Listeria monocytogenes Internalin and E-cadherin: From Bench to Bedside

Listeria monocytogenes is a Gram-positive bacterium responsible for a severe infection associated with different clinical features (gastroenteritis, meningoencephalitis, and abortion in pregnant women). These pathologies are caused by the unusual capacity of the bacterium to cross three host barriers during infection and to invade nonphagocytic cells. To invade host cells, Listeria uses two proteins, InlA and InlB, which have specific receptors on the host-cell surface, E-cadherin and Met, respectively. Here, we discuss the specificity of the InlA–E-cadherin interaction, the signaling cascade activated on E-cadherin engagement by InlA, and the role of InlA and E-cadherin in the breaching of host barriers and the dissemination of the infection.Listeriosis is a potentially lethal food-borne infection with a mortality rate up to 30%. It has emerged as a significant human infection in industrialized countries along with the development of large-scale agro-industrial plants and refrigerated food. Opposite to most food-borne infections, listeriosis is rare but potentially very severe, because it remains often under-diagnosed at its early stages (Lecuit 2007). The etiological agent of listeriosis is Listeria monocytogenes, a Gram-positive bacterium that contaminates meat, dairy products, and ready to eat food. Upon ingestion of contaminated food, L. monocytogenes can colonize the intestine and gives rise to gastroenteritis in case of the absorption of a high inoculum. Strikingly, L. monocytogenes has the capacity to cross the intestinal barrier and disseminate to the mesenteric lymph nodes, spleen, and liver. In immunocompromised individuals, L. monocytogenes may replicate in the spleen and liver, cause prolonged and sustained bacteremia, cross the blood–brain barrier and the placental barrier, and disseminate to the brain and placenta, causing meningitis, encephalitis, abortion in pregnant women, and neonatal infections (Hamon et al. 2006; Bonazzi et al. 2009).The capacity of L. monocytogenes to cross multiple host barriers relies on the ability of the bacterium to invade nonphagocytic cells, such as epithelial cells, by interacting with host cell-surface receptors. Adhesion to host cells is a key step underlying bacterial pathogenicity and it is required to counteract the mechanical clearance at tissue surfaces provided by intestinal peristaltism and blood flow. Internalization allows persistence in a shielded niche, away from the soluble effectors of the host immune system (Cossart and Sansonetti 2004; Pizarro-Cerda and Cossart 2006), and access to target organs, as illustrated by L. monocytogenes (Bonazzi et al. 2009).Bacterial surface proteins that engage host receptors are generally called adhesins, although it is now clear that many of them not only mediate adhesion, but also bacterial internalization (Boyle and Finlay 2003; Hauck et al. 2006; Pizarro-Cerda and Cossart 2006). Adhesion to and internalization of L. monocytogenes within epithelial cells is mainly mediated by two bacterial surface protein members of the internalin family, namely internalin (InlA) and InlB, that use E-cadherin and Met as receptors, respectively, on the surface of host cells (Hamon et al. 2006; Pizarro-Cerda and Cossart 2006; Bonazzi et al. 2009). Upon receptor-mediated internalization, L. monocytogenes is engulfed into the cell and becomes surrounded by a tight phagocytic vacuole that the bacterium can lyse by means of the pore-forming toxin listeriolysin O (LLO). Once free in the cytoplasm of the host cell, L. monocytogenes uses the protein ActA to harness the actin polymerization machinery and facilitate its intracellular movement via the formation of so-called actin “comet tails.” Actin-based motility is fundamental for L. monocytogenes direct cell-to-cell spread, a typical feature that allows the dissemination of the infection to neighboring cells via the formation of plasma membrane protrusions. Once internalized by neighboring cells, L. monocytogenes is confined in a double-membrane vacuole from which it escapes to restart its life cycle (Fig. 1) (Hamon et al. 2006).Open in a separate windowFigure 1.The cell cycle of L. monocytogenes. (1) L. monocytogenes adheres to the surface of epithelial cells via the interactions of the surface proteins InlA and InlB with E-cadherin and the Met receptor, respectively. (2) On internalization, L. monocytogenes is engulfed in a phagocytic vacuole. (3) L. monocytogenes lyses vacuolar membranes by means of the toxin LLO. (4) L. monocytogenes uses the protein ActA to harness the actin polymerization machinery and facilitate its intracellular movement via the formation of so-called actin “comet tails.” (5) L. monocytogenes exploits actin-based motility for direct cell-to-cell spread to allow the dissemination of the infection to neighboring cells via the formation of plasma membrane protrusions. (6) Once internalized by neighboring cells, L. monocytogenes is confined in a double-membrane vacuole from which it escapes to restart its life cycle.Its remarkable adaptation to the cellular environment and its capacity to exploit cellular receptor-mediated signaling pathways and the actin polymerization machinery have made L. monocytogenes an exceptional tool for the study of a wide array of cellular functions (Cossart and Sansonetti 2004; Bonazzi and Cossart 2006; Hamon et al. 2006; Pizarro-Cerda and Cossart 2006; Veiga and Cossart 2005a; Bonazzi et al. 2009). Here, we review the interaction of InlA with E-cadherin, the signaling pathway initiated by this interaction that results in the internalization of L. monocytogenes, and the role of InlA-E-cadherin interaction during listeriosis.