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Published, Version of Record (VoR)CC BY V4.0, Open
Journal article
Antagonistic Pleiotropy in the Bifunctional Surface Protein FadL (OmpP1) during Adaptation of Haemophilus influenzae to Chronic Lung Infection Associated with Chronic Obstructive Pulmonary Disease
mBio, v 9(5)
25 Sep 2018
PMID: 30254117
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Tracking bacterial evolution during chronic infection provides insights into how host selection pressures shape bacterial genomes. The human-restricted opportunistic pathogen nontypeable
(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
(also called
), 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
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
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.
Nontypeable
is an important pathogen in patients with chronic obstructive pulmonary disease (COPD). To elucidate the bacterial pathways undergoing
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
(
) 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 Δ
strains' niche. These results show how
adapts to host-generated inflammatory mediators in the COPD airways.
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Details
- 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
- Creators
- Javier Moleres - Universidad Publica de NavarraAriadna Fernández-Calvet - Universidad Publica de NavarraRachel L Ehrlich - Drexel UniversitySara Martí - Bellvitge University HospitalLucía Pérez-Regidor - Centro de Investigaciones BiológicasBegoña Euba - Universidad Publica de NavarraIrene Rodríguez-Arce - Universidad Publica de NavarraSergey Balashov - Drexel UniversityEster Cuevas - Bellvitge University HospitalJosefina Liñares - Bellvitge University HospitalCarmen Ardanuy - Bellvitge University HospitalSonsoles Martín-Santamaría - Centro de Investigaciones BiológicasGarth D Ehrlich - Drexel UniversityJoshua Chang Mell - Drexel UniversityJunkal Garmendia - Universidad Publica de Navarra
- Publication Details
- mBio, v 9(5)
- Publisher
- American Society for Microbiology (ASM)
- Grant note
- U01 DK082316 / NIDDK NIH HHS R01 DC002148 / NIDCD NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000449472200046
- Scopus ID
- 2-s2.0-85054092392
- Other Identifier
- 991019167717904721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Microbiology