title: B lymphocytes undergo TLR2-dependent apoptosis upon Shigella infection.
abstract: Antibody-mediated immunity to Shigella, the causative agent of bacillary dysentery, requires several episodes of infection to get primed and is short-lasting, suggesting that the B cell response is functionally impaired. We show that upon ex vivo infection of human colonic tissue, invasive S. flexneri interacts with and occasionally invades B lymphocytes. The induction of a type three secretion apparatus (T3SA)-dependent B cell death is observed in the human CL-01 B cell line in vitro, as well as in mouse B lymphocytes in vivo. In addition to cell death occurring in Shigella-invaded CL-01 B lymphocytes, we provide evidence that the T3SA needle tip protein IpaD can induce cell death in noninvaded cells. IpaD binds to and induces B cell apoptosis via TLR2, a signaling receptor thus far considered to result in activation of B lymphocytes. The presence of bacterial co-signals is required to sensitize B cells to apoptosis and to up-regulate tlr2, thus enhancing IpaD binding. Apoptotic B lymphocytes in contact with Shigella-IpaD are detected in rectal biopsies of infected individuals. This study therefore adds direct B lymphocyte targeting to the diversity of mechanisms used by Shigella to dampen the host immune response.
authors.affiliation: Institut Pasteur, INSERM U786, Unité de Pathogénie Microbienne Moléculaire, 75015 Paris, FranceInstitut Pasteur, INSERM U786, Unité de Pathogénie Microbienne Moléculaire, 75015 Paris, France.
authors.forename: Katharina
authors.initials: K
authors.lastname: Nothelfer
authors.affiliation: Institut Pasteur, INSERM U786, Unité de Pathogénie Microbienne Moléculaire, 75015 Paris, FranceInstitut Pasteur, INSERM U786, Unité de Pathogénie Microbienne Moléculaire, 75015 Paris, France.
authors.forename: Ellen T
authors.initials: ET
authors.lastname: Arena
authors.affiliation: Institut Pasteur, INSERM U786, Unité de Pathogénie Microbienne Moléculaire, 75015 Paris, FranceInstitut Pasteur, INSERM U786, Unité de Pathogénie Microbienne Moléculaire, 75015 Paris, France Université Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur UPMC, 75013 Paris, France.
authors.forename: Laurie
authors.initials: L
authors.lastname: Pinaud
authors.affiliation: INSERM U913, Institut des Maladies de l'Appareil Digestif du Centre Hospitalier Universitaire de Nantes, 44093 Nantes, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Neunlist
authors.affiliation: Institut Pasteur, INSERM U1041, Unité de Régulation Immunitaire et Vaccinologie, 75015 Paris, France Institut Pasteur, INSERM U1041, Unité de Régulation Immunitaire et Vaccinologie, 75015 Paris, France.
authors.forename: Brian
authors.initials: B
authors.lastname: Mozeleski
authors.affiliation: Institut Pasteur, INSERM U786, Unité de Pathogénie Microbienne Moléculaire, 75015 Paris, FranceInstitut Pasteur, INSERM U786, Unité de Pathogénie Microbienne Moléculaire, 75015 Paris, France.
authors.forename: Ilia
authors.initials: I
authors.lastname: Belotserkovsky
authors.affiliation: Institut Pasteur, INSERM U786, Unité de Pathogénie Microbienne Moléculaire, 75015 Paris, FranceInstitut Pasteur, INSERM U786, Unité de Pathogénie Microbienne Moléculaire, 75015 Paris, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Parsot
authors.affiliation: Discovery Department, Sanofi Pasteur, 69280 Marcy l'Etoile, France.
authors.forename: Premkumar
authors.initials: P
authors.lastname: Dinadayala
authors.affiliation: Molekulare Biotechnologie, Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB, 70569 Stuttgart, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Burger-Kentischer
authors.affiliation: Laboratory Sciences Division, International Centre for Diarrhoeal Diseases Research, Bangladesh (ICDDR,B), Dhaka 1000, Bangladesh.
authors.forename: Rubhana
authors.initials: R
authors.lastname: Raqib
authors.affiliation: Institut Pasteur, INSERM U786, Unité de Pathogénie Microbienne Moléculaire, 75015 Paris, FranceInstitut Pasteur, INSERM U786, Unité de Pathogénie Microbienne Moléculaire, 75015 Paris, France Chaire de Microbiologie et Maladies Infectieuses, Collège de France, 75005 Paris, France.
authors.forename: Philippe J
authors.initials: PJ
authors.lastname: Sansonetti
authors.affiliation: Institut Pasteur, INSERM U786, Unité de Pathogénie Microbienne Moléculaire, 75015 Paris, FranceInstitut Pasteur, INSERM U786, Unité de Pathogénie Microbienne Moléculaire, 75015 Paris, France armelle.phalipon@pasteur.fr.
authors.forename: Armelle
authors.initials: A
authors.lastname: Phalipon
mesh_terms: D000328:Adult; D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D004405:Dysentery, Bacillary / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D005260:Female; D005434:Flow Cytometry; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009154:Mutation; D041681:NIH 3T3 Cells; D011485:Protein Binding / Q000276:immunology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012763:Shigella flexneri / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D051017:Apoptosis Regulatory Proteins; D001426:Bacterial Proteins; C095770:IpaD protein, Shigella flexneri; D051195:Toll-Like Receptor 2