From Pores to Rafts to Toll - The Adventures of L. monocytogenes on Host Cell Membranes

Abstract

The Listeria monocytogenes (L.m) is the causative agent of Listeriosis. The ability of L.m to infect a wide range of animal species is attributed to several virulence factors. The pore-forming toxin, Listeriolysin O (LLO), is the most important virulence factor of L.m. It allows the bacteria to cross membrane barriers during its intracellular life cycle. LLO also act as a pseudo cytokine / chemokine, which induces a broad spectrum of host responses influencing the outcome of listeriosis. How LLO triggers signalling in host cells is not fully understood. LLO triggers signalling in the host cell via pore dependent and pore independent mechanisms. It is herein shown that the pore dependent mechanism of signal induction by LLO is in part due influx of extracellular Ca2+ and release from intracellular stores in host cells. LLO accomplishes this by first forming membrane LLO pores thus allowing influx of Ca2+ into the cytosol. LLO also causes the release of stored Ca2+ by causing injury to intracellular Ca2+ stores. The study shows that the pore independent mechanism of signal induction by LLO is due to the aggregation of lipid rafts associated signalling molecules. LLO accomplishes this by aggregating cholesterol - the main structural component of lipid rafts. The data further demostrates the functional significance of signalling by LLO. In mast cells, LLO induces release of preformed inflammatory factors and their de novo synthesis. Release of such inflammatory mediators following activation of mast cells by LLO or L.m triggers host reactions necessary for the control of L.m. infection. The role of Toll-like receptors (TLRs) in the proinflammatory signals by L.m was also evaluated. The findings indicate a redundancy in the proinflammatory signals induced by LLO and other L.m components that signal via the TLRs. Thus, although L.m cell wall components do trigger signalling via TLRs, such signals seem to be dispensable as they can be compensate for by LLO.