Identification of conserved Klebsiella pneumoniae virulence factors

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  • March 20, 2019
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  • Palacios, Michelle
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Klebsiella pneumoniae is an urgent threat to public health due to nosocomial outbreaks of multi-drug resistant strains and the emergence of hypervirulent community acquired infections. Only in recent years have we gained a better understanding of the population structure of emergent clones and insight on the high level of strain-to-strain genomic variation K. pneumoniae strains display. While capsule and siderophores are considered primary virulence factors of K. pneumoniae, the number of siderophore types encoded and the capsule type can vary significantly from strain-to-strain. Thus, identifying highly conserved virulence mechanisms is essential for therapeutic development. This work focused on the use of a murine pneumonia model of infection and a sputum-derived isolate of K. pneumoniae to identify previously uncharacterized virulence factors. In Chapter 2, we describe how a serendipitous mutation led us to identify the periplasmic importer of enterobactin, FepB, as being a unique contributor to virulence. Interestingly, the contribution of FepB to virulence was greater than the contribution of enterobactin to virulence suggesting a greater role than enterobactin transport. Given that FepB is present in other pathogenic Enterobacteriaceae, our findings may be applicable to other pathogens. In an attempt to expand our knowledge of the repertoire of K. pneumoniae virulence factors, we also conducted an in vivo screen of the contribution of MarR-like transcriptional regulators to virulence in Chapter 3. We identified two previously unidentified regulators of virulence in K. pneumoniae, and have named these KvrA and KvrB. KvrA and KvrB are highly conserved across K. pneumoniae species. Both regulators regulated capsule expression and production, and this regulation appeared to be conserved in an isolate of a different capsule type. Interestingly, while KvrA and KvrB regulate capsule in a similar fashion, the in vivo kinetics of infection of the kvrA and kvrB mutants were quite distinct suggesting that the regulons of KvrA and KvrB are unique from each other. Because our studies focused on highly conserved virulence factors, our work has implications for the development of novel anti-Klebsiella therapeutics.
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  • In Copyright
Advisor
  • Arthur, Janelle
  • Maile, Robert
  • Kawula, Thomas
  • Cotter, Peggy
  • Miller, Virginia
  • Cairns, Bruce
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2017
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