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Journal article
Phase Variation in HMW1A Controls a Phenotypic Switch in Haemophilus influenzae Associated with Pathoadaptation during Persistent Infection
mBio, pp e0078921-e0078921
22 Jun 2021
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Human-adapted bacterial pathogens have evolved specific mechanisms to colonize their host niche. Phase variation is a contingency strategy to allow adaptation to changing conditions, as phase-variable bacterial loci rapidly and reversibly switch their expression.
ABSTRACT Genetic variants arising from within-patient evolution shed light on bacterial adaptation during chronic infection. Contingency loci generate high levels of genetic variation in bacterial genomes, enabling adaptation to the stringent selective pressures exerted by the host. A significant gap in our understanding of phase-variable contingency loci is the extent of their contribution to natural infections. The human-adapted pathogen nontypeable Haemophilus influenzae (NTHi) causes persistent infections, which contribute to underlying disease progression. The phase-variable high-molecular-weight (HMW) adhesins located on the NTHi surface mediate adherence to respiratory epithelial cells and, depending on the allelic variant, can also confer high epithelial invasiveness or hyperinvasion. In this study, we characterize the dynamics of HMW-mediated hyperinvasion in living cells and identify a specific HMW binding domain shared by hyperinvasive NTHi isolates of distinct pathological origins. Moreover, we observed that HMW expression decreased over time by using a longitudinal set of persistent NTHi strains collected from chronic obstructive pulmonary disease (COPD) patients, resulting from increased numbers of simple-sequence repeats (SSRs) downstream of the functional P2 hmw1A promoter, which is the one primarily driving HMW expression. Notably, the increased SSR numbers at the hmw1 promoter region also control a phenotypic switch toward lower bacterial intracellular invasion and higher biofilm formation, likely conferring adaptive advantages during chronic airway infection by NTHi. Overall, we reveal novel molecular mechanisms of NTHi pathoadaptation based on within-patient lifestyle switching controlled by phase variation. IMPORTANCE Human-adapted bacterial pathogens have evolved specific mechanisms to colonize their host niche. Phase variation is a contingency strategy to allow adaptation to changing conditions, as phase-variable bacterial loci rapidly and reversibly switch their expression. Several NTHi adhesins are phase variable. These adhesins are required for colonization but also immunogenic, in such a way that bacteria with lower adhesin levels are better equipped to survive an immune response, making their contribution to natural infections unclear. We show here that the major NTHi adhesin HMW1A displays allelic variation, which can drive a phase-variable epithelial hyperinvasion phenotype. Over time, hmw1A phase variation lowers adhesin expression, which controls an NTHi lifestyle switch from high epithelial invasiveness to lower invasion and higher biofilm formation. This reversible loss of function aligns with the previously stated notion that epithelial infection is essential for NTHi infection establishment, but once established, persistence favors gene inactivation, in this case facilitating biofilm growth.
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- Title
- Phase Variation in HMW1A Controls a Phenotypic Switch in Haemophilus influenzae Associated with Pathoadaptation during Persistent Infection
- Creators
- Ariadna Fernández-Calvet - Instituto de Agrobiotecnología, Consejo Superior de Investigaciones Científicas (IdAB-CSIC)-Gobierno de Navarra, Mutilva, SpainBegoña Euba - Instituto de Agrobiotecnología, Consejo Superior de Investigaciones Científicas (IdAB-CSIC)-Gobierno de Navarra, Mutilva, SpainCelia Gil-Campillo - Instituto de Agrobiotecnología, Consejo Superior de Investigaciones Científicas (IdAB-CSIC)-Gobierno de Navarra, Mutilva, SpainArancha Catalan-Moreno - Instituto de Agrobiotecnología, Consejo Superior de Investigaciones Científicas (IdAB-CSIC)-Gobierno de Navarra, Mutilva, SpainJavier Moleres - Instituto de Agrobiotecnología, Consejo Superior de Investigaciones Científicas (IdAB-CSIC)-Gobierno de Navarra, Mutilva, SpainSara Martí - Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain, Microbiology Department, Hospital Universitari Bellvitge, University of Barcelona, IDIBELL, Barcelona, SpainAlexandra Merlos - Department of Pathology and Experimental Therapeutics, IDIBELL-University of Barcelona, L’Hospitalet de Llobregat, Barcelona, SpainJeroen D Langereis - Section Pediatric Infectious Diseases, Laboratory of Medical Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands, Section Pediatric Infectious Diseases, Laboratory of Medical Immunology, Radboud Center for Infectious Diseases, Radboudumc, Nijmegen, The NetherlandsFrancisco García-del Portillo - Laboratorio de Patógenos Bacterianos Intracelulares, Centro Nacional de Biotecnología (CNB)-CSIC, Madrid, SpainLauren O Bakaletz - Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, USA, Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, USAGarth D Ehrlich - Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA, Center for Genomic Sciences, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA, Center for Advanced Microbial Processing, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA, Center for Surgical Infections and Biofilms, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA, Department of Otolaryngology, Head and Neck Surgery, Drexel University College of Medicine, Philadelphia, Pennsylvania, USAEric A Porsch - Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USAMargarita Menéndez - Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain, Instituto de Química Física Rocasolano (IQFR-CSIC), Madrid, SpainJoshua C Mell - Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA, Center for Genomic Sciences, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA, Center for Advanced Microbial Processing, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA, Center for Surgical Infections and Biofilms, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania, USAAlejandro Toledo-Arana - Instituto de Agrobiotecnología, Consejo Superior de Investigaciones Científicas (IdAB-CSIC)-Gobierno de Navarra, Mutilva, SpainJunkal Garmendia - Instituto de Agrobiotecnología, Consejo Superior de Investigaciones Científicas (IdAB-CSIC)-Gobierno de Navarra, Mutilva, Spain, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
- Contributors
- Melinda M Pettigrew (Editor)
- Publication Details
- mBio, pp e0078921-e0078921
- Publisher
- American Society for Microbiology (ASM)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000693447800012
- Scopus ID
- 2-s2.0-85112119912
- Other Identifier
- 991015238289304721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Microbiology