Regulated Alteration of Mycolic Acid Structure in the Cell Wall of Mycobacterium Tuberculosis

Worldwide, 9 to 10 million new cases of tuberculosis occur each year. Tuberculosis is caused by Mycobacterium tuberculosis, which has the distinct ability to persist in a human host for many years. Part of its long term survival strategy may involve its highly protective cell envelope. A large portion of the coding capacity of the M. tuberculosis genome is devoted to lipid biosynthesis and degradation . About 40- 60% of the cell wall dry weight is estimated to be made up of lipids. Mycolic acids, which are α-alkyl, β-hydroxy fatty acids, are a major constituent of these lipids , and as such, their role in tuberculosis pathogenesis as well as M. tuberculosis persistence has been the subject of many investigations. Structural alterations and relative differences in the amount of different classes of mycolic acids (α-, keto- , and methoxy-mycolates) in the cell wall can exert a profound effect on clinical outcomes of infected hosts.

Cell Wall of Mycobacterium Tuberculosis

M. tuberculosis contains 4 homologous copies of an operon designated mce1-4, which resemble ATP-Binding Cassette (ABC) transporters possibly involved in lipid importation. Shimono et al. showed that M. tuberculosis disrupted in one of these operons mce1 failed to elicit a strong Th1-type immune response and caused a formation of poorly organized mouse lung granulomas comprised mostly of lipid-rich foamy macrophages. Casali et al. showed that mce1 operon is negatively regulated intracellularly by mce1R, located immediately upstream of the operon. Uchida et al. showed that a mutant disrupted in mce1R gene causes accelerated immunopathologic response in mice, in which there is rapid progression to death of the animal following massive granuloma formation in their lungs. These studies indicated that differential in vivo expression of the mce1 genes correlates with distinct pro-inflammatory responses in mice.

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