Structural Basis for Human PECAM-1-Mediated Trans-homophilic Cell Adhesion

Wyder

et al. 2020

Cell Host & Microbe

Section: Discussionmentioning

confidence: 99%

CD31 (PECAM-1) Serves as the Endothelial Cell-Specific Receptor of Clostridium perfringens β-Toxin

Wyder

et al. 2020

Cell Host & Microbe

“…The induced mutation is predicted to be located in the loop between beta strand four and five. Assuming a similar fold of Ig6 as membrane distal domains Ig1 and Ig2 (Hu et al, 2016), it would be located in a loop between beta strand four and five, a very exposed surface for potential binding partners.…”

Section: Discussionmentioning

confidence: 99%

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

Wyder

et al. 2019

Preprint

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.

“…CD31 s adhesive properties are mediated by its extracellular domain via binding to other CD31 ectodomains (homophilic adhesion) or other ligands (heterophilic adhesion) [24]. CD31/CD31 homophilic interactions are mediated by the Ig1 and Ig2 domain [31][32][33][34].…”

Section: Blocking the Cd31 Ig6 Domain Protects Sensitive Cells Against Cpb Induced Cytotoxicitymentioning

confidence: 99%

“…Ig domains consist of seven to nine antiparallel β-strands arranged into two sheets linked by a disulfide bond [42]. Assuming a similar fold of Ig6 as in the Ig1 and Ig2 domains [31], the entire region now defined by two independent approaches seems to be important for CPB cytotoxicity and oligomer formation. This region is located in a surface-exposed loop between two beta strands of the Ig 6 domain.…”

Section: Blocking the Cd31 Ig6 Domain Protects Sensitive Cells Against Cpb Induced Cytotoxicitymentioning

confidence: 99%

Platelet Endothelial Cell Adhesion Molecule 1 (CD31) Is Essential for Clostridium perfringens Beta-Toxin Mediated Cytotoxicity in Human Endothelial and Monocytic Cells

Cattalani

et al. 2021

Toxins

Beta toxin (CPB) is a small hemolysin beta pore-forming toxin (β-PFT) produced by Clostridium perfringens type C. It plays a central role in the pathogenesis of necro-hemorrhagic enteritis in young animals and humans via targeting intestinal endothelial cells. We recently identified the membrane protein CD31 (PECAM-1) as the receptor for CPB on mouse endothelial cells. We now assess the role of CD31 in CPB cytotoxicity against human endothelial and monocytic cells using a CRISPR/Cas9 gene knockout and an antibody blocking approach. CD31 knockout human endothelial and monocytic cells were resistant to CPB and CPB oligomers only formed in CD31-expressing cells. CD31 knockout endothelial and monocytic cells could be selectively enriched out of a polyclonal cell population by exposing them to CPB. Moreover, antibody mediated blocking of the extracellular Ig6 domain of CD31 abolished CPB cytotoxicity and oligomer formation in endothelial and monocytic cells. In conclusion, this study confirms the role of CD31 as a receptor of CPB on human endothelial and monocytic cells. Specific interaction with the CD31 molecule can thus explain the cell type specificity of CPB observed in vitro and corresponds to in vivo observations in naturally diseased animals.