Listeria monocytogenes: cell biology of invasion and intracellular growth

Abstract

The Gram-positive pathogen Listeria monocytogenes is able to promote its entry into a diverse range of mammalian host cells by triggering plasma membrane remodeling, leading to bacterial engulfment. Upon cell invasion, L. monocytogenes disrupts its internalization vacuole and translocates to the cytoplasm, where bacterial replication takes place. Subsequently, L. monocytogenes uses an actin-based motility system that allows bacterial cytoplasmic movement and cell-to-cell spread. L. monocytogenes therefore subverts host cell receptors, organelles and the cytoskeleton at different infection steps, manipulating diverse cellular functions that include ion transport, membrane trafficking, post-translational modifications, phosphoinositide production, innate immune responses as well as gene expression and DNA stability.

FIGURE 1

Cellular receptors for L. monocytogenes in host cells. The receptor for InlA in nonphagocytic polarized cells (including goblet cells) is the transmembrane molecule E-cadherin. Interaction takes place between the InlA leucine-rich repeats (LRRs) and the first extracellular domain of E-cadherin, leading to phosphorylation and ubiquitylation of the cytoplasmic domain of E-cadherin by the kinase Src and the ubiquitin ligase Hakai, respectively. Clustering of E-cadherin requires the presence of lipid rafts (left panel). Via its C-terminal glycine-tryptophan (GW) repeats, InlB interacts with the receptor for the globular part of the C1q complement component (gC1qR) and glycosaminoglycans, which enable interaction of the N-terminal LRRs of InlB with the tyrosine receptor kinase Met in nonphagocytic cells (including trophoblasts). Met dimerization upon interaction with InlB leads to autophosphorylation and recruitment of the ubiquitin ligase Cbl, which ubiquitylates the cytoplasmic tail of Met (center panel). In fibroblasts and monocytes, a function for the FcγRIA receptor has been described for L. monocytogenes internalization, via interaction with a still unidentified L. monocytogenes surface molecule (right panel). Modified from reference .

FIGURE 2

L. monocytogenes intracellular stages. L. monocytogenes is able to induce its entry into nonphagocytic cells mainly via the interaction of InlA and InlB with host cells receptors that promote actin recruitment, remodeling of the plasma membrane, and bacterial engulfment. The surface molecule ActA and the secreted pore-forming toxin LLO have also been implicated in the early L. monocytogenes entry steps (left cell, upper left). In goblet cells, upon internalization, L. monocytogenes is localized in a vacuole, and through transcytosis the bacterium is translocated to the lamina propria (left cell, left). In other cells, the combined activity of diverse virulence factors, including the pore-forming LLO, the metalloprotease Mpl, the phospholipases PlcA and PlcB, and the pheromone pPplA, favor disruption of the vacuole and L. monocytogenes release in the cytosol, where the bacteria takes advantage of host metabolites via the phosphate transporter Hpt and the lipoate protein ligase LplA. The surface protein ActA promotes actin-based motility, and the secreted protein InlC favors reduction of plasma membrane cortical tension, allowing L. monocytogenes to form protrusions and to invade neighboring cells. LLO and the phospholipases PlcA and PlcB contribute to the disruption of the double-membrane vacuole (right cell). L. monocytogenes has been observed in large spacious compartments that may arise rapidly after internalization of bacteria or upon decrease of ActA expression in already cytoplasmic bacteria (left cell, upper center). Extracellular LLO is able to modulate different cellular functions, including mitochondrial fission, lysosomal permeabilization, protein SUMOylation, ER stress, DNA damage, and chromatin remodeling. The phospholipases PlcA and PlcB, together with actin polymerization by ActA, have been implicated in the resistance to autophagy (195). The secreted molecule InlC prevents NF-κB translocation to the nucleus. Modified from reference .