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Title: Antagonistic pleiotropy in the bifunctional surface protein FadL (OmpP1) during adaptation of Haemophilus influenzae to chronic lung infection associated with Chronic Obstructive Pulmonary Disease
Author: Moleres, Javier
Fernández Calvet, Ariadna
Ehrlich, Rachel L.
Martí Martí, Sara
Pérez Regidor, Lucía
Euba, Begoña
Rodríguez Arce, Irene
Balashov, Sergey
Cuevas, Ester
Liñares Louzao, Josefina
Ardanuy Tisaire, María Carmen
Martín Santamaría, Sonsoles
Ehrlich, Gareth D.
Mell, Joshua Chang
Garmendia, Junkal
Keywords: Malalties pulmonars obstructives cròniques
Bacteris gramnegatius
Chronic obstructive pulmonary diseases
Gram-negative bacteria
Issue Date: 25-Sep-2018
Publisher: American Society for Microbiology
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 9years. 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 DeltafadL strains' niche. These results show how H. influenzae adapts to host-generated inflammatory mediators in the COPD airways.
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It is part of: mBio, 2018, vol. 9, num. 5, p. e01176-18
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ISSN: 2150-7511
Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Medicina)

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