Effect of Mycolic Acids on Host Immunity and Lipid Metabolism

Abstract

Mycolic acids constitute pivotal constituents within the cell wall structure of Mycobacterium tuberculosis. Due to their structural diversity, the composition of mycolic acids exhibits substantial variations among different strains, endowing them with the distinctive label of being the 'signature' feature of mycobacterial species. Within Mycobacterium tuberculosis, the primary classes of mycolic acids include α-, keto-, and methoxy-mycolic acids. While these mycolic acids are predominantly esterified to the cell wall components (such as arabinogalactan, alginate, or glucose) of Mycobacterium tuberculosis, a fraction of free mycolic acids are secreted during in vitro growth of the bacterium. Remarkably, different types of mycolic acids possess varying capabilities to induce foamy macro-phages and trigger immune responses. Additionally, mycolic acids play a regulatory role in the lipid metabolism of host cells, thereby exerting influence over the progression of tuberculosis. Consequently, the multifaceted properties of mycolic acids shape the immune evasion strategy employed by Mycobacterium tuberculosis. A comprehensive understanding of mycolic acids is of paramount significance in the pursuit of developing tuberculosis therapeutics and unraveling the intricacies of its pathogenic mechanisms.

Keywords: Mycobacterium tuberculosis; immune response; lipid metabolism; mycolic acids.

Figure 1

Structure of the cell wall of Mycobacterium tuberculosis. The cell wall of Mtb is formed by parallel arrangement of MA chains (represented by red wavy lines), which are linked to AG (depicted as green pentagons), while AG is covalently attached to peptidoglycan (PG) (shown as purple hexagons); the inner layer of the mycomembrane is presumably composed of free lipids, including TDM (depicted in gray), TMM (in yellow), and PDIM (in green spheres), along with the presence of proteins.

Figure 2

Major types of mycolic acid from M. tuberculosis complex. A α-MAs molecule has two cis-cyclopropane ring structures. The keto- and methoxy-mycocerosic acid molecules have one cis and one trans-cyclopropane ring structure.

Figure 3

Different types of mycolic acids activate host cellular immunity and cholesterol accumulation. (A) TDM binding to Mincle triggers activation and upregulation of the NLRP3 inflammasome in macrophage, leading to release of caspase-1, which can promote the maturation of IL-1β (red arrow). In addition, TDM also promote the activation of Mincle–Syk-CARD9/Bcl10/MALT1 complex to mediate NF-κB signaling pathway to produce IL-1β (green arrow). MCL binds to Mincle to help recognize TDM. The synthetic analogue of TDM is TDB, which is an agonist for Mincle. TDB activates MYD88 pathway and enhances cytokine secretion through recognizing Mincle and TLR4 receptors. In addition, MYD88 pathway phosphorylates PtdIns3K, STAT1 to promote autophagy. This mechanism played a key role in controlling the growth of Mtb (orange arrow). Non-glycosylated mycolic acids play roles in host immunity. Free MAs are recognized by TREM2 receptor, which induces STING-dependent upregulation of TREM2 expression, which, in turn, enhances IFN-β and IL-10 secretion. The secretion of IFN-β inhibits proinflammatory cytokine production, which results in the increased intracellular survival of Mtb. Meanwhile, the expression of TREM2 inhibits the activation of Mincle to aggravate Mtb infection (gray arrow). (B) Mincle triggers phosphorylation of the MEK1/2 in neutrophils, resulting in the phosphorylation of ERK1/2 protein into the nucleus to promote the secretion of cytokines and the expression of CD11b and CD 18 molecules (purple arrow). (B) Once inside the host, Mtb is retained within the phagosomes, and secretes its cell wall components. Thereafter, the secreted components, mainly lipids and mycolic acid, are trafficked from the phagosome into the cytosol. Various host factors are present as sensors and effectors in the cellular milieu. The nuclear receptor TR4 binds to the secreted mycolic acid (keto-MA). Activation of the receptor by ligand binding leads to downstream regulation of gene involved in lipid biogenesis through its binding to its target gene having the TR4 response element (blue arrow).