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Proc Natl Acad Sci U S A. 2018 Apr 3;115(14):E3256-E3265. doi: 10.1073/pnas.1719654115. Epub 2018 Mar 19.

Haemophilus influenzae genome evolution during persistence in the human airways in chronic obstructive pulmonary disease.

Author information

1
Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT 06510.
2
Department of Microbiology and Immunology, University at Buffalo, The State University of New York, Buffalo, NY 14203.
3
Clinical and Translational Research Center, University at Buffalo, The State University of New York, Buffalo, NY 14203.
4
Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT 06510.
5
Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510.
6
Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT 06510.
7
W.M. Keck Foundation Biotechnology Resource Laboratory, Yale School of Medicine, New Haven, CT 06510.
8
Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201.
9
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201.
10
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University at Buffalo, The State University of New York, Buffalo, NY 14203.
11
Department of Medicine, Veterans Affairs Western New York Healthcare System, Buffalo, NY 14215.
12
Department of Microbiology and Immunology, University at Buffalo, The State University of New York, Buffalo, NY 14203; murphyt@buffalo.edu.
13
Division of Infectious Diseases, Department of Medicine, University at Buffalo, The State University of New York, Buffalo, NY 14203.

Abstract

Nontypeable Haemophilus influenzae (NTHi) exclusively colonize and infect humans and are critical to the pathogenesis of chronic obstructive pulmonary disease (COPD). In vitro and animal models do not accurately capture the complex environments encountered by NTHi during human infection. We conducted whole-genome sequencing of 269 longitudinally collected cleared and persistent NTHi from a 15-y prospective study of adults with COPD. Genome sequences were used to elucidate the phylogeny of NTHi isolates, identify genomic changes that occur with persistence in the human airways, and evaluate the effect of selective pressure on 12 candidate vaccine antigens. Strains persisted in individuals with COPD for as long as 1,422 d. Slipped-strand mispairing, mediated by changes in simple sequence repeats in multiple genes during persistence, regulates expression of critical virulence functions, including adherence, nutrient uptake, and modification of surface molecules, and is a major mechanism for survival in the hostile environment of the human airways. A subset of strains underwent a large 400-kb inversion during persistence. NTHi does not undergo significant gene gain or loss during persistence, in contrast to other persistent respiratory tract pathogens. Amino acid sequence changes occurred in 8 of 12 candidate vaccine antigens during persistence, an observation with important implications for vaccine development. These results indicate that NTHi alters its genome during persistence by regulation of critical virulence functions primarily by slipped-strand mispairing, advancing our understanding of how a bacterial pathogen that plays a critical role in COPD adapts to survival in the human respiratory tract.

KEYWORDS:

Haemophilus influenzae; candidate vaccine antigens; chronic obstructive pulmonary disease; genome evolution; whole-genome sequencing

PMID:
29555745
PMCID:
PMC5889651
DOI:
10.1073/pnas.1719654115
[Indexed for MEDLINE]
Free PMC Article

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