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Abstract

Mycobacteria, including the pathogenic species Mycobacterium tuberculosis (Mtb), possess a unique cell envelope structure that confers resistance to environmental stresses and antimicrobial agents. Mtb, the causative agent of tuberculosis (TB), is a global health concern with increasing drug resistance. The ESX-3 secretion system found in Mtb and other mycobacteria plays a crucial role in the secretion of effector proteins that confer pathogenicity. This thesis focuses on studying the ESX-3 secretion system in mycobacteria by: 1) determining the localization of the secreted substrates PE5-PPE4 in M. smegmatis, and 2) characterizing the in vivo structure of the ESX-3 from Mtb. Briefly, the ESX-3 substrate PPE4 was found localized to the MOM of M. smegmatis, and ESX-3 from Mtb was found to localize to the poles of M. marinum forming a putative trans envelope structure. Together, this research contributes to our understanding of the role of ESX-3 in pathogenicity of mycobacteria and may inform the development of novel TB treatments that inhibit secretion via the ESX-3.