Targeting Type IV pili as an antivirulence strategy against invasive meningococcal disease

Autor: Jean-Philippe Barnier, Haniaa Bouzinba-Segard, Anne Gouge, Anne Jamet, Mathieu Coureuil, Philippe Morand, Xavier Nassif, Philippe Pelissier, Frank Lafont, Béatrice Durel, Marion Le Bris, Sandrine Bourdoulous, Olivier Join-Lambert, Nicolas Barois, Daniel Euphrasie, Kevin Denis, Loic Le Guennec, Camille Faure
Přispěvatelé: Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre hospitalier Saint-Joseph [Paris], K.D. and L.LG. were supported by a doctoral fellowship from la Region Ile de France and the Fondation pour la Recherche Médicale, respectively. This work was supported by collaborative research grants from the Agence Nationale de la Recherche of France (grant no. ANR-14-IFEC14-0006) to S.B. and X.N. in the framework of the Infect-ERA joint transnational call (European funding for infectious diseases research), by the Société d’Accélération du Transfert de Technologie (grant no. ANR-10-SATT-05-01) to S.B. and by grant no. ANR-10-EQPX-04-01 to F.L., We thank M. Robert-Genthon and F. Chretien for providing the P. aeruginosa PAO1 strain and brain tissues, M. Favier of the histology facility, A. Schmitt and T. Guilbert of the imaging facility, and K. Bailly and M. Andrieu of the cytometry facility of the Institut Cochin for their expert technical help., ANR-10-SATT-0005,SATT Erganeo,ERGANEO(2010), ANR-10-EQPX-0004,Imaginex BioMed,Plateau de microscopie de criblage à haut débit et d'analyse à très haute résolution(2010), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), ANR-10-SATT-0005,SATT ERGANEO,SATT ERGANEO (EX IDF INNOV)(2010), Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Groupe hospitalier Paris Saint-Joseph - Hôpital, ANR: 10-SATT-0005,SATT IDF INNOV,IDF INNOV(2010), ANR-10-EQPX-0004/10-EQPX-0004,Imaginex BioMed,Plateau de microscopie de criblage à haut débit et d'analyse à très haute résolution(2010)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Nature Microbiology
Nature Microbiology, Nature Publishing Group, 2019, 4 (6), pp.972-984. ⟨10.1038/s41564-019-0395-8⟩
Nature Microbiology, 2019, 4 (6), pp.972-984. ⟨10.1038/s41564-019-0395-8⟩
ISSN: 2058-5276
Popis: Bacterial virulence factors are attractive targets for the development of therapeutics. Type IV pili, which are associated with a remarkable array of properties including motility, the interaction between bacteria and attachment to biotic and abiotic surfaces, represent particularly appealing virulence factor targets. Type IV pili are present in numerous bacterial species and are critical for their pathogenesis. In this study, we report that trifluoperazine and related phenothiazines block functions associated with Type IV pili in different bacterial pathogens, by affecting piliation within minutes. Using Neisseria meningitidis as a paradigm of Gram-negative bacterial pathogens that require Type IV pili for pathogenesis, we show that piliation is sensitive to altered activity of the Na+ pumping NADH–ubiquinone oxidoreductase (Na+−NQR) complex and that these compounds probably altered the establishment of the sodium gradient. In vivo, these compounds exert a strong protective effect. They reduce meningococcal colonization of the human vessels and prevent subsequent vascular dysfunctions, intravascular coagulation and overwhelming inflammation, the hallmarks of invasive meningococcal infections. Finally, they reduce lethality. This work provides a proof of concept that compounds with activity against bacterial Type IV pili could beneficially participate in the treatment of infections caused by Type IV pilus-expressing bacteria. Phenothiazines inhibit Type IV pili function in Neisseria meningitidis and protect against bacterial colonization of blood vessels and lethality during infection.
Databáze: OpenAIRE
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