Towards understanding the functional diversity of cell wall mycolic acids of Mycobacterium tuberculosis

Abstract

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.

CD1b-restricted GEM T cell responses are modulated byMycobacterium tuberculosismycolic acid meromycolate chains

“…Different strains of Mtb and other mycobacteria express significantly different MA structural profiles and Mtb is known to considerably change its MA composition in response to different growth conditions and virulence stages (22,43,44). It is therefore essential to understand the structure-function relationships of Mtb-derived mycolates using synthetic lipids due to the complex mixtures and difficulty in isolating a single natural molecule.…”

“…However, the major source of mycolate diversity is derived from structural determinants within the meromycolate chain which are distal to the head group moiety (22). This feature has not been systematically investigated in relation to T cell activation.…”

“…Three major mycolate classes exist in Mtb, including α-, keto-and methoxy-, based on functional groups within the meromycolate chain, which are proximal or distal to the head group moiety (Fig. S1A) (22). In addition, mycolates occur with different chain lengths, and stereo-arrangements of functional groups, generating a large spectrum of possible mycolate structures.…”

“…(A) Representative flow cytometry plots showing GEM18-TCR activation through upregulation of CD69 (y-axis) on Jurkat T cells. GEM18-TCR transduced Jurkat T cells, but not mock transduced Jurkat T cells, upregulate CD69 when cultured with CD1b + T2 lymphoblasts in the presence of the MA JR1080 (Table S1) are all CD1b-presented lipid antigens (22)(23)(24). When bound to CD1b, the meromycolate chain positions itself within the long A', T' and F' super channel of CD1b, while the shorter α-alkyl chain occupies the C' channel, via hydrophobic interactions (25).…”

Pathophysiological Implications of Cell Envelope Structure in Mycobacterium tuberculosis and Related Taxa

“…Similarly, a detailed exploration of protein content is not given, even for structurally vital proteins such as well-characterised porins [12]. The main chemical structures that must be accommodated in the cell envelope of M. tuberculosis are considered in the following sections, commencing with the long-chain mycolic acids that are mycobacterial signature components [4,[13][14][15][16][17][18].…”