Targeting and crossing of the human maternofetal barrier byListeria monocytogenes: Role of internalin interaction with trophoblast E-cadherin

Abstract

Listeria monocytogenes produces severe fetoplacental infections in humans. How it targets and crosses the maternofetal barrier is unknown. We used immunohistochemistry to examine the location of L. monocytogenes in placental and amniotic tissue samples obtained from women with fetoplacental listeriosis. The results raised the possibility that L. monocytogenes crosses the maternofetal barrier through the villous syncytiotrophoblast, with secondary infection occurring via the amniotic epithelium. Because epidemiological studies indicate that the bacterial surface protein, internalin (InlA), may play a role in human fetoplacental listeriosis, we investigated the cellular patterns of expression of its host receptor, E-cadherin, at the maternofetal interface. E-cadherin was found on the basal and apical plasma membranes of syncytiotrophoblasts and in villous cytotrophoblasts. Established trophoblastic cell lines, primary trophoblast cultures, and placental villous explants were each exposed to isogenic InlA؉ or InlA؊ strains of L. monocytogenes, and to L. innocua expressing or not InlA. Quantitative assays of cellular invasion demonstrated that bacterial entry into syncytiotrophoblasts occurs via the apical membrane in an InlA-E-cadherin dependent manner. In human placental villous explants, bacterial invasion of the syncytiotrophoblast barrier and underlying villous tissue and subsequent replication produces histopathological lesions that mimic those seen in placentas of women with listeriosis. Thus, the InlA-E-cadherin interaction that plays a key role in the crossing of the intestinal barrier in humans is also exploited by L. monocytogenes to target and cross the placental barrier. Such a ligand-receptor interaction allowing a pathogen to specifically cross the placental villous trophoblast barrier has not been reported previously.

Invasive Pathway of Listeria Ivanovii in Human Amnion-Derived Wish Cells

“…Interestingly, similarly to Karunasagar and co-workers (30) observations in enterocytic cells, we detected a significantly higher internalisation of L. ivanovii in amniotic cells compared to that of L. monocytogenes. As E-cadherin is present on both intestinal and amniotic epithelial cells (38), it is likely that L. monocytogenes penetrates WISH cells after the interaction of InlA with E-cadherin whereas L. ivanovii gains more easily epithelial cell cytoplasm probably also utilizing different unknown receptors.…”

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

“…InlA was shown to interact with E-cadherin present at the basal and apical membranes of syncytiotrophoblasts and villous cytotrophoblasts, mediating the crossing of the feto-placental barrier. 68 On the other hand, syncytiotrophoblasts were shown to be highly resistant to L. monocytogenes infection. 69 Epidemiological studies showed that InlA plays a key role in human listeriosis: 96% of clinical strains express a full-length functional form of InlA, while only 65% of food-isolated strains contained the fulllength form.…”

Host Specificity of Bacterial Pathogens

“…Although mice are naturally resistant to oral challenge with L. monocytogenes, transgenic mice expressing human E-cadherin in the intestine become susceptible to infection by this route (Lecuit et al 2001). The interaction between InlA and human E-cadherin also plays an important role in the ability of L. monocytogenes to cross the placental barrier and cause severe in utero infections (Lecuit et al 2004). A second invasion protein of L. monocytogenes, InlB, mediates binding to the hepatocyte growth factor receptor (Met) of murine and human cells, but not to Met from rabbits or guinea pigs (Khelef et al 2006), which represents another example of species specificity.…”

“…A second invasion protein of L. monocytogenes, InlB, mediates binding to the hepatocyte growth factor receptor (Met) of murine and human cells, but not to Met from rabbits or guinea pigs (Khelef et al 2006), which represents another example of species specificity. Both InlA and InlB have been implicated in species-specific interactions involved in crossing the placental barrier in vivo (Lecuit et al 2004;Disson et al 2008).…”