Cell-specific targeting byClostridium perfringensβ-toxin unraveled: the role of CD31 as the toxin receptor

Abstract

Clostridium perfringens β-toxin (CPB) is a highly active hemolysin β-pore forming toxin and the essential virulence factor for a severe, necro-hemorrhagic enteritis in animals and humans. In vivo and in vitro it exerts a remarkable cell type specificity towards endothelial cells, platelets and some leucocytic cell lines. The target cell specificity of CPB is, however, poorly understood and a receptor explaining this selective toxicity has not been identified. This has hampered further research into the pathogenesis of C. perfringens type C induced enteritis. Here we identify Platelet Endothelial Cell Adhesion Molecule-1 (CD31 or PECAM-1) as the specific membrane receptor for CPB on endothelial cells. CD31 expression is essential for CPB toxicity in endothelial cells and lethality in mice and sufficient to render previously resistant cells highly susceptible to the toxin. We further demonstrate, that the extracellular membrane proximal Ig6 domain of CD31 is required for the interaction with CPB and that expression of CD31 corresponds with the specificity of the toxin towards cultured cell lines. Our results thus provide an explanation for the cell type specificity of CPB and can be linked to the characteristic lesions observed a devastating enteric disease in animals and humans.

Application of the MISTEACHING(S) disease susceptibility framework to Actinobacillus pleuropneumoniae to identify research gaps: an exemplar of a veterinary pathogen

“…The facilitation of leukocyte transendothelial migration is considered pro-inflammatory, while functions including dampening of leukocyte activation, suppression of pro-inflammatory cytokine production, and maintenance of endothelial barrier integrity are considered anti-inflammatory. In pigs, PECAM-1 has been identified as the receptor for Clostridium perfringens beta-toxin (Bruggisser et al, 2020). PECAM-1 deficient mice were more sensitive to systemic administration of E. coli LPS than wild-type mice (Maas et al, 2005).…”