12 research outputs found
CD1b-restricted GEM T cell responses are modulated by Mycobacterium tuberculosis mycolic acid meromycolate chains
Tuberculosis, caused by Mycobacterium tuberculosis, remains a major human pandemic. Germline-encoded mycolyl lipid-reactive (GEM) T cells are donor-unrestricted and recognize CD1b-presented mycobacterial mycolates. However, the molecular requirements governing mycolate antigenicity for the GEM T cell receptor (TCR) remain poorly understood. Here, we demonstrate CD1b expression in tuberculosis granulomas and reveal a central role for meromycolate chains in influencing GEM-TCR activity. Meromycolate fine structure influences T cell responses in TB-exposed individuals, and meromycolate alterations modulate functional responses by GEM-TCRs. Computational simulations suggest that meromycolate chain dynamics regulate mycolate head group movement, thereby modulating GEM-TCR activity. Our findings have significant implications for the design of future vaccines that target GEM T cells
Synthesis of epoxy-mycolic acids
Abstract Mycolic acids are major components of the cell wall of Mycobacterium tuberculosis and other mycobacteria. They are usually long chain high molecular mass branched ~- hydroxy fatty acids, containing 70-90 carbons, a-alkyl (C22-C24) and containing different functionalities in the main chain. Their presence is thought to explain the characteristic resistance of these mycobacteria to most antibiotics and other chemotherapeutic agents. Synthetic mycolic acids have applications in the detection and treatment of tuberculosis and in the treatment of asthma. This P!oject consists of three parts. The first part was to synthesise (R,R)-epoxy-trans-alkene-mycolic acid (I) and (S,S)-epoxy-trans-alkene-mycolic acid (11). The target for this part of the project was an epoxy-mycolate present in the cell wall of Mycobacterium fortuitum. Two synthetic stereoisomers (I) and (11) were compared by 'n and l3C NMR spectra with natural epoxy-trans-alkene mycolic acid and the stereochemistry of natural mycolic acid was also proved to be as in compound (11). The second part was to synthesise (S,R)-eis- cyclopropane (R,R)-epoxy-mycolic acid (Ill) and (S,R)-cis-cyclopropane (S,S)-epoxy- mycolic acid (IV) from Mycobacterium smegmatis. Two synthetic stereoisomers (Ill) and (IV) were compared by proton NMR spectroscopy with natural eis-cyclopropane epoxy mycolic acid isolated from M smegmatis. The third part was to synthesise (E/Z)- (R,R)-epoxy-alkene mycolic acid methyl ester (V) and (E/Z)-(S,S)-epoxy-alkene mycolic acid methyl ester (VI) from M smegmatis. An attempt was made to separate the (E/Z)-alkene-epoxy mycolic, acid methyl esters by silver ion TLC but was not successful.EThOS - Electronic Theses Online ServiceGBUnited Kingdo
Towards understanding the functional diversity of cell wall mycolic acids of Mycobacterium tuberculosis
Mycolic acids constitute the waxy layer of the outer cell wall of Mycobacterium spp and
a few other genera. They are diverse in structure, providing a unique chromatographic foot-print
for almost each of the more than seventy Mycobacterium species. Although mainly esterified to
cell wall arabinogalactan, trehalose or glucose, some free mycolic acid is secreted during in vitro
growth of M. tuberculosis. In M. tuberculosis, alpha-, keto- and methoxy-mycolic acids are the
main classes, each differing in their ability to attract neutrophils, induce foamy macrophages or
adopt an antigenic structure for antibody recognition. Of interest is their particular relationship to
cholesterol, discovered by their ability to attract cholesterol, to bind Amphotericin B or to be
recognised by monoclonal antibodies that cross-react with cholesterol. The structural elements
that determine this diverse functionality include the carboxylic acid in the mycolic motif, as well
as the nature and stereochemistry of the two functional groups in the merochain. The functional
diversity of mycolic acid classes implies that much information may be contained in the selective
expression and secretion of mycolic acids to establish tuberculosis after infection of the host.
Their cholesteroid nature may relate to how they utilize host cholesterol for their persistent
survival.South African National Research Foundationhttp://www.elsevier.com/locate/plipresnf201