Antagonistic Pleiotropy in the Bifunctional Surface Protein FadL (OmpP1) during Adaptation of <named-content content-type="genus-species">Haemophilus influenzae</named-content> to Chronic Lung Infection Associated with Chronic Obstructive Pulmonary Disease

ABSTRACT Tracking 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 pulmon...

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Autores principales:	Javier Moleres, Ariadna Fernández-Calvet, Rachel L. Ehrlich, Sara Martí, Lucía Pérez-Regidor, Begoña Euba, Irene Rodríguez-Arce, Sergey Balashov, Ester Cuevas, Josefina Liñares, Carmen Ardanuy, Sonsoles Martín-Santamaría, Garth D. Ehrlich, Joshua Chang Mell, Junkal Garmendia
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	CEACAM1 FadL/OmpP1 Haemophilus influenzae adaptive evolution antagonistic pleiotropic chronic obstructive pulmonary disease Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/cb2d1564d60c4e4f982642d3ba3cf375
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spelling	oai:doaj.org-article:cb2d1564d60c4e4f982642d3ba3cf3752021-11-15T15:58:20ZAntagonistic Pleiotropy in the Bifunctional Surface Protein FadL (OmpP1) during Adaptation of <named-content content-type="genus-species">Haemophilus influenzae</named-content> to Chronic Lung Infection Associated with Chronic Obstructive Pulmonary Disease10.1128/mBio.01176-182150-7511https://doaj.org/article/cb2d1564d60c4e4f982642d3ba3cf3752018-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01176-18https://doaj.org/toc/2150-7511ABSTRACT Tracking 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.Javier MoleresAriadna Fernández-CalvetRachel L. EhrlichSara MartíLucía Pérez-RegidorBegoña EubaIrene Rodríguez-ArceSergey BalashovEster CuevasJosefina LiñaresCarmen ArdanuySonsoles Martín-SantamaríaGarth D. EhrlichJoshua Chang MellJunkal GarmendiaAmerican Society for MicrobiologyarticleCEACAM1FadL/OmpP1Haemophilus influenzaeadaptive evolutionantagonistic pleiotropicchronic obstructive pulmonary diseaseMicrobiologyQR1-502ENmBio, Vol 9, Iss 5 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	CEACAM1 FadL/OmpP1 Haemophilus influenzae adaptive evolution antagonistic pleiotropic chronic obstructive pulmonary disease Microbiology QR1-502
spellingShingle	CEACAM1 FadL/OmpP1 Haemophilus influenzae adaptive evolution antagonistic pleiotropic chronic obstructive pulmonary disease Microbiology QR1-502 Javier Moleres Ariadna Fernández-Calvet Rachel L. Ehrlich Sara Martí Lucía Pérez-Regidor Begoña Euba Irene Rodríguez-Arce Sergey Balashov Ester Cuevas Josefina Liñares Carmen Ardanuy Sonsoles Martín-Santamaría Garth D. Ehrlich Joshua Chang Mell Junkal Garmendia Antagonistic Pleiotropy in the Bifunctional Surface Protein FadL (OmpP1) during Adaptation of <named-content content-type="genus-species">Haemophilus influenzae</named-content> to Chronic Lung Infection Associated with Chronic Obstructive Pulmonary Disease
description	ABSTRACT Tracking 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.
format	article
author	Javier Moleres Ariadna Fernández-Calvet Rachel L. Ehrlich Sara Martí Lucía Pérez-Regidor Begoña Euba Irene Rodríguez-Arce Sergey Balashov Ester Cuevas Josefina Liñares Carmen Ardanuy Sonsoles Martín-Santamaría Garth D. Ehrlich Joshua Chang Mell Junkal Garmendia
author_facet	Javier Moleres Ariadna Fernández-Calvet Rachel L. Ehrlich Sara Martí Lucía Pérez-Regidor Begoña Euba Irene Rodríguez-Arce Sergey Balashov Ester Cuevas Josefina Liñares Carmen Ardanuy Sonsoles Martín-Santamaría Garth D. Ehrlich Joshua Chang Mell Junkal Garmendia
author_sort	Javier Moleres
title	Antagonistic Pleiotropy in the Bifunctional Surface Protein FadL (OmpP1) during Adaptation of <named-content content-type="genus-species">Haemophilus influenzae</named-content> to Chronic Lung Infection Associated with Chronic Obstructive Pulmonary Disease
title_short	Antagonistic Pleiotropy in the Bifunctional Surface Protein FadL (OmpP1) during Adaptation of <named-content content-type="genus-species">Haemophilus influenzae</named-content> to Chronic Lung Infection Associated with Chronic Obstructive Pulmonary Disease
title_full	Antagonistic Pleiotropy in the Bifunctional Surface Protein FadL (OmpP1) during Adaptation of <named-content content-type="genus-species">Haemophilus influenzae</named-content> to Chronic Lung Infection Associated with Chronic Obstructive Pulmonary Disease
title_fullStr	Antagonistic Pleiotropy in the Bifunctional Surface Protein FadL (OmpP1) during Adaptation of <named-content content-type="genus-species">Haemophilus influenzae</named-content> to Chronic Lung Infection Associated with Chronic Obstructive Pulmonary Disease
title_full_unstemmed	Antagonistic Pleiotropy in the Bifunctional Surface Protein FadL (OmpP1) during Adaptation of <named-content content-type="genus-species">Haemophilus influenzae</named-content> to Chronic Lung Infection Associated with Chronic Obstructive Pulmonary Disease
title_sort	antagonistic pleiotropy in the bifunctional surface protein fadl (ompp1) during adaptation of <named-content content-type="genus-species">haemophilus influenzae</named-content> to chronic lung infection associated with chronic obstructive pulmonary disease
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/cb2d1564d60c4e4f982642d3ba3cf375
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Antagonistic Pleiotropy in the Bifunctional Surface Protein FadL (OmpP1) during Adaptation of <named-content content-type="genus-species">Haemophilus influenzae</named-content> to Chronic Lung Infection Associated with Chronic Obstructive Pulmonary Disease

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