factors, including surface layer proteins and flagella proteins, are detected by host cell surface signal molecules that trigger downstream cell-mediated immune pathways.Human studies have identified a role for serum and faecal immunoglobulin levels in protection from disease, but the recent development of a mouse model of CDI has enabled studies into the precise molecular interactions that trigger the immune response during infection. Key effector molecules have been identified that can drive towards a protective anti-inflammatory response or a damaging proinflammatory response.The limitations of current antimicrobial therapies for CDI have led to the development of both active and passive immunotherapies, none of which have, as yet been formally approved for CDI. However, recent advances in our understanding of the molecular basis of host immune protection against CDI may provide an exciting opportunity for novel therapeutic developments in the future.

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Section: Clostridium Difficile Virulence Factorsmentioning

confidence: 99%

The host immune response to Clostridium difficile infection

Solomon

2013

Therapeutic Advances in Infection

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“…Indeed, our previous studies have shown that among the normal human colonic mucosal cells, epithelial cells and macrophages (and also monocytes) are more sensitive than lymphocytes to toxin A-induced cell death (25,26,42). Although direct comparisons have not been Compared to myofibroblasts cultured in control medium (0 g/ml) for the relevant periods, there were significant reductions in mitochondrial dehydrogenase activity in cells exposed to 0.1 g/ml toxin B for 72 h and to 1 and 10 g/ml toxin B for 24 h, 48 h, and 72 h. ϩ, P Ͻ 0.02; * , P Ͻ 0.0001.…”

Section: Discussionmentioning

confidence: 99%

“…The nuclear morphologies of control and toxin-exposed myofibroblasts were studied by fluorescence microscopy after staining with Hoechst 33342 dye (42). Immunohistochemical studies were undertaken using monoclonal antibodies to alpha-smooth muscle actin, desmin, and vimentin (all from Sigma).…”

Section: Methodsmentioning

confidence: 99%

“…Other early responses by intestinal epithelial cells exposed to toxin A include changes in the cytoskeleton (10,15) and secretion of cytokines, such as transforming growth factor beta (TGF-␤) (20) and interleukin-8 (5,13,26), before the cells undergo programmed cell death (6,26). Our previous studies have shown that primary human intestinal epithelial cells, monocytes, and intestinal macrophages are more sensitive than lymphocytes to C. difficile toxin A-induced cell death (25,26,42).…”

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confidence: 99%

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Primary Human Colonic Myofibroblasts Are Resistant toClostridium difficileToxin A-Induced, but Not Toxin B-Induced, Cell Death

2011

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Colonic inflammation in Clostridium difficile infection is mediated by released toxins A and B. We investigated responses to C. difficile toxins A and B by isolated primary human colonic myofibroblasts, which represent a distinct subpopulation of mucosal cells that are normally located below the intestinal epithelium. Following incubation with either purified toxin A or B, there was a change in myofibroblast morphology to stellate cells with processes that were immunoreactive for alpha-smooth muscle actin. Most of the myofibroblasts remained viable, with persistence of stellate morphology, despite exposure to high concentrations (up to 10 g/ml) of toxin A for 72 h. In contrast, a majority of the toxin B-exposed myofibroblasts lost their processes prior to cell death over 24 to 72 h. At low concentrations, toxin A provided protection against toxin B-induced cell death. Within 4 h, myofibroblasts exposed to either toxin A or toxin B lost expression of the nonglucosylated form of Rac1, and there was also a loss of the active form of RhoA. Despite preexposure to high concentrations of toxin A for 3 h, colonic myofibroblasts were able to recover their morphology and proliferative capacity during prolonged culture in medium. However, toxin B-preexposed myofibroblasts were not able to recover. In conclusion, primary human colonic mucosal myofibroblasts are resistant to toxin A (but not toxin B)-induced cell death. Responses by colonic myofibroblasts may play an important role in mucosal protection, repair, and regeneration in colitis due to C. difficile infection.

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“…These recruit circulating inflammatory cells such as neutrophils into the site of infection and perpetuate the inflammation and fluid secretion associated with CDI (Pothoulakis, 2000). In addition to the indirect effect of the toxins on cells of the immune system, C. difficile toxin A has also been shown to directly bind to peripheral blood mononuclear cells, most notably monocytes and induce cell death by apoptosis (Modi et al, 2011;Solomon et al, 2005). This highlights the essential role that toxins play in initiating and prolonging bacterial infection by inactivating key elements of the host protective immune response.…”

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confidence: 99%