Mycobacterial glycolipids: pathways to synthesis and role in virulence

Sarkar, Debasmita (2012). Mycobacterial glycolipids: pathways to synthesis and role in virulence. University of Birmingham. Ph.D.

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Abstract

Mycobacterial diseases are responsible for numerous deaths worldwide, the major pathogens being Mycobacterium tuberculosis and Mycobacterium leprae. Also, in recent years threats from opportunistic pathogens, such as Mycobacterium marinum and Mycobacterium kansasii have been on the rise. These mycobacteria possess a unique lipid-rich cell wall with an array of mycolic acids and species-specific antigenic glycolipids, like the lipooligosaccharides. Some of these solvent extractable lipids possess immunomodulatory properties and play an important role during infection.
Lipooligosaccharides (LOS) are surface exposed, polar, antigenic glycolipids that are present in several mycobacterial species. This study used the opportunistic human pathogens M. marinum and M. kansasii as a model system to unravel the genes involved in the biosynthesis of LOSs in Mycobacterium. Using directed mutagenesis and transposon mutagenesis, mutant strains defective in various parts of the LOS biosynthetic pathway were isolated. Analysis of these strains helped in further delineating the pathway and understanding the role of LOSs in virulence.
A part of this thesis focussed on studying mycolic acid processing and transport using Mycobacterium smegmatis as a surrogate system. Mycolic acids are the most distinctive components of the mycobacterial cell wall. While their biosynthesis has been studied in detail, processing and transport across the membrane is not well understood. This study attempted to explore the roles of the two putative type II mycolyltransferases MSMEG3437 and MSMEG5851 in mycolic acid processing. Additionally, the role of M. tuberculosis mmpL11 gene was probed as the Mtb-mmpL11 had been reported to be involved in virulence. A null ii mutant of the M. smegmatis homologue, Ms-mmpL11 (MSMEG0241) was generated and analysed for the above study. Deletion mutant strains of the two putative mycolyltransferase II did not show any phenotype, suggesting that their roles are redundant in vivo. Although the Ms-mmpL gene was found to be non-essential, it was found to be involved in transport of free mycolic acids.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):