1. A toll-like receptor 5 agonist improves the efficacy of antibiotics in the treatment of primary and influenza-associated pneumococcal mouse infections
- Author
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Natalia Muñoz-Wolf, Frédéric Wallet, Rémi Porte, José A. Chabalgoity, François Trottein, Christophe Paget, Julien Tabareau, Anne-France Georgel, Christophe Carnoy, Delphine Fougeron, Jean-Claude Sirard, 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), Universidad de la República [Montevideo] (UCUR), Groupe Hospitalier de l'Institut Catholique de Lille (GHICL), Service de Bactériologie, Virologie, Hygiène [CHU Limoges], CHU Limoges, This work was funded by INSERM, CNRS, Institut Pasteur de Lille, and Université de Lille (to R.P., D.F., J.T., A.-F.G., C.P., F.T., C.C., and J.-C.S), Région Nord Pas de Calais (Ph.D. fellowship), and Inserm-Transfert (CoPoC grant 'Innatebiotic')., We thank Delphine Cayet and Daphnée Soulard for technical assistance in the production and quality control of recombinant proteins and Isabelle Wolowczuk, Sandra Weller, and Philippe Gosset for critical reading of the manuscript., 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), Universidad de la República [Montevideo] (UDELAR), Université catholique de Lille (UCL), and Sirard, Jean-Claude
- Subjects
Antibiotics ,MESH: Pneumococcal Infections/drug therapy ,medicine.disease_cause ,MESH: Flagellin/therapeutic use ,Mice ,0302 clinical medicine ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,MESH: Trimethoprim, Sulfamethoxazole Drug Combination/therapeutic use ,MESH: Toll-Like Receptor 5/agonists ,Pharmacology (medical) ,MESH: Animals ,MESH: Streptococcus pneumoniae/pathogenicity ,MESH: Immunity, Innate/drug effects ,0303 health sciences ,Mice, Inbred BALB C ,3. Good health ,Anti-Bacterial Agents ,Infectious Diseases ,Streptococcus pneumoniae ,Neutrophil Infiltration ,[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Female ,medicine.drug ,medicine.drug_class ,MESH: Mice, Inbred BALB C ,Biology ,Pneumococcal Infections ,Microbiology ,03 medical and health sciences ,Immunity ,MESH: Streptococcus pneumoniae/drug effects ,Trimethoprim, Sulfamethoxazole Drug Combination ,medicine ,Animals ,MESH: Neutrophil Infiltration/drug effects ,Experimental Therapeutics ,MESH: Amoxicillin/therapeutic use ,MESH: Mice ,030304 developmental biology ,MESH: Anti-Bacterial Agents/therapeutic use ,Pharmacology ,Amoxicillin ,medicine.disease ,Immunity, Innate ,Pneumonia ,Toll-Like Receptor 5 ,TLR5 ,Immunology ,biology.protein ,Nasal administration ,MESH: Female ,Flagellin ,030215 immunology - 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.
- Published
- 2015
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