title: Phase variation and host immunity against high molecular weight (HMW) adhesins shape population dynamics of nontypeable Haemophilus influenzae within human hosts.
abstract: Nontypeable Haemophilus influenzae (NTHi) is a bacterium that resides within the human pharynx. Because NTHi is human-restricted, its long-term survival is dependent upon its ability to successfully colonize new hosts. Adherence to host epithelium, mediated by bacterial adhesins, is one of the first steps in NTHi colonization. NTHi express several adhesins, including the high molecular weight (HMW) adhesins that mediate attachment to the respiratory epithelium where they interact with the host immune system to elicit a strong humoral response. hmwA, which encodes the HMW adhesin, undergoes phase variation mediated by 7-base pair tandem repeats located within its promoter region. Repeat number affects both hmwA transcription and HMW-adhesin production such that as the number of repeats increases, adhesin production decreases. Cells expressing large amounts of HMW adhesins may be critical for the establishment and maintenance of NTHi colonization, but they might also incur greater fitness costs when faced with an adhesin-specific antibody-mediated immune response. We hypothesized that the occurrence of large deletion events within the hmwA repeat region allows NTHi cells to maintain adherence in the presence of antibody-mediated immunity. To study this, we developed a mathematical model, incorporating hmwA phase variation and antibody-mediated immunity, to explore the trade-off between bacterial adherence and immune evasion. The model predicts that antibody levels and avidity, catastrophic loss rates, and population carrying capacity all significantly affected numbers of adherent NTHi cells within a host. These results suggest that the occurrence of large, yet rare, deletion events allows for stable maintenance of a small population of adherent cells in spite of HMW adhesin specific antibody-mediated immunity. These adherent subpopulations may be important for sustaining colonization and/or maintaining transmission.
authors.affiliation: Department of Epidemiology, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109, USA. Electronic address: gsdavis@gwu.edu.
authors.forename: Gregg S
authors.initials: GS
authors.lastname: Davis
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, 1150 West Medical Center Drive, 5641 Med Sci II SPC 5620, Ann Arbor, MI 48109, USA. Electronic address: simeonem@umich.edu.
authors.forename: Simeone
authors.initials: S
authors.lastname: Marino
authors.affiliation: Department of Epidemiology, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109, USA. Electronic address: cfmarrs@umich.edu.
authors.forename: Carl F
authors.initials: CF
authors.lastname: Marrs
authors.affiliation: Department of Epidemiology, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109, USA; Department of Pediatrics, University of Michigan Medical School, L2225 Women׳s Hospital, Ann Arbor, MI 48109, USA. Electronic address: gilsdorf@med.umich.edu.
authors.forename: Janet R
authors.initials: JR
authors.lastname: Gilsdorf
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, 1150 West Medical Center Drive, 5641 Med Sci II SPC 5620, Ann Arbor, MI 48109, USA; UMHS Pediatric Infectious Diseases, University of Michigan Health System, D5101 MPB, Ann Arbor, MI 48109, USA. Electronic address: sdawid@med.umich.edu.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Dawid
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, 1150 West Medical Center Drive, 5641 Med Sci II SPC 5620, Ann Arbor, MI 48109, USA. Electronic address: kirschne@umich.edu.
authors.forename: Denise E
authors.initials: DE
authors.lastname: Kirschner
mesh_terms: D018829:Adhesins, Bacterial / Q000276:immunology*; D000907:Antibodies, Bacterial / Q000276:immunology; D006192:Haemophilus Infections / Q000276:immunology*; D006193:Haemophilus influenzae / Q000276:immunology*; D006801:Humans; D056724:Immunity, Humoral; D018448:Models, Immunological; D020545:Respiratory Mucosa / Q000276:immunology* / Q000382:microbiology
chemical_list: D018829:Adhesins, Bacterial; D000907:Antibodies, Bacterial
keywords: Acute otitis media (AOM); Bacterial adherence; Bacterial colonization; Bacterial transmission; Chronic obstructive pulmonary disease (COPD)
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