Haemophilus influenzae genome evolution during persistence in the human airways in chronic obstructive pulmonary disease
JournalProceedings of the National Academy of Sciences of the United States of America
PublisherNational Academy of Sciences
MetadataShow full item record
AbstractNontypeable 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. Copyright 2018 National Academy of Sciences. All Rights Reserved.
SponsorsThis work was supported by National Institute of Allergy and Infectious Diseases of the National Institutes of Health Grant R01AI019641 (to T.F.M. and M.M.P.), the Department of Veterans Affairs (S.S. and T.F.M.), and National Center for Advancing Translational Sciences Award UL1TR001412 to the University at Buffalo.
KeywordCandidate vaccine antigens
Chronic obstructive pulmonary disease
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85044869488&doi=10.1073%2fpnas.1719654115&partnerID=40&md5=b1f3c945fc3ba95a1349a25a59e55923; http://hdl.handle.net/10713/9479
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