title: PI3-kinase activation is critical for host barrier permissiveness to Listeria monocytogenes.
abstract: Invasion of nonphagocytic cells, a critical property of Listeria monocytogenes (Lm) that enables it to cross host barriers, is mediated by the interaction of two bacterial surface proteins, InlA and InlB, with their respective receptors E-cadherin and c-Met. Although InlA-E-cadherin interaction is necessary and sufficient for Lm crossing of the intestinal barrier, both InlA and InlB are required for Lm crossing of the placental barrier. The mechanisms underlying these differences are unknown. Phosphoinositide 3-kinase (PI3-K) is involved in both InlA- and InlB-dependent pathways. Indeed, InlA-dependent entry requires PI3-K activity but does not activate it, whereas InlB-c-Met interaction activates PI3-K. We show that Lm intestinal target cells exhibit a constitutive PI3-K activity, rendering InlB dispensable for InlA-dependent Lm intestinal barrier crossing. In contrast, the placental barrier does not exhibit constitutive PI3-K activity, making InlB necessary for InlA-dependent Lm placental invasion. Here, we provide the molecular explanation for the respective contributions of InlA and InlB to Lm host barrier invasion, and reveal the critical role of InlB in rendering cells permissive to InlA-mediated invasion. This study shows that PI3-K activity is critical to host barrier permissiveness to microbes, and that pathogens exploit both similarities and differences of host barriers to disseminate.
authors.affiliation: Institut Pasteur, Biology of Infection Unit, F-75015 Paris, France Institut National de la Santé et de la Recherche Médicale, U1117, F-75015 Paris, France Université Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, F-75013 Paris, France.
authors.forename: Grégoire
authors.initials: G
authors.lastname: Gessain
authors.affiliation: Institut Pasteur, Biology of Infection Unit, F-75015 Paris, France Institut National de la Santé et de la Recherche Médicale, U1117, F-75015 Paris, France Université Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, F-75013 Paris, France.
authors.forename: Yu-Huan
authors.initials: YH
authors.lastname: Tsai
authors.affiliation: Institut Pasteur, Biology of Infection Unit, F-75015 Paris, France Institut National de la Santé et de la Recherche Médicale, U1117, F-75015 Paris, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Travier
authors.affiliation: Institut Pasteur, Bacteria Cell Interaction Unit, F-75015 Paris, France Institut National de la Santé et de la Recherche Médicale, U604, F-75015 Paris, France Institut National de la Recherche Agronomique USC2020, F-75015 Paris, France.
authors.forename: Matteo
authors.initials: M
authors.lastname: Bonazzi
authors.affiliation: Institut Pasteur, Biology of Infection Unit, F-75015 Paris, France Institut National de la Santé et de la Recherche Médicale, U1117, F-75015 Paris, France.
authors.forename: Solène
authors.initials: S
authors.lastname: Grayo
authors.affiliation: Institut Pasteur, Bacteria Cell Interaction Unit, F-75015 Paris, France Institut National de la Santé et de la Recherche Médicale, U604, F-75015 Paris, France Institut National de la Recherche Agronomique USC2020, F-75015 Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Cossart
authors.affiliation: Institut Pasteur, Biology of Infection Unit, F-75015 Paris, France Institut National de la Santé et de la Recherche Médicale, U1117, F-75015 Paris, France Institut Pasteur, French National Reference Center and World Health Organization Collaborating Centre on Listeria, F-75015 Paris, France Paris Descartes University, Sorbonne Paris Cité, Division of Infectious Diseases and Tropical Medicine, Necker-Enfants Malades University Hospital, Institut Imagine, F-75015 Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Charlier
authors.affiliation: Institut Pasteur, Biology of Infection Unit, F-75015 Paris, France Institut National de la Santé et de la Recherche Médicale, U1117, F-75015 Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Disson
authors.affiliation: Institut Pasteur, Biology of Infection Unit, F-75015 Paris, France Institut National de la Santé et de la Recherche Médicale, U1117, F-75015 Paris, France Institut Pasteur, French National Reference Center and World Health Organization Collaborating Centre on Listeria, F-75015 Paris, France Paris Descartes University, Sorbonne Paris Cité, Division of Infectious Diseases and Tropical Medicine, Necker-Enfants Malades University Hospital, Institut Imagine, F-75015 Paris, France marc.lecuit@pasteur.fr.
authors.forename: Marc
authors.initials: M
authors.lastname: Lecuit
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D002824:Chorionic Villi / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D004789:Enzyme Activation; D005260:Female; D020397:Goblet Cells / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D007422:Intestines / Q000276:immunology / Q000382:microbiology; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010581:Peyer's Patches / Q000276:immunology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D010920:Placenta / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D011247:Pregnancy; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014327:Trophoblasts / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D015820:Cadherins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt