Identification and characterization of novel loci required for ESX-1 protein secretion in Mycobacterium marinum

Doctoral Dissertation
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Abstract

Mycobacterium tuberculosis is the etiological agent of human tuberculosis (TB), a disease responsible for more than one million deaths in 2013. A major mechanism by which this bacterial pathogen mediates infection is through the export of virulence factors from the ESAT-6 System-1 (ESX-1). To better understand mycobacterial pathogenicity, we studied the basic genetic and molecular requirements of ESX-1 secretion and virulence in pathogenic mycobacteria. Using Mycobacterium marinum as a model species, we screened a near-saturating transposon-insertion library for mutant strains exhibiting morphology defects. We report here the identification and characterization of two mutant M. marinum strains that are deficient for ESX-1 function and attenuated in infection models. From these analyses we expanded the genetic requirements for ESX-1 secretion in M. marinum to include MMAR4414 and the MMAR1663-MMAR1668 locus. We also determined that ESX-1-dependent virulence is mediated through the proteins substrates associated with the bacterial surface, contrary to the assumption that true exo-proteins facilitate virulence. Finally, we determined that the protein product of MMAR4414 directly interacts with EccA, an established component of the ESX-1 system. In summary, these studies identified two major genetic loci required for ESX-1 function and provide novel insights into the working model of ESX-1 secretion in pathogenic mycobacteria. The continued study of these, and other yet still undiscovered ESX-1 components, may contribute to the future control and prevention of M. tuberculosis infection.

Attributes

Attribute NameValues
URN
  • etd-04072015-142915

Author George M Kennedy
Advisor Patricia Champion
Contributor Patricia Clark, Committee Member
Contributor Shaun Lee, Committee Member
Contributor Patricia Champion, Committee Chair
Contributor Jeffrey Schorey, Committee Member
Degree Level Doctoral Dissertation
Degree Discipline Biological Sciences
Degree Name PhD
Defense Date
  • 2015-01-13

Submission Date 2015-04-07
Country
  • United States of America

Subject
  • tuberculosis

  • protein secretion

  • ESAT-6 System-1

Publisher
  • University of Notre Dame

Language
  • English

Record Visibility Public
Content License
  • All rights reserved

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