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Immune evasion tactics and immunopathology of mixed mucoid and nonmucoid Pseudomonas aeruginosa populations in cystic fibrosis

Malhotra, Sankalp
http://orcid.org/0000-0002-9263-0661
http://rave.ohiolink.edu/etdc/view?acc_num=osu1524156292309518

Abstract Details

2018, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Pseudomonas aeruginosa is an opportunistic pathogen that causes devastating, chronic pulmonary infections in patients with cystic fibrosis (CF). During persistent infection of the CF lung, P. aeruginosa acquires adaptive mutations that confer resistance to antimicrobials and host responses. Most strikingly, mutation of mucA results in the conversion of initially colonizing nonmucoid strains to the mucoid phenotype, which is defined by overproduction of the exopolysaccharide, alginate. Though mucoidy provides advantages to P. aeruginosa in withstanding environmental pressures within the airway, mucoid strains often revert back to a nonmucoid phenotype in vitro and in vivo . Importantly, mixed populations of both mucoid and nonmucoid variants are often isolated from chronically-infected CF patients, suggesting a selective advantage for the coexistence of these variants within the host. In Chapter 2, we report that within mixed-variant communities, P. aeruginosa exhibits enhanced resistance to innate immune effectors, LL-37 and hydrogen peroxide (H2O2). Immune evasion is mediated by the production and sharing of “public goods” by both P. aeruginosa variants: While mucoid constituents provide protection from LL-37 via alginate production, nonmucoid revertants shield the population from (H2O2) via catalase (KatA). We further demonstrate that katA expression is negatively regulated by AlgT and AlgR, two transcription factors that are essential for alginate biosynthesis. Additionally, we provide evidence that an endolysin encoded by lys, which is implicated in P. aeruginosa autolysis and extracellular DNA release, is also responsible for catalase release from nonmucoid revertants. Given these findings, we wanted to better understand how mixed-variant P. aeruginosa communities interact with the host in vivo. Tissue damage to the CF lung is heterogeneously manifested across the organ, wherein the upper lobes of the lung are typically more damaged than the lower lobes. Existing hypotheses in the field suggested that these patterns of focal pathology in CF could be due to unequal distribution of bacterial and host factors in different areas of the organ. As such, in Chapter 3, we sought to investigate whether mucoid and nonmucoid P. aeruginosa, in single- or mixed-variant populations, spatially localize within certain lobes of the CF lung, and if both morphotypes differentially affect the regional, inflammatory microenvironment. Utilizing the collection of lobe-specific BAL fluid from CF patients, in combination with standard culture-based techniques, we showed that both mucoid and nonmucoid P. aeruginosa are distributed throughout the CF lung. However, mucoid variants are specifically associated with higher regional indices of inflammation (i.e. proinflammatory cytokines) compared to nonmucoid variants. In total, our findings here contribute to a better understanding of intraspecies interactions of P. aeruginosa that enable evasion of the host response during chronic infection. Furthermore, our data support the development of therapeutics that would target both mucoid and nonmucoid P. aeruginosa within diversified communities in vivo, as both variants likely contribute to the progression and pathology of CF lung disease.
Daniel J. Wozniak, PhD (Advisor)
Kevin M. Mason, PhD (Committee Chair)
Amal O. Amer, MD/PhD (Committee Member)
Santiago Partida-Sanchez, PhD (Committee Member)
243 p.
Biomedical Research
Pseudomonas aeruginosa; cystic fibrosis; reactive oxygen species; antimicrobial peptides; H2O2; LL-37

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Citations

  • Malhotra, S. (2018). Immune evasion tactics and immunopathology of mixed mucoid and nonmucoid Pseudomonas aeruginosa populations in cystic fibrosis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1524156292309518

    APA Style (7th edition)

  • Malhotra, Sankalp. Immune evasion tactics and immunopathology of mixed mucoid and nonmucoid Pseudomonas aeruginosa populations in cystic fibrosis. 2018. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1524156292309518.

    MLA Style (8th edition)

  • Malhotra, Sankalp. "Immune evasion tactics and immunopathology of mixed mucoid and nonmucoid Pseudomonas aeruginosa populations in cystic fibrosis." Doctoral dissertation, Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1524156292309518

    Chicago Manual of Style (17th edition)

osu1524156292309518
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This open access ETD is published by The Ohio State University and OhioLINK.