title: A Toll-Like Receptor 5 Agonist Improves the Efficacy of Antibiotics in Treatment of Primary and Influenza Virus-Associated Pneumococcal Mouse Infections.
abstract: Prophylactic intranasal administration of the Toll-like receptor 5 (TLR5) agonist flagellin protects mice against respiratory pathogenic bacteria. We hypothesized that TLR5-mediated stimulation of lung immunity might improve the therapeutic index of antibiotics for the treatment of Streptococcus pneumoniae respiratory infections in mice. Intranasal administration of flagellin was combined with either oral administration of amoxicillin or intraperitoneal injection of trimethoprim-sulfamethoxazole to treat S. pneumoniae-infected animals. Compared with standalone treatments, the combination of antibiotic and flagellin resulted in a lower bacterial load in the lungs and greater protection against S. pneumoniae dissemination and was associated with an early increase in neutrophil infiltration in the airways. The antibiotic-flagellin combination treatment was, however, not associated with any exacerbation of inflammation. Moreover, combination treatment was more efficacious than standalone antibiotic treatments in the context of post-influenza virus pneumococcal infection. Lastly, TLR5 signaling was shown to be mandatory for the efficacy of the combined antibacterial therapy. This report is the first to show that combining antibiotic treatment with the stimulation of mucosal innate immunity is a potent antibacterial strategy against pneumonia.
authors.affiliation: Centre d'Infection et d'Immunité de Lille, Institut Pasteur de Lille, Lille, France Institut National de la Santé et de la Recherche Médicale, U1019, Lille, France Centre National de la Recherche Scientifique, UMR 8204, Lille, France Université de Lille, Lille, France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Porte
authors.affiliation: Centre d'Infection et d'Immunité de Lille, Institut Pasteur de Lille, Lille, France Institut National de la Santé et de la Recherche Médicale, U1019, Lille, France Centre National de la Recherche Scientifique, UMR 8204, Lille, France Université de Lille, Lille, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Fougeron
authors.affiliation: Laboratory for Vaccine Research, Department of Biotechnology, Instituto de Higiene, Facultad de Medicina, Universidad de la Republica, Montevideo, Uruguay.
authors.forename: Natalia
authors.initials: N
authors.lastname: Muñoz-Wolf
authors.affiliation: Centre d'Infection et d'Immunité de Lille, Institut Pasteur de Lille, Lille, France Institut National de la Santé et de la Recherche Médicale, U1019, Lille, France Centre National de la Recherche Scientifique, UMR 8204, Lille, France Université de Lille, Lille, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Tabareau
authors.affiliation: Centre d'Infection et d'Immunité de Lille, Institut Pasteur de Lille, Lille, France Institut National de la Santé et de la Recherche Médicale, U1019, Lille, France Centre National de la Recherche Scientifique, UMR 8204, Lille, France Université de Lille, Lille, France Groupement des Hôpitaux de l'Institut Catholique de Lille, Lille, France.
authors.forename: Anne-France
authors.initials: AF
authors.lastname: Georgel
authors.affiliation: Laboratoire de Bactériologie Hygiène, Institut de Microbiologie, Centre de Biologie Pathologie, CHRU Lille, Lille, France.
authors.forename: Fréderic
authors.initials: F
authors.lastname: Wallet
authors.affiliation: Centre d'Infection et d'Immunité de Lille, Institut Pasteur de Lille, Lille, France Institut National de la Santé et de la Recherche Médicale, U1019, Lille, France Centre National de la Recherche Scientifique, UMR 8204, Lille, France Université de Lille, Lille, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Paget
authors.affiliation: Centre d'Infection et d'Immunité de Lille, Institut Pasteur de Lille, Lille, France Institut National de la Santé et de la Recherche Médicale, U1019, Lille, France Centre National de la Recherche Scientifique, UMR 8204, Lille, France Université de Lille, Lille, France.
authors.forename: François
authors.initials: F
authors.lastname: Trottein
authors.affiliation: Laboratory for Vaccine Research, Department of Biotechnology, Instituto de Higiene, Facultad de Medicina, Universidad de la Republica, Montevideo, Uruguay.
authors.forename: José A
authors.initials: JA
authors.lastname: Chabalgoity
authors.affiliation: Centre d'Infection et d'Immunité de Lille, Institut Pasteur de Lille, Lille, France Institut National de la Santé et de la Recherche Médicale, U1019, Lille, France Centre National de la Recherche Scientifique, UMR 8204, Lille, France Université de Lille, Lille, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Carnoy
authors.affiliation: Centre d'Infection et d'Immunité de Lille, Institut Pasteur de Lille, Lille, France Institut National de la Santé et de la Recherche Médicale, U1019, Lille, France Centre National de la Recherche Scientifique, UMR 8204, Lille, France Université de Lille, Lille, France jean-claude.sirard@inserm.fr.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Sirard
mesh_terms: D000658:Amoxicillin / Q000627:therapeutic use; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D005260:Female; D005408:Flagellin / Q000627:therapeutic use*; D007113:Immunity, Innate / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000187:drug effects; D011008:Pneumococcal Infections / Q000188:drug therapy*; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000472:pathogenicity; D051198:Toll-Like Receptor 5 / Q000819:agonists*; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D051198:Toll-Like Receptor 5; D005408:Flagellin; D000658:Amoxicillin; D015662:Trimethoprim, Sulfamethoxazole Drug Combination