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Immune resistance mechanisms of the Bordetella pertussis polysaccharide Bps

Fullen, Audra R
http://orcid.org/0000-0002-8444-6039
http://rave.ohiolink.edu/etdc/view?acc_num=osu1669917282636996

Abstract Details

2022, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Infections and disease caused by the obligate human pathogen Bordetella pertussis (Bp) are resurging worldwide, despite widespread vaccinations. The current acellular pertussis vaccines remain ineffective against nasopharyngeal colonization, carriage, and transmission. To develop more effective vaccines, it is important to understand how Bp resists killing actions of host immunity. In the current work, we tested the hypothesis that Bordetella polysaccharide (Bps), a member of the poly-􀈕-1,6-N-acetyl-D-glucosamine (PNAG) family, promotes respiratory tract colonization of Bp by resisting killing from two major innate immune factors: (1) antimicrobial peptides (AMPs) and (2) neutrophils. First, we show that Bps enhanced Bp survival in the presence of AMPs by functioning both as a surface shield and a decoy. While surface-bound Bps inhibited AMP binding to the bacterial surface, soluble Bps neutralized AMP activity by direct binding interactions. Simultaneous infection of mice with Bps-proficient and Bps-deficient strains resulted in greater survival of the Bps-deficient strain in the mouse respiratory tract. Furthermore, production of Bps in a nonpathogenic E. coli strain increased AMP resistance in vitro, and increased bacterial survival and augmented pathology in the mouse respiratory tract. Second, we show that Bps enhanced survival in the presence of hydrogen peroxide and hypochlorous acid in vitro. Consistent with these data, Bps enhanced resistance to killing by human neutrophils and suppressed oxidative burst and neutrophil extracellular trap (NET) formation. Together, the results obtained from studies involving AMPs and neutrophils serve as a foundation for studying other PNAG polysaccharides, as well as for the development of an effective Bp vaccine that includes Bps. Traditionally, pertussis is described as an acute disease with coughing fits and other severe symptoms. However, in recent years, many individuals who contract pertussis are either asymptomatic or show very mild symptoms. We hypothesize that biofilms, a community mode of existence, prolong the human carriage of Bp, thereby contributing to continued bacterial survival and transmission. While factors that drive biofilm formation on abiotic surfaces have been wellcharacterized,biofilm architecture and matrix composition in humans are ill-defined. Therefore, we utilized a well-differentiated primary human airway epithelial culture system grown at airliquid interface. We show that these airway cells promoted robust growth of cilia-adherent, structured Bp biofilms. Bacterial cells that attached to cilia were encased in an extracellular matrix (ECM) consisting of the polysaccharide Bps and extracellular DNA (eDNA). Distinct complexes (mono-, bi-, and tripartite) between the ECM and bacterial cells were visualized. Mutant strains that fail to produce the polysaccharide Bps or the protein filamentous hemagglutinin (FHA) were defective in attaching to cilia and in biofilm formation compared to the WT strain. Contrary to previous reports of abiotic biofilms, adenylate cyclase toxin (ACT) was required for mature Bp biofilm formation on human airway epithelial cells. This highlights the importance of utilizing systems resembling the natural infection of a microbial pathogen to gain insights regarding their pathogenesis. Altogether, the studies conducted in this thesis provide new insights into how Bp has evolved to survive in the mammalian respiratory tract.
Rajendar Deora, Ph.D. (Advisor)
Paul Stoodley, Ph.D. (Committee Chair)
Daniel Wozniak, Ph.D. (Committee Member)
Santiago Partida-Sanchez, Ph.D. (Committee Member)
John Gunn, Ph.D. (Committee Member)
187 p.
Biomedical Research; Immunology; Microbiology
Bordetella pertussis; innate immune resistance; bacterial exopolysaccharides; antimicrobial peptides; neutrophils; biofilms; human airway epithelial cells

Recommended Citations

Citations

  • Fullen, A. R. (2022). Immune resistance mechanisms of the Bordetella pertussis polysaccharide Bps [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1669917282636996

    APA Style (7th edition)

  • Fullen, Audra. Immune resistance mechanisms of the Bordetella pertussis polysaccharide Bps. 2022. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1669917282636996.

    MLA Style (8th edition)

  • Fullen, Audra. "Immune resistance mechanisms of the Bordetella pertussis polysaccharide Bps." Doctoral dissertation, Ohio State University, 2022. http://rave.ohiolink.edu/etdc/view?acc_num=osu1669917282636996

    Chicago Manual of Style (17th edition)

osu1669917282636996
© 2022, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.
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