Journalartikel

Jahr der Veröffentlichung: 2022

Zeitschrift: Frontiers in Immunology

Bandnummer: 13

ISSN: 1664-3224

Open Access Status: Gold

DOI Link: https://doi.org/10.3389/fimmu.2022.945656

Verlag: Frontiers Media

Abstract: 
Pneumolysin (PLY) is a bacterial pore forming toxin and primary virulence factor of Streptococcus pneumonia, a major cause of pneumonia. PLY binds cholesterol-rich domains of the endothelial cell (EC) plasma membrane resulting in pore assembly and increased intracellular (IC) Ca2+ levels that compromise endothelial barrier integrity. Caveolae are specialized plasmalemma microdomains of ECs enriched in cholesterol. We hypothesized that the abundance of cholesterol-rich domains in EC plasma membranes confers cellular susceptibility to PLY. Contrary to this hypothesis, we found increased PLY-induced IC Ca2+ following membrane cholesterol depletion. Caveolin-1 (Cav-1) is an essential structural protein of caveolae and its regulation by cholesterol levels suggested a possible role in EC barrier function. Indeed, Cav-1 and its scaffolding domain peptide protected the endothelial barrier from PLY-induced disruption. In loss of function experiments, Cav-1 was knocked-out using CRISPR-Cas9 or silenced in human lung microvascular ECs. Loss of Cav-1 significantly enhanced the ability of PLY to disrupt endothelial barrier integrity. Rescue experiments with re-expression of Cav-1 or its scaffolding domain peptide protected the EC barrier against PLY-induced barrier disruption. Dynamin-2 (DNM2) is known to regulate caveolar membrane endocytosis. Inhibition of endocytosis, with dynamin inhibitors or siDNM2 amplified PLY induced EC barrier dysfunction. These results suggest that Cav-1 protects the endothelial barrier against PLY by promoting endocytosis of damaged membrane, thus reducing calcium entry and PLY-dependent signaling.

Harvard-Zitierstil: Batori, R., Chen, F., Bordan, Z., Haigh, S., Su, Y., Verin, A., et al. (2022) Protective role of Cav-1 in pneumolysin-induced endothelial barrier dysfunction, Frontiers in Immunology, 13, Article 945656. https://doi.org/10.3389/fimmu.2022.945656

APA-Zitierstil: Batori, R., Chen, F., Bordan, Z., Haigh, S., Su, Y., Verin, A., Barman, S., Stepp, D., Chakraborty, T., Lucas, R., & Fulton, D. (2022). Protective role of Cav-1 in pneumolysin-induced endothelial barrier dysfunction. Frontiers in Immunology. 13, Article 945656. https://doi.org/10.3389/fimmu.2022.945656