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Conjugated action of two species-specific invasion proteins for fetoplacental listeriosis

Abstract

The ability to cross host barriers is an essential virulence determinant of invasive microbial pathogens. Listeria monocytogenes is a model microorganism that crosses human intestinal and placental barriers, and causes severe maternofetal infections by an unknown mechanism1. Several studies have helped to characterize the bacterial invasion proteins InlA and InlB2. However, their respective species specificity has complicated investigations on their in vivo role3,4. Here we describe two novel and complementary animal models for human listeriosis: the gerbil, a natural host for L. monocytogenes, and a knock-in mouse line ubiquitously expressing humanized E-cadherin. Using these two models, we uncover the essential and interdependent roles of InlA and InlB in fetoplacental listeriosis, and thereby decipher the molecular mechanism underlying the ability of a microbe to target and cross the placental barrier.

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Figure 1: InlA and InlB internalization pathways in gerbils.
Figure 2: In vivo real-time imaging of fetoplacental listeriosis in gerbils.
Figure 3: Interdependent roles of InlA and InlB in placental invasion and fetal infection in gerbils.
Figure 4: Infection of primary epithelial cells and mice expressing a humanized mEcad able to interact with InlA.

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Data deposits

The Gerbil Ecad and Gerbil Met nucleotide sequences are deposited in GenBank under accession numbers EU878370 and EU878371, respectively.

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Acknowledgements

This paper is dedicated to the memory of Charles Babinet, our friend and colleague, who died a few days before the submission of this manuscript. We thank his collaborators S. Vandormael-Pournin, C. Kress and M. Cohen-Tannoudji, as well as L. Larue and S. Tajbakhsh for help in generating the knock-in mice. We thank C. Hill for the gift of the pPL2lux-P hlyA plasmid, M.-A. Nahori for help with animal experiments, P. Roux for help with confocal imaging, P.-M. Lledo and M. Gabellec for help with vibratome sectioning, V. Masse for help with statistical analysis and O. Lortholary for his support. We also thank S. Mostowy for reading the paper. This work received financial support from the Institut Pasteur, Inserm and INRA. O. Disson received financial support from the Fondation pour la Recherche Médicale (FRM) and Inserm, P.C. is an Howard Hughes Medical Institute international research scholar and M.L. is a recipient of an Inserm interface contract.

Author Contributions M.L. planned the project and analysed the experiments, together with P.C., as well as O. Disson, S.G., E.H. and G.N. O. Disson, S.G., E.H. and G.N. performed the experiments. Engineering of knock-in mice was done with F.L.-V. and C.B. O. Dussurget was involved in bioluminescence imaging; M.R. and A.L.M. were involved in the epidemiological study. M.L. wrote the manuscript and all co-authors commented on it.

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Correspondence to Marc Lecuit.

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Disson, O., Grayo, S., Huillet, E. et al. Conjugated action of two species-specific invasion proteins for fetoplacental listeriosis. Nature 455, 1114–1118 (2008). https://doi.org/10.1038/nature07303

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