<unk>  is synthesized via addition of mannose residues to phosphoinositol by a series of mannosyltransferases to produce PIMs and lipomannan (LM). PIM and LM are then glycosylated with arabinan to form<unk> .<unk>  is known to have three primary structural domains. These include a glycosylphosphatidyl anchor which attaches the molecule to the cell wall, a D-mannan core serving as a carbohydrate skeleton, and a terminal D-arabinan, also composing the carbohydrate skeleton. Many arabinofuranosyl side chains branch off the mannose core. It is the covalent modifications to this terminal D-arabinan that creates various<unk>  structures with their own unique functions to mediate bacterial survival within a host. The presence and the structure of capping allow classification of<unk>  molecules into three major classes.<unk>  Mannosylated<unk> s<unk>  are characterized by the presence of mannosyl caps on the terminal D-arabinan. These types of<unk> s are most commonly found in more pathogenic Mycobacterium species such as M. tuberculosis, M. leprae, and M. bovis.<unk>  has been shown to be an anti-inflammatory molecule that inhibits production of TNF-α and IL-12 production by human dendritic cells and human macrophages in vitro and to modulate M. tuberculosis-induced macrophage apoptosis via binding to host macrophage mannose receptors. This is particularly important in deactivating host macrophages to allow the bacteria to survive and multiply within them. Proposed Mechanisms There are many proposed mechanisms behind<unk>  function. Activation of a PI3K pathway is sufficient to trigger phosphorylation of the Bcl-2 family member Bad by<unk> .<unk>  is able to activate the serine/threonine kinase Akt via phosphorylation which is then able to phosphorylate Bad. Dephosphorylated Bad serves as a pro-apoptotic protein and its activation allows for cell survival. This demonstrates one virulence-associated mechanism by which bacteria are able to up-regulate signaling pathways to control host cell apoptosis.<unk>  may also directly activate SHP-1, a phosphotyrosine phosphatase known to be involved in terminating activation signals. SHP-1 negatively regulates pathways related to the actions of IFN-γ and insulin.<unk>  may regulate SHP-1 by multiple mechanisms including direct interactions, phosphorylation, and subcellular localization. Once activated, SHP-1 translocates from the cytosol to the membrane. By activating a phosphatase,<unk>  can inhibit LPS and IFN-γ induced protein tyrosine phosphorylation in monocytes. This decreases production of TNF-α, a molecule necessary in forming granulomas against M. tuberculosis and important in macrophage defense against bacterium via nitrogen oxide production.<unk> 's activation of SHP-1 also works to deactivate IL-12. IL-12 is important for innate resistance to M. tuberculosis infections. It activates natural killer cells which produce IFN-γ to activate macrophages. By impairing the function of these two molecules by SHP-1 activation,<unk>  may promote intracellular survival. Other models suggest that<unk>  acts to mediate immunosuppressive effects through suppression of LPS-induced IL-12 p40 protein production.<unk>  is thought to inhibit the IL-1 receptor-associated kinase (IRAK)-TRAF6 interaction, IκB-α phosphorylation, and nuclear translocation of c-Rel and p50 which causes reduced IL-12 p40 production. Proposed mechanisms of<unk>  functions PILAM<unk> S capped with phosphoinositol are typically found in nonpathogenic species including M. smegmatis. In contrast to<unk> s, PILAMs are pro-inflammatory. CD14, a recognition receptor present on macrophages, associate with toll-like receptor 2 (TLR2) is described to be a receptor for PILAM. Binding of PILAM to the receptor elicits the activation of an intracellular signaling cascade which activates transcription factors that initiate transcription of proinflammatory cytokine genes. This may lead to TNF-α, IL-8, and IL-12 activation and apoptosis of macrophages. AraLAM (CheLAM) Certain species of rapid-growing bacterium such as M. chelonae and laboratory strains (H37Ra) contain<unk> s that are absent of both mannose and phosphoinosital caps. This form of<unk>  is characterized by 1,3 –mannosyl side chains instead of the 1,2 commonly found in others mycobacterial species. These forms are considered to be more potent than the mannose-capped<unk>  in inducing functions associated with macrophage activation. In addition to stimulation of early genes such as c-fos, KC, and JE, AraLAM induces transcription of the mRNA for cytokines (such as TNF-α, IL 1-α, IL 1-β, IL-6, IL-8, and IL-10) characteristically produced by macrophages. Proto-oncogenes c-fos and c-myc are involved in the regulation of gene transcription while JE and KC are peptide cytokines that serve as specific chemoattractants for neutrophils and monocytes. Activation of TNF-α creates pathologic manifestations of disease such as tissue necrosis, nerve damage, and protective immunity. O-acyl groups of the arabinomannan moiety may be responsible for TNF-inducing activity which causes the tuberculosis symptoms of fever, weight loss, and necrosis. However, the presence of<unk> s decreases AraLAM activity, suppressing an immune response.
Lipoarabinomannan
Glucomannan
Polysaccharide-K
Lecithin
Polysaccharide peptide
Galactooligosaccharide
Delta-Palutoxin
Mirificin