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Dissertation_S Malhotra_FINAL-2.pdf (3.62 MB)
ETD Abstract Container
Abstract Header
Immune evasion tactics and immunopathology of mixed mucoid and nonmucoid
Pseudomonas aeruginosa
populations in cystic fibrosis
Author Info
Malhotra, Sankalp
ORCID® Identifier
http://orcid.org/0000-0002-9263-0661
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=osu1524156292309518
Abstract Details
Year and Degree
2018, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Abstract
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 (H
2
O
2
). 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 (H
2
O
2
) 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.
Committee
Daniel J. Wozniak, PhD (Advisor)
Kevin M. Mason, PhD (Committee Chair)
Amal O. Amer, MD/PhD (Committee Member)
Santiago Partida-Sanchez, PhD (Committee Member)
Pages
243 p.
Subject Headings
Biomedical Research
Keywords
Pseudomonas aeruginosa
;
cystic fibrosis
;
reactive oxygen species
;
antimicrobial peptides
;
H2O2
;
LL-37
Recommended Citations
Refworks
EndNote
RIS
Mendeley
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)
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Document number:
osu1524156292309518
Download Count:
492
Copyright Info
© 2018, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.