Multifaceted Activity of Listeriolysin O, the Cholesterol-Dependent Cytolysin of Listeria monocytogenes

Abstract

The cholesterol-dependent cytolysins (CDCs) are a large family of pore-forming toxins that are produced by numerous Gram-positive bacterial pathogens. These toxins are released in the extracellular environment as water-soluble monomers or dimers that bind to cholesterol-rich membranes and assemble into large pore complexes. Depending upon their concentration, the nature of the host cell and membrane (cytoplasmic or intracellular) they target, the CDCs can elicit many different cellular responses. Among the CDCs, listeriolysin O (LLO), which is a major virulence factor of the facultative intracellular pathogen Listeria monocytogenes, is involved in several stages of the intracellular lifecycle of the bacterium and displays unique characteristics. It has long been known that following L. monocytogenes internalization into host cells, LLO disrupts the internalization vacuole, enabling the bacterium to replicate into the host cell cytosol. LLO is then used by cytosolic bacteria to spread from cell to cell, avoiding bacterial exposure to the extracellular environment. Although LLO is continuously produced during the intracellular lifecycle of L. monocytogenes, several processes limit its toxicity to ensure the survival of infected cells. It was previously thought that LLO activity was limited to mediating vacuolar escape during bacterial entry and cell to cell spreading. This concept has been challenged by compelling evidence suggesting that LLO secreted by extracellular L. monocytogenes perforates the host cell plasma membrane, triggering important host cell responses. This chapter provides an overview of the well-established intracellular activity of LLO and the multiple roles attributed to LLO secreted by extracellular L. monocytogenes.

Listeria monocytogenes and Shigella flexneri Activate the NLRP1B Inflammasome

“…We next addressed whether Listeria Δhly or ΔactA mutant is able to activate the NLRP1B inflammasome. hly encodes listeriolysin O (LLO), a pore-forming toxin essential for endosomal escape (22). ActA is a protein on the bacterial cell surface that initiates actin-based motility and consequently promotes spreading of bacteria to neighboring cells (18,23).…”

Human Defensins Facilitate Local Unfolding of Thermodynamically Unstable Regions of Bacterial Protein Toxins

“…Since none of the tested mammalian proteins were affected by HNP1 in a comparable way, we speculate that defensins take advantage of intrinsic thermodynamic instability of bacterial toxins required to maintain their high structural plasticity, which, in turn, is essential for forming pores or passing across the host cell membranes. Thus, pore-forming CDC toxins (Marriott et al, 2008; Seveau, 2014) undergo dramatic conformational reshaping upon binding to cholesterol on host membranes culminated in the refolding of critical α-helices into β-strands for the formation of the β-barrel pore-complex (Dunstone and Tweten, 2012). Many membrane-penetrating exotoxins also demonstrate high degree of instability required for their efficient translocation across the membrane.…”

The membrane attack complex, perforin and cholesterol-dependent cytolysin superfamily of pore-forming proteins

“…Following their internalisation, Listeria initially reside in an endosome. Here, listeriolysin pore formation is essential for the bacteria to escape from this phagocytic vesicle into the cytoplasm, where they can divide and then spread from cell to cell; this pathway avoids exposure of the bacteria to the extracellular environment and thus detection by immune surveillance systems (Seveau, 2014).…”