Inactivation of the Thymidylate synthase thyA in non-typeable Haemophilus influenzae modulates antibiotic resistance and has a strong impact on its interplay with the host airways

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dc.contributor.authorRodríguez Arce, Irene
dc.contributor.authorMartí, Sara
dc.contributor.authorEuba, Begoña
dc.contributor.authorFernández Calvet, Ariadna
dc.contributor.authorMoleres Apilluelo, Javier
dc.contributor.authorLópez López, Nahikari
dc.contributor.authorBarberán, Montserrat
dc.contributor.authorRamos Vivas, José
dc.contributor.authorTubau, Fe
dc.contributor.authorLosa, Carmen
dc.contributor.authorArdanuy, Carmen
dc.contributor.authorLeiva, José
dc.contributor.authorYuste, José R.
dc.contributor.authorGarmendia García, Juncal
dc.contributor.departmentIdAB. Instituto de Agrobiotecnología / Agrobioteknologiako Institutuaes_ES
dc.contributor.funderUniversidad Pública de Navarra / Nafarroako Unibertsitate Publikoaes
dc.contributor.funderGobierno de Navarra / Nafarroako Gobernuaes
dc.date.accessioned2018-09-04T06:43:47Z
dc.date.available2018-09-04T06:43:47Z
dc.date.issued2017
dc.description.abstractAntibacterial treatment with cotrimoxazol (TxS), a combination of trimethoprim and sulfamethoxazole, generates resistance by, among others, acquisition of thymidine auxotrophy associated with mutations in the thymidylate synthase gene thyA, which can modify the biology of infection. The opportunistic pathogen non-typeable Haemophilus influenzae (NTHi) is frequently encountered in the lower airways of chronic obstructive pulmonary disease (COPD) patients, and associated with acute exacerbation of COPD symptoms. Increasing resistance of NTHi to TxS limits its suitability as initial antibacterial against COPD exacerbation, although its relationship with thymidine auxotrophy is unknown. In this study, the analysis of 2,542 NTHi isolates recovered at Bellvitge University Hospital (Spain) in the period 2010–2014 revealed 119 strains forming slow-growing colonies on the thymidine low concentration medium Mueller Hinton Fastidious, including one strain isolated from a COPD patient undergoing TxS therapy that was a reversible thymidine auxotroph. To assess the impact of thymidine auxotrophy in the NTHi-host interplay during respiratory infection, thyA mutants were generated in both the clinical isolate NTHi375 and the reference strain RdKW20. Inactivation of the thyA gene increased TxS resistance, but also promoted morphological changes consistent with elongation and impaired bacterial division, which altered H. influenzae self-aggregation, phosphorylcholine level, C3b deposition, and airway epithelial infection patterns. Availability of external thymidine contributed to overcome such auxotrophy and TxS effect, potentially facilitated by the nucleoside transporter nupC. Although, thyA inactivation resulted in bacterial attenuation in a lung infection mouse model, it also rendered a lower clearance upon a TxS challenge in vivo. Thus, our results show that thymidine auxotrophy modulates both the NTHi host airway interplay and antibiotic resistance, which should be considered at the clinical setting for the consequences of TxS administration.en
dc.description.sponsorshipIR is funded by a Ph.D. studentship from Universidad Pública de Navarra, Spain; JM is funded by Ph.D. studentship BES-2013-062644 from Ministerio Economía y Competitividad-MINECO, Spain; SM is funded by a postdoctoral contract from CIBER Enfermedades Respiratorias (CIBERES); NL is funded by a contract from Department of Economy, Regional Govern from Navarra, Spain, reference 0011-1307-2015-000037. This work has been funded by grants from MINECO SAF2012-31166 and SAF2015-66520-R, Health Department, Regional Govern from Navarra, Spain, reference 03/2016, and SEPAR 31/2015 to JG. CIBERES is an initiative from Instituto de Salud Carlos III (ISCIII), Madrid, Spain. The authors acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).en
dc.format.extent19 p.
dc.format.mimetypeapplication/pdfen
dc.format.mimetypeapplication/zipen
dc.identifier.doi10.3389/fcimb.2017.00266
dc.identifier.issn2235-2988 (Electronic)
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/30431
dc.language.isoengen
dc.publisherFrontiers Mediaen
dc.relation.ispartofFrontiers in Cellular and Infection Microbiology, 7: 266en
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//SAF2012-31166/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//SAF2015-66520-R/ES/
dc.relation.publisherversionhttps://doi.org/10.3389/fcimb.2017.00266
dc.rights© 2017 Rodríguez-Arce, Martí, Euba, Fernández-Calvet, Moleres, López-López, Barberán, Ramos-Vivas, Tubau, Losa, Ardanuy, Leiva, Yuste and Garmendia. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.en
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectHaemophilus influenzaeen
dc.subjectThymidylate synthaseen
dc.subjectThymidine auxotrophyen
dc.subjectThymidine uptakeen
dc.subjectBacterial morphologyen
dc.subjectAntibiotic resistanceen
dc.subjectAirway infectionen
dc.titleInactivation of the Thymidylate synthase thyA in non-typeable Haemophilus influenzae modulates antibiotic resistance and has a strong impact on its interplay with the host airwaysen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
relation.isAuthorOfPublication94ad1041-7e91-4171-9452-f4e270bd5dee
relation.isAuthorOfPublicationeab5adde-437b-46f6-9496-2fa2b16b308f
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relation.isAuthorOfPublication9fc7a317-1022-4fd5-b6ae-5a3065d960c1
relation.isAuthorOfPublication.latestForDiscovery94ad1041-7e91-4171-9452-f4e270bd5dee

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