Abstract
The hallmark of infection caused by Mycobacterium tuberculosis, the agent of tuberculosis, is its ability to persist in a human host for many years. The lipid-rich cell wall of M. tuberculosis serves as an effective barrier against many chemotherapeutic agents and toxic host cell effector molecules, and it may contribute to the mechanism of persistence. M. tuberculosis strains mutated in a 13-gene operon called mce1, which encodes a putative ABC lipid transporter, induce aberrant granulomatous response in mouse lungs. Because of the postulated role of the mce1 operon in lipid importation, we compared the cell wall lipid composition of wild type and mce1 operon mutant M. tuberculosis strains. High resolution mass spectrometric analyses of the mce1 mutant lipid extracts showed unbound mycolic acids to accumulate in the cell wall. Quantitative analysis revealed more than 10-fold greater amount of free mycolates in the mutant compared to that of the wild type strain. The mycolates from the wild type and mce1 operon mutant strains showed no difference in the fractions covalently attached to trehalose or arabinogalactan, indicating that the accumulation of free mycolic acid was not due to a defect in substrate mycolation. No differences were observed in colony morphology between wild type and mce1 operon mutant strains. Since the mce1 operon's expression is regulated in vivo in wild type M. tuberculosis, the above observations suggest that bacterial cell wall can undergo dynamic structural alterations during a course of infection, which may serve as an adaptive strategy for this organism to maintain persistence in a host.
Highlights
IntroductionTuberculosis is caused by Mycobacterium tuberculosis, which has the distinct ability to persist in a human host for many years
Worldwide, 9 to 10 million new cases of tuberculosis occur each year [1]
Since mycobacterial lipids are generally made of six elements, the exact mass provided sufficient information to propose the molecular formula for these products
Summary
Tuberculosis is caused by Mycobacterium tuberculosis, which has the distinct ability to persist in a human host for many years. About 4060% of the cell wall dry weight is estimated to be made up of lipids [3]. Mycolic acids, which are α-alkyl, β-hydroxy fatty acids, are a major constituent of these lipids [4,5], and as such, their role in tuberculosis pathogenesis as well as M. tuberculosis persistence has been the subject of many investigations [6,7,8,9,10,11]. 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 [7,12,13,14,15]
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