Shared Characteristics Between Mycobacterium tuberculosis and Fungi Contribute to Virulence

Sam Willcocks; Brendan W Wren


Future Microbiol. 2014;9(5):657-668. 

In This Article

Cell Wall Composition

Perhaps the best described mycobacterial virulence factor, trehalose dimycolate (TDM), formerly known as 'cord factor', is a major part of the cell wall and is unique to the genus. TDM is important because it confers protection against desiccation, oxidative stress,[20] antimicrobial peptides,[21] antibiotics,[22] and it inhibits phagosome maturation,[23] as well as inducing the clumping that confers many of the qualities of a biofilm.[24] Relative abundance as well as variation in the cyclopropanation of the mycolate component of TDM may partly account for the variation in virulence seen between strains of mycobacteria.[12,25] The ability to synthesize TDM is similar to a fungal-like ability to utilize trehalose. Trehalose is metabolized by various fungi and bacteria for energy, but with the exception of Corynebacterium spp., mycobacteria are unique among prokaryotes in using this molecule as an integral structural component. Its trehalose biosynthesis pathway is similarly unique among bacteria, but common among fungi.[26]

De novo synthesis of another molecule also groups mycobacteria together with fungi rather than other prokaryotes. Inositol is an important precursor molecule for cell wall components such as phosphatidylinositol (PI), phosphatidyl inositol mannoside (PIM), LM and lipoarabinomannan (LAM), as well as mycothiol, while in eukaryotic counterparts it is used to make PI as well as sphingolipids and GPI anchors. The mechanism for inositol synthesis is conserved among eukaryotes and mycobacteria, but not other prokaryotes, and mutation of the genes involved in this pathway results in attenuation.[27]

The presence of mannose-capped LAM, ManLAM, in the cell wall of mycobacteria is particularly associated with the virulent species. Recognition of ManLAM by macrophage-expressed mannose receptor (MR) supports uptake into the cell where the bacteria can replicate. MR has been reported to bind to non-mycobacteria as well; however, this is largely due to the recognition of lower affinity carbohydrate ligands rather than mannose, which has an extremely high affinity for MR. Conversely, not all bacterial structures containing mannose residues are able to bind MR, as with the capsular polysaccharide of Klebsiella pneumonia.[28] It is the end terminal conformation of mannose that is such a strong target for MR, and this is uniquely expressed among prokaryotes by virulent Mycobacterium spp. Other than M. tuberculosis, the best known example of end-terminal mannose expression and high MR affinity can be found in polymer form as mannan in the cell wall component of true fungi. In fungi, mannan serves as a store of carbohydrate, but like mycobacterial trehalose, it is primarily a structural component. However, its function can vary according to its branched structure, similar to the mycolic acids of M. tuberculosis. While fungi do not possess LAM or PIMs, the polymerization of mannose into mannan is a feature common to both fungi and mycobacteria. Mannan from Saccharomyces cerevisiae is a high-affinity ligand for mannose-binding lectin (MBL), a serum complement factor that was one of the first of its kind to be described. MBL also recognizes mycobacterial mannan, resulting in opsonization that enhances phagocytosis by macrophages, favoring intracellular replication of mycobacteria and exacerbating disease.[29] Interestingly, mycobacterial-derived mannan has also been shown to inhibit phagocytic killing mechanisms against bacteria that do not themselves contain mannan, such as Escherichia coli.[30] The similarity between fungal and mycobacterial mannan has even been suggested as an exacerbating factor in Crohn's disease, following the observation that antibodies that detect ManLAM can crossreact with mannans found in the S. cerevisiae cell wall, leading to nonspecific inflammation. These antibodies are rarely found in healthy human controls.[31]

The similar conformational expression of mannose between M. tuberculosis and fungi, as well as the ability of mannose-containing molecules such as the higher-order PIMs to engage host receptors are vital aspects of mycobacterial virulence.[32–35]