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Antagonistic pleiotropy in the bifunctional surface protein fadl (OmpP1) during adaptation of Haemophilus influenzae to chronic lung infection associated with chronic obstructive pulmonary disease

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dc.contributor.authorMoleres Apilluelo, Javier
dc.contributor.authorFernández Calvet, Ariadna
dc.contributor.authorEhrlich, Rachel L.
dc.contributor.authorMartí, Sara
dc.contributor.authorPérez Regidor, Lucía
dc.contributor.authorEuba, Begoña
dc.contributor.authorRodríguez Arce, Irene
dc.contributor.authorBalashov, Sergey
dc.contributor.authorCuevas, Ester
dc.contributor.authorLiñares, Josefina
dc.contributor.authorArdanuy, Carmen
dc.contributor.authorMartín Santamaría, Sonsoles
dc.contributor.authorEhrlich, Garth D.
dc.contributor.authorMell, Joshua Chang
dc.contributor.authorGarmendia García, Juncal
dc.contributor.departmentIdAB. Instituto de Agrobiotecnología / Agrobioteknologiako Institutuaes_ES
dc.contributor.funderGobierno de Navarra / Nafarroako Gobernuaes
dc.contributor.funderUniversidad Pública de Navarra / Nafarroako Unibertsitate Publikoaes
dc.date.accessioned2019-07-17T12:13:10Z
dc.date.available2019-07-17T12:13:10Z
dc.date.issued2018
dc.description.abstractTracking bacterial evolution during chronic infection provides insights into how host selection pressures shape bacterial genomes. The human-restricted opportunistic pathogen nontypeable Haemophilus influenzae (NTHi) infects the lower airways of patients suffering chronic obstructive pulmonary disease (COPD) and contributes to disease progression. To identify bacterial genetic variation associated with bacterial adaptation to the COPD lung, we sequenced the genomes of 92 isolates collected from the sputum of 13 COPD patients over 1 to 9 years. Individuals were colonized by distinct clonal types (CTs) over time, but the same CT was often reisolated at a later time or found in different patients. Although genomes from the same CT were nearly identical, intra-CT variation due to mutation and recombination occurred. Recurrent mutations in several genes were likely involved in COPD lung adaptation. Notably, nearly a third of CTs were polymorphic for null alleles of ompP1 (also called fadL), which encodes a bifunctional membrane protein that both binds the human carcinoembryonic antigen-related cell adhesion molecule 1 (hCEACAM1) receptor and imports long-chain fatty acids (LCFAs). Our computational studies provide plausible three-dimensional models for FadL’s interaction with hCEACAM1 and LCFA binding. We show that recurrent fadL mutations are likely a case of antagonistic pleiotropy, since loss of FadL reduces NTHi’s ability to infect epithelia but also increases its resistance to bactericidal LCFAs enriched within the COPD lung. Supporting this interpretation, truncated fadL alleles are common in publicly available NTHi genomes isolated from the lower airway tract but rare in others. These results shed light on molecular mechanisms of bacterial pathoadaptation and guide future research toward developing novel COPD therapeutics. IMPORTANCE Nontypeable Haemophilus influenzae is an important pathogen in patients with chronic obstructive pulmonary disease (COPD). To elucidate the bacterial pathways undergoing in vivo evolutionary adaptation, we compared bacterial genomes collected over time from 13 COPD patients and identified recurrent genetic changes arising in independent bacterial lineages colonizing different patients. Besides finding changes in phase-variable genes, we found recurrent loss-of-function mutations in the ompP1 (fadL) gene. We show that loss of OmpP1/FadL function reduces this bacterium’s ability to infect cells via the hCEACAM1 epithelial receptor but also increases its resistance to bactericidal fatty acids enriched within the COPD lung, suggesting a case of antagonistic pleiotropy that restricts ΔfadL strains’ niche. These results show how H. influenzae adapts to host-generated inflammatory mediators in the COPD airways.en
dc.description.sponsorshipThis work has been funded by MINECO grants SAF2012-31166 and SAF2015-66520-R to J.G. and grants CTQ2014-57141-R and CTQ2017-88353-R to S.M.-S.; grant 03/2016 from the Health Department, Regional Government of Navarra, Spain, and SEPAR grant 31/2015 to J.G.; and NIDCD grant 5R01 DC 02148 and NIDDK grant 1U01 DK082316 from the U.S. National Institutes of Health to G.D.E. CIBERES is an initiative from the Instituto de Salud Carlos III (ISCIII), Madrid, Spain. J.M. and L.P.-R. were funded by Ph.D. studentships BES-2013-062644 and BES-2012-053653 from MINECO, Spain. A.F.-C. was funded by a contract from MINECO, reference number 20132RC947. I.R.-A. was funded by a Ph.D. studentship from the Universidad Pública de Navarra, Spain. S.M. is funded by a postdoctoral contract from CIBERES.en
dc.format.extent23 p.
dc.format.mimetypeapplication/pdfen
dc.format.mimetypeapplication/zipen
dc.identifier.doi10.1128/mBio.01176-18
dc.identifier.issn2161-2129
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/33610
dc.language.isoengen
dc.publisherAmerican Society for Microbiologyen
dc.relation.ispartofMbio, Sep 2018, 9 (5) e01176-18en
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//SAF2012-31166/ES/en
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//SAF2015-66520-R/ES/en
dc.relation.publisherversionhttps://doi.org/10.1128/mBio.01176-18
dc.rights© 2018 Moleres et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.en
dc.rights.accessRightsinfo:eu-repo/semantics/openAccessen
dc.rights.accessRightsAcceso abierto / Sarbide irekiaes
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAdaptive evolutionen
dc.subjectAntagonistic pleiotropicen
dc.subjectCEACAM1en
dc.subjectChronic obstructive pulmonary diseaseen
dc.subjectComparative genomicsen
dc.subjectConvergent evolutionen
dc.subjectFaDl/OmpP1en
dc.subjectFree fatty acidsen
dc.subjectHaemophilus influenzaeen
dc.subjectIn situ evolutionen
dc.titleAntagonistic pleiotropy in the bifunctional surface protein fadl (OmpP1) during adaptation of Haemophilus influenzae to chronic lung infection associated with chronic obstructive pulmonary diseaseen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersionen
dc.type.versionVersión publicada / Argitaratu den bertsioaes
dspace.entity.typePublication
relation.isAuthorOfPublication0e8e1c09-428a-47b7-819c-7c372f0c7242
relation.isAuthorOfPublicationeab5adde-437b-46f6-9496-2fa2b16b308f
relation.isAuthorOfPublication94ad1041-7e91-4171-9452-f4e270bd5dee
relation.isAuthorOfPublication.latestForDiscovery0e8e1c09-428a-47b7-819c-7c372f0c7242

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