The multiple mechanisms of Ca2+ signalling by listeriolysin O, the cholesterol-dependent cytolysin of Listeria monocytogenes

Cholesterol-dependent cytolysins (CDCs) represent a large family of conserved pore-forming toxins produced by several Gram-positive bacteria such as Listeria monocytogenes, Streptococcus pyrogenes and Bacillus anthracis. These toxins trigger a broad range of cellular responses that greatly influence pathogenesis. Using mast cells, we demonstrate that listeriolysin O (LLO), a prototype of CDCs produced by L. monocytogenes, triggers cellular responses such as degranulation and cytokine synthesis in a Ca2+-dependent manner. Ca2+ signalling by LLO is due to Ca2+ influx from extracellular milieu and release of from intracellular stores. We show that LLO-induced release of Ca2+ from intracellular stores occurs via at least two mechanisms: (i) activation of intracellular Ca2+ channels and (ii) a Ca2+ channels independent mechanism. The former involves PLC-IP3R operated Ca2+ channels activated via G-proteins and protein tyrosine kinases. For the latter, we propose a novel mechanism of intracellular Ca2+ release involving injury of intracellular Ca2+ stores such as the endoplasmic reticulum. In addition to Ca2+ signalling, the discovery that LLO causes damage to an intracellular organelle provides a new perspective in our understanding of how CDCs affect target cells during infection by the respective bacterial pathogens.