More Than a Pore: The Cellular Response to Cholesterol-Dependent Cytolysins

Abstract

Targeted disruption of the plasma membrane is a ubiquitous form of attack used in all three domains of life. Many bacteria secrete pore-forming proteins during infection with broad implications for pathogenesis. The cholesterol-dependent cytolysins (CDC) are a family of pore-forming toxins expressed predominately by Gram-positive bacterial pathogens. The structure and assembly of some of these oligomeric toxins on the host membrane have been described, but how the targeted cell responds to intoxication by the CDCs is not as clearly understood. Many CDCs induce lysis of their target cell and can activate apoptotic cascades to promote cell death. However, the extent to which intoxication causes cell death is both CDC- and host cell-dependent, and at lower concentrations of toxin, survival of intoxicated host cells is well documented. Additionally, the effect of CDCs can be seen beyond the plasma membrane, and it is becoming increasingly clear that these toxins are potent regulators of signaling and immunity, beyond their role in intoxication. In this review, we discuss the cellular response to CDC intoxication with emphasis on the effects of pore formation on the host cell plasma membrane and subcellular organelles and whether subsequent cellular responses contribute to the survival of the affected cell.

Mini-Review: Novel Therapeutic Strategies to Blunt Actions of Pneumolysin in the Lungs

“…As of its discovery as a hemolytic factor [24], several characteristics typical for the cholesterol-dependent cytolysin (CDC) family, as cholesterol dependence and increased activity under reducing conditions [25,26,27,28], have been identified. CDCs are exclusively produced by Gram-positive bacteria and of all 25 known CDCs, generated by 27 bacterial species, PLY is the only one that is not secreted into the extracellular medium (reviewed in [29]). PLY has been cloned, sequenced, and purified [30,31,32], in order to better understand its role in pneumococcal pathogenesis.…”

Vaginolysin Drives Epithelial Ultrastructural Responses to Gardnerella vaginalis

“…At lower (sublytic) concentrations, PFT exposure induces complex defense pathways that promote cellular survival (12,13) and may still affect barrier or immune function. Relevant signaling pathways include p38 mitogen-activated protein kinase-dependent cascades, endocytic/ vesicle trafficking, and membrane repair and lipid biosynthesis modules (11,12,14,15).…”

PSM Peptides of Staphylococcus aureus Activate the p38–CREB Pathway in Dendritic Cells, Thereby Modulating Cytokine Production and T Cell Priming

“…Pore-forming toxins (PFTs) constitute ∼25% of all bacterial toxins and represent the largest class of bacterial virulence factors (24,25). The amphipathic PSMa peptide d-toxin was shown to form receptor-independent transient pores in solution (5,23).…”