Mycobacterial lipoarabinomannan: An extraordinary lipoheteroglycan with profound physiological effects

Abstract

Detailed structural and functional studies over the last decade have led to current recognition of the mycobacterial lipoarabinomannan (LAM) as a phosphatidylinositol anchored lipoglycan with diverse biological activities. Fatty acylation has been demonstrated to be essential for LAM to maintain its functional integrity although the focus has largely been on the arabinan motifs and the terminal capping function. It has recently been shown that the mannose caps may be involved not only in attenuating host immune response, but also in mediating the binding of mycobacteria to and subsequent entry into macrophages. This may further be linked to an intracellular trafficking pathway through which LAM is thought to be presented by CD1 to subsets of T-cells. The implication of LAM as major histocompatibility complex (MHC)-independent T-cell epitope and the ensuing immune response is an area of intensive studies. Another recent focus of research is the biosynthesis of arabinan which has been shown to be inhibitable by the anti-tuberculosis drug, ethambutol. The phenomenon of truncated LAM as synthesized by ethambutol resistant strains provides an invaluable handle for dissecting the array of arabinosyltransferases involved, as well as generating much needed structural variants for further structural and functional studies. It is hoped that with more systematic investigations based on clinical isolates and human cell lines, the true significance of LAM in the immunopathogenesis of tuberculosis and leprosy can eventually be explained.

Structural characterization of phosphatidyl-myo-inositol mannosides from Mycobacterium bovis bacillus calmette guérin by multiple-stage quadrupole ion-trap mass spectrometry with electrospray ionization. I. PIMs and lyso-PIMs

“…PIMs form the common anchor of LM and LAM and play an important role in the biological functions of these molecules [10]. PIM 2 was shown to elicit the production of proinflammatory cytokines from macrophages [11] and also has been shown to recruit natural killer T cells, which have a primary role in the local granulomatous response [12][13][14]. A role for surface-exposed PIMs as M. tuberculosis adhesins that mediate attachment to nonphagocytic cells has also been established [15,16].…”

Structural characterization of lipoarabinomannans fromMycobacterium tuberculosisandMycobacterium smegmatisby ESI mass spectrometry

“…The immunological properties of LAM from both virulent and avirulent species have been studied [7][8][9][10][11][12], and it is becoming increasingly apparent that subtle differences in LAM structure may shape the host response to various species. For instance, mannose-capped LAM from M. tuberculosis causes apoptosis inhibition and suppresses TNF-␣ and IL-12 production, while PILAM from M. smegmatis invoke entirely opposite macrophage functions [8,12]. ManLAM, unlike PILAM, have been shown to bind to the mannose receptor [13] which aids in macrophage phagocytosis [11].…”

Broadening Our View About the Role of Mycobacterium tuberculosis Cell Envelope Components During Infection: A Battle for Survival

“…The anchor structure in M.tb ManLAM is similar to the one in PIMs, and consists in an nsglycerol 3-phospho-(1-D-myo-inositol) unit with a -D-mannopyranosyl residue at C-2 of the myo-inositol (MPI). In the C-6 position of this myo-inositol there is O-linked the mannan polymer described previously (Chatterjee & Khoo, 1998). Some of the heterogeneity that characterizes ManLAM occurs through the number, the location, and the nature of the fatty acids esterifying the PI anchor.…”

“…M.tb ManLAM is an extremely heterogeneous lipoglycan with a defined tripartite structure that possesses a carbohydrate core, a mannosyl-phophatidyl-myo-inositol anchor (MPI) and various capping motifs. Following the earlier work performed by Chatterjee and co-workers (Chatterjee & Khoo, 1998), a series of detailed structural analyses have produced evidence of this tripartite structure, in which ManLAM was distinguished from the related lipomannan (LM) by virtue of having an additional immunodominant arabinan domain that extends from a common phosphatidyl-myo-inositol mannan core in an as yet undefined manner. The polysaccharide core of M.tb ManLAM consists of two very well differentiated polymers, a D-mannan and a D-arabinan.…”