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

Antibacterial 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 opportunisti...

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Authors: Rodríguez-Arce, Irene, Martí, Sara, Euba, Begoña, Fernández-Calvet, Ariadna, Moleres, Javier, López-López, Nahikari, Barberán, Montserrat, Ramos-Vivas, José, Tubau, Fe, Losa, Carmen, Ardanuy, Carmen, Leiva, José, Yuste, José, Garmendia, Juncal
Format: article
Status:Published version
Publication Date:2017
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/167510
Online Access:http://hdl.handle.net/10261/167510
Access Level:Open access
Keyword:Haemophilus influenzae
Thymidylate synthase
Thymidine auxotrophy
Thymidine uptake
Bacterial morphology
Antibiotic resistance
Airway infection
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repository_id_str
dc.title.none.fl_str_mv 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
title 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
spellingShingle 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
Rodríguez-Arce, Irene
Haemophilus influenzae
Thymidylate synthase
Thymidine auxotrophy
Thymidine uptake
Bacterial morphology
Antibiotic resistance
Airway infection
title_short 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_sort 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
dc.creator.none.fl_str_mv Rodríguez-Arce, Irene
Martí, Sara
Euba, Begoña
Fernández-Calvet, Ariadna
Moleres, Javier
López-López, Nahikari
Barberán, Montserrat
Ramos-Vivas, José
Tubau, Fe
Losa, Carmen
Ardanuy, Carmen
Leiva, José
Yuste, José
Garmendia, Juncal
author Rodríguez-Arce, Irene
author_facet Rodríguez-Arce, Irene
Martí, Sara
Euba, Begoña
Fernández-Calvet, Ariadna
Moleres, Javier
López-López, Nahikari
Barberán, Montserrat
Ramos-Vivas, José
Tubau, Fe
Losa, Carmen
Ardanuy, Carmen
Leiva, José
Yuste, José
Garmendia, Juncal
author_role author
author2 Martí, Sara
Euba, Begoña
Fernández-Calvet, Ariadna
Moleres, Javier
López-López, Nahikari
Barberán, Montserrat
Ramos-Vivas, José
Tubau, Fe
Losa, Carmen
Ardanuy, Carmen
Leiva, José
Yuste, José
Garmendia, Juncal
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad Pública de Navarra
Ministerio de Economía y Competitividad (España)
Centro de Investigación Biomédica en Red Enfermedades Respiratorias (España)
Nafarroako Gobernua
CSIC - Unidad de Recursos de Información Científica para la Investigación (URICI)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Haemophilus influenzae
Thymidylate synthase
Thymidine auxotrophy
Thymidine uptake
Bacterial morphology
Antibiotic resistance
Airway infection
topic Haemophilus influenzae
Thymidylate synthase
Thymidine auxotrophy
Thymidine uptake
Bacterial morphology
Antibiotic resistance
Airway infection
description Antibacterial 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.
publishDate 2017
dc.date.none.fl_str_mv 2017
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/167510
url http://hdl.handle.net/10261/167510
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-66520-R
http://dx.doi.org/10.3389/fcimb.2017.00266
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
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spelling 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 AirwaysRodríguez-Arce, IreneMartí, SaraEuba, BegoñaFernández-Calvet, AriadnaMoleres, JavierLópez-López, NahikariBarberán, MontserratRamos-Vivas, JoséTubau, FeLosa, CarmenArdanuy, CarmenLeiva, JoséYuste, JoséGarmendia, JuncalHaemophilus influenzaeThymidylate synthaseThymidine auxotrophyThymidine uptakeBacterial morphologyAntibiotic resistanceAirway infectionAntibacterial 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.IR 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. We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).Peer reviewedFrontiers MediaUniversidad Pública de NavarraMinisterio de Economía y Competitividad (España)Centro de Investigación Biomédica en Red Enfermedades Respiratorias (España)Nafarroako GobernuaCSIC - Unidad de Recursos de Información Científica para la Investigación (URICI)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201820182017info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/167510reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-66520-Rhttp://dx.doi.org/10.3389/fcimb.2017.00266Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1675102026-05-22T06:33:51Z
score 15,812429

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