Genome expression profiling-based identification and administration efficacy of host-directed antimicrobial drugs against respiratory infection by nontypeable Haemophilus influenzae

Euba, Begoña; Moleres Apilluelo, Javier; Segura, Víctor; Viadas Martínez, Cristina; Morey Sancho, Pau; Moranta, David; Leiva, José; Torres, Juan de; Bengoechea Alonso, José Antonio; Garmendia García, Juncal

Publication:
Genome expression profiling-based identification and administration efficacy of host-directed antimicrobial drugs against respiratory infection by nontypeable Haemophilus influenzae

dc.contributor.author	Euba, Begoña
dc.contributor.author	Moleres Apilluelo, Javier
dc.contributor.author	Segura, Víctor
dc.contributor.author	Viadas Martínez, Cristina
dc.contributor.author	Morey Sancho, Pau
dc.contributor.author	Moranta, David
dc.contributor.author	Leiva, José
dc.contributor.author	Torres, Juan de
dc.contributor.author	Bengoechea Alonso, José Antonio
dc.contributor.author	Garmendia García, Juncal
dc.contributor.department	IdAB. Instituto de Agrobiotecnología / Agrobioteknologiako Institutua	es_ES
dc.contributor.funder	Gobierno de Navarra / Nafarroako Gobernua	es
dc.date.accessioned	2019-01-10T08:27:50Z
dc.date.available	2019-01-10T08:27:50Z
dc.date.issued	2015
dc.description.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.	en
dc.description.sponsorship	J.M. is funded by Ph.D. studentship BES-2013-062644 from the Ministerio Economía y Competitividad-MINECO, Spain. This study was funded by grants from ISCIII (PS09/00130), the Ministerio Economía y Competitividad (MINECO SAF2012-31166), and the Departamento de Salud Gobierno Navarra (359/2012) to J.G.	en
dc.format.extent	12 p.
dc.format.mimetype	application/pdf	en
dc.format.mimetype	application/zip	en
dc.identifier.doi	10.1128/aac.01278-15
dc.identifier.issn	0066-4804 (Print)
dc.identifier.issn	1098-6596 (Electronic)
dc.identifier.uri	https://academica-e.unavarra.es/handle/2454/31928
dc.language.iso	eng	en
dc.publisher	American Society for Microbiology	en
dc.relation.ispartof	Antimicrobial Agents and Chemotherapy, 9:7581–7592	en
dc.relation.projectID	info:eu-repo/grantAgreement/MINECO//SAF2012-31166/ES/	en
dc.relation.publisherversion	https://doi.org/10.1128/aac.01278-15
dc.rights	© 2015, American Society for Microbiology. All Rights Reserved.	en
dc.rights.accessRights	info:eu-repo/semantics/openAccess	en
dc.rights.accessRights	Acceso abierto / Sarbide irekia	es
dc.subject	Nontypeable Haemophilus influenzae (NTHi)	en
dc.subject	Host-directed antimicrobial drugs	en
dc.title	Genome expression profiling-based identification and administration efficacy of host-directed antimicrobial drugs against respiratory infection by nontypeable Haemophilus influenzae	en
dc.type	info:eu-repo/semantics/article	en
dc.type	Artículo / Artikulua	es
dc.type.version	info:eu-repo/semantics/publishedVersion	en
dc.type.version	Versión publicada / Argitaratu den bertsioa	es
dspace.entity.type	Publication
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