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.
Highlights
IntroductionThe cholesterol-dependent cytolysins (CDCs) are a family of pore-forming proteins expressed by several genera of pathogenic, primarily Gram-positive bacteria that cause very different diseases
The cholesterol-dependent cytolysins (CDCs) are a family of pore-forming proteins expressed by several genera of pathogenic, primarily Gram-positive bacteria that cause very different diseases.Examples include Streptococcus pyogenes, a common cause of upper respiratory infections, Bacillus anthracis, which mostly causes cutaneous infections, and Listeria monocytogenes, which causes gastroenteritis
An intact eukaryotic cell membrane is critical for cell survival and yet this barrier is routinely assaulted by CDC toxins during infection
Summary
The cholesterol-dependent cytolysins (CDCs) are a family of pore-forming proteins expressed by several genera of pathogenic, primarily Gram-positive bacteria that cause very different diseases. CDC intoxication may result in some characteristic hallmarks of membrane damage, such as ion flux across the targeted cell membrane, loss of cytosolic contents, stimulation of repair mechanisms, and host cell lysis. A more recent study by Hamon and Cossart demonstrated that LLO pre-treated with cholesterol still allowed K+ flux across the plasma membrane, which suggests that cholesterol-treated LLO may retain some membrane damaging capacity [8] Mutations in these pore-forming proteins that destroy their ability to lyse red blood cells may still allow some activity in other cell types, as demonstrated for the perfringolysin O (PFO) G461D mutant protein [9]. The structural similarities between CDCs, perforin, and PLP1, for example, suggest that the target cell may sense membrane damage caused by these toxins in similar ways. Given that plasma membrane disruption is ubiquitous among all forms of life, the study of the cellular response to the insult of pore formation may provide insight into broadly relevant mechanisms for cellular preservation and survival
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