The role of SecA2 protein export in the virulence of Mycobacterium tuberculosis

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  • March 21, 2019
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  • Zulauf, Katelyn
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • In order to promote disease, Mycobacterium tuberculosis exports proteins outside of the bacterial cell into the host environment where the proteins can interfere with host defense mechanisms such as phagosome maturation. The SecA2 pathway is one system M. tuberculosis utilizes to export such proteins. SecA2 is a non-essential specialized SecA ATPase required for exporting a relatively small subset of proteins. The SecA2 pathway, although not essential for growth of M. tuberculosis in vitro, is required for virulence of M. tuberculosis. The requirement for SecA2 during infection suggests that SecA2 and its exported effectors play important roles in M. tuberculosis pathogenesis. Therefore, we set out to both identify M. tuberculosis proteins that are exported by the SecA2 pathway and identify functions of SecA2 in M. tuberculosis virulence. Using quantitative proteomics, we identified solute binding proteins and Mce proteins as two classes of proteins exported by SecA2 as well additional proteins of unknown function that may account for the role of SecA2 in virulence. We additionally investigated the function of the SecA2 pathway in phagosome maturation arrest which is critical for M. tuberculosis replication and pathogenesis, by identifying and investigating proteins exported by the SecA2 pathway that play essential roles in this process. Work presented in this dissertation shows that SecA2 exports two effectors of phagosome maturation arrest: SapM and PknG. We further show that the role of SecA2 in exporting these effectors contributes to phagosome maturation arrest and growth of M. tuberculosis in macrophages. Finally, to further elucidate the functions and mechanisms of the SecA2 export pathway of M. tuberculosis beyond phagosome maturation arrest, we utilized genome-wide genetic interaction mapping of secA2. Our results expand our understanding of the SecA2 pathway by identifying candidate substrates and components of the export machinery and by revealing roles for SecA2 in M. tuberculosis processes involving transporters, phosphate import, copper resistance, peptidoglycan synthesis, and lipid metabolism and homeostasis. Taken together, the findings presented in this dissertation have significantly advanced our understanding of the roles of the SecA2 export pathway in the virulence of M. tuberculosis.
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  • In Copyright
Advisor
  • Goldman, William
  • Kawula, Thomas
  • Tamayo, Rita
  • Braunstein, Miriam
  • Cotter, Peggy
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2017
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