title: Genome Expression Profiling-Based Identification and Administration Efficacy of Host-Directed Antimicrobial Drugs against Respiratory Infection by Nontypeable Haemophilus influenzae.
abstract: Therapies that are safe, effective, and not vulnerable to developing resistance are highly desirable to counteract bacterial infections. Host-directed therapeutics is an antimicrobial approach alternative to conventional antibiotics based on perturbing host pathways subverted by pathogens during their life cycle by using host-directed drugs. In this study, we identified and evaluated the efficacy of a panel of host-directed drugs against respiratory infection by nontypeable Haemophilus influenzae (NTHi). NTHi is an opportunistic pathogen that is an important cause of exacerbation of chronic obstructive pulmonary disease (COPD). We screened for host genes differentially expressed upon infection by the clinical isolate NTHi375 by analyzing cell whole-genome expression profiling and identified a repertoire of host target candidates that were pharmacologically modulated. Based on the proposed relationship between NTHi intracellular location and persistence, we hypothesized that drugs perturbing host pathways used by NTHi to enter epithelial cells could have antimicrobial potential against NTHi infection. Interfering drugs were tested for their effects on bacterial and cellular viability, on NTHi-epithelial cell interplay, and on mouse pulmonary infection. Glucocorticoids and statins lacked in vitro and/or in vivo efficacy. Conversely, the sirtuin-1 activator resveratrol showed a bactericidal effect against NTHi, and the PDE4 inhibitor rolipram showed therapeutic efficacy by lowering NTHi375 counts intracellularly and in the lungs of infected mice. PDE4 inhibition is currently prescribed in COPD, and resveratrol is an attractive geroprotector for COPD treatment. Together, these results expand our knowledge of NTHi-triggered host subversion and frame the antimicrobial potential of rolipram and resveratrol against NTHi respiratory infection.
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, CIBERES, Madrid, Spain Instituto de Agrobiotecnología, CSIC-Universidad Pública Navarra-Gobierno Navarra, Mutilva, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Euba
authors.affiliation: Instituto de Agrobiotecnología, CSIC-Universidad Pública Navarra-Gobierno Navarra, Mutilva, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Moleres
authors.affiliation: Centro Investigación Médica Aplicada, Universidad de Navarra, Pamplona, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Segura
authors.affiliation: Instituto de Agrobiotecnología, CSIC-Universidad Pública Navarra-Gobierno Navarra, Mutilva, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Viadas
authors.affiliation: Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Pau
authors.initials: P
authors.lastname: Morey
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, CIBERES, Madrid, Spain Programme Infection and Immunity, Fundación de Investigación Sanitaria de las Islas Baleares-Instituto de Investigación Sanitaria de Palma, Mallorca, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Moranta
authors.affiliation: Servicio de Microbiología, Clínica Univesidad de Navarra, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Leiva
authors.affiliation: Servicio de Neumología, Clínica Universidad de Navarra, Pamplona, Spain.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: de-Torres
authors.affiliation: Centre for Infection and Immunity, Queen's University, Belfast, United Kingdom Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Bengoechea
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, CIBERES, Madrid, Spain Instituto de Agrobiotecnología, CSIC-Universidad Pública Navarra-Gobierno Navarra, Mutilva, Spain juncal.garmendia@unavarra.es.
authors.forename: Junkal
authors.initials: J
authors.lastname: Garmendia
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics* / Q000378:metabolism; D004359:Drug Therapy, Combination; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015894:Genome, Human; D006192:Haemophilus Infections / Q000188:drug therapy* / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D006193:Haemophilus influenzae / Q000187:drug effects / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D051379:Mice; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D000077185:Resveratrol; D020889:Rolipram / Q000494:pharmacology*; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D058988:Phosphodiesterase 4 Inhibitors; D013267:Stilbenes; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D020889:Rolipram; D000077185:Resveratrol