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Figure 3 | Veterinary Research

Figure 3

From: Rethinking the role of alpha toxin in Clostridium perfringens-associated enteric diseases: a review on bovine necro-haemorrhagic enteritis

Figure 3

Hypothesis on key events in C. perfringens type A-induced intestinal necrosis. Key risk factors for the onset of disease are an intestinal environment that favours growth of C. perfringens and/or induces initial epithelial damage. 1 Disease starts with rapid, presumably mucus-associated, proliferation of C. perfringens. Production of a variety of mucin-degrading enzymes leads to breakdown of the protective mucus layer and sialidases remove sialic acid residues from the cells, making the epithelial cells easier to reach and unmasking potential binding sites for other C. perfringens toxins and enzymes. Furthermore, free sialic acid and mucin fragments provide a source of carbon and nitrogen, favouring further clostridial growth and toxin production. 2 C. perfringens produces a variety of toxins and enzymes. Alpha toxin and perfringolysin O stimulate endothelial cells for the production of IL-8, adhesion molecules (by alpha toxin) and ICAM-1 and PAF (by perfringolysin O), leading to trafficking of neutrophils into the tissue space. Furthermore alpha toxin induces TNF-α production by monocytes and may have an effect on host MMPs. 3 The earliest histopathological changes observed are epithelial sloughing and capillary congestion evolving to haemorrhages. Interestingly, the epithelial lining appears intact at this stage. Alpha toxin induces epithelial sloughing, probably through TNF-α and through host MMP activity on the basal membrane. Furthermore TNF-α and PAF likely contribute to the increased vascular permeability. C. perfringens collagenase has haemorrhagic activities and may be involved in the breakdown of the basal membrane and further connective tissue destruction. This mucosal damage is a result from various factors, including alpha toxin-induced activation of endogenous PLA2 and neutrophil-derived oxidants, proteolytic enzymes and cytotoxic proteins. 4 All these events eventually lead to fulminant intestinal necrosis and allow absorption of inflammatory cytokines (such as TNF-α) and toxins from the intestinal lumen into the systemic circulation, leading to shock and rapid death. Dashed arrow: hypothetical activities. Full arrow: proven intestinal activities.

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