A single amino acid in E-cadherin responsible for host specificity towards the human pathogen Listeria monocytogenes

Abstract

Human E-cadherin promotes entry of the bacterial pathogen Listeria monocytogenes into mammalian cells by interacting with internalin (InlA), a bacterial surface protein. Here we show that mouse E-cadherin, although very similar to human E-cadherin (85% identity), is not a receptor for internalin. By a series of domainswapping and mutagenesis experiments, we identify Pro16 of E-cadherin as a residue critical for specificity: a Pro→Glu substitution in human E-cadherin totally abrogates interaction, whereas a Glu→Pro substitution in mouse E-cadherin results in a complete gain of function. A correlation between cell permissivity and the nature of residue 16 in E-cadherins from several species is established. The location of this key specificity residue in a region of E-cadherin not involved in cellcell adhesion and the stringency of the interaction demonstrated here have important consequences not only for the understanding of internalin function but also for the choice of the animal model to be used to study human listeriosis: mouse, albeit previously widely used, and rat appear as inappropriate animal models to study all aspects of human listeriosis, as opposed to guinea-pig, which now stands as a small animal of choice for future in vivo studies.

PI3-kinase activation is critical for host barrier permissiveness to Listeria monocytogenes

“…As previously shown in cells expressing hEcad (Mengaud et al, 1996;Lecuit et al, 1999), the entry of Lm inlA deletion mutant (inlA) was reduced compared with WT Lm in both LS174T and Jar cells (Fig. 4, A and B).…”

The arsenal of virulence factors deployed byListeria monocytogenesto promote its cell infection cycle

“…In contrast, mouse E-cadherin cannot interact with InlA because the proline is replaced by a glutamic acid residue. 65 The crystal structure of the LRR region of InlA in association with the extracellular domain of human E-cadherin corroborated this observation and revealed that a hydrophobic pocket on the LRR accommodates the E-cadherin proline 16 residue. 66 Oral inoculation of a transgenic mouse model that synthesizes the human E-cadherin in the intestine showed the crucial role of InlA in the crossing of the intestinal epithelium.…”

Intestinal and Splenic T Cell Responses to EntericListeria monocytogenesInfection: Distinct Repertoires of Responding CD8 T Lymphocytes

“…Recent studies have demonstrated that L. monocytogenes internalin exhibits decreased association with murine E-cadherin compared with human E-cadherin (43), thereby substantially reducing infection of intestinal epithelial cells. It is possible, therefore, that enteric infection of mice with L. monocytogenes disseminates primarily through M cells lining the small intestine, a route that is believed to be followed by many different enteric bacterial pathogens (44).…”