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6 Structure, Biosynthesis, and Activities of the Phosphatidyl-myo-Inositol-Based Lipoglycans
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Mycobacterium tuberculosis bacilli are phagocytozed mostly by alveolar macrophages following entry into the lung. M. tuberculosis interactions with phagocytes are central to both host protective immunity and tuberculosis pathogenesis. The M. tuberculosis envelope lipids include phosphatidyl-myo-inositol mannosides (PIM) and their multiglycosylated counterparts, lipomannans (LM) and mannosylated lipoarabinomannans (ManLAM). These molecules are involved in the modulation of the host immune responses. PIM are found in the plasma membrane among other phospholipids and also in the capsule, where they seem to be randomly distributed from the cell surface to its innermost layers. The biosynthetic pathway of polar and apolar PIM, although incomplete, is by far the best documented aspect of the biosynthesis of PI-based lipoglycans. Defective or deficient PIM/LM/LAM synthesis is associated with lethality or growth defects, and this raises the issue of the contribution of these complex molecules to the physiology of Mycobacterium sp. The ability of soluble lipoglycans to bind C-type lectins and TLR2 is of particular interest because mycobacterial compounds, including lipoglycans and PIM, are delivered from infected macrophages, through exosomes or apoptotic vesicles, to noninfected bystander dendritic cells (DCs). Toll-like receptors (TLRs) play a crucial role in innate immunity by the recognition of molecular patterns associated with mycobacteria. ManLAM binding to the C-type lectins, MR and DC-SIGN elicits cell signaling pathways. PIM and LM stimulate non-conventional αβT cells restricted by the CD1 proteins and innate immunity through TLR2 binding.
Key Concept Ranking
- Major Histocompatibility Complex Class I
Schematic representation of mycobacterial LAM. Araf, arabinofuranose; Ins, myo-inositol; Manp, mannopyranose; MPI, mannosyl-phosphatidyl-myo-inositol; Rn, fatty acyl residue. The mean molecular mass of M. tuberculosis and M. bovisBCG ManLAM is around 17 kDa, with a heterogeneity estimated at 6 kDa ( Venisse et al., 1993 ). We estimate that these ManLAM contain approximately 60 Araf and 50 Manp units. Manp units are distributed between the mannose caps and the mannan core (30 to 35 Manp units) ( Nigou et al., 2000 ). The mannan domain of the M. kansasii ManLAM contains a low proportion of disaccharide side chains ( Guerardel et al., 2003 ). 5-Methylthiopentose (MTP) was identified as 5-deoxy-5-methylthio-xylo-furanose ( Joe et al., 2006 ) and has been described on the ManLAM of M. tuberculosis strains ( Ludwiczak et al., 2002 ; Treumann et al., 2002 ) and ManLAM and LM of a M. kansasii clinical isolate ( Guerardel et al., 2003 ). Succ indicates succinyl residues located on the arabinan domain of ManLAM of M. bovis BCG ( Delmas et al., 1997 ) and of a M. kansasii clinical isolate ( Guerardel et al., 2003 ). One to four succinyl groups, depending on the M. bovis BCG strain, esterify the 3,5-α-Araf units at position O-2 ( Delmas et al., 1997 ), and an average of two succinic acids per LAM was found in the case of M. kansasii ManLAM ( Guerardel et al., 2003 ). (See the color insert for the color version of this figure.)
LAM biosynthesis schema. The biosynthesis of the triacylated forms of PIM and lipoglycans is shown. PimA is essential in M. smegmatis ( Kordulakova et al., 2002 ). Rv2611c appears to be essential in M. tuberculosis, but not in M. smegmatis ( Kordulakova et al., 2003 ; G. Stadthagen, M. Jackson, and B. Gicquel, unpublished results). AcylT, acyl-transferase; ManT(s), mannosyl-transferase(s); AraT(s), arabinosyl-transferase(s); C35/C50, polyprenol; C35/C50-P-Man, polyprenolmonophosphorylmannose; C35/C50-P-Araf, polyprenol-monophosphoryl-β-D-Araf. (See the color insert for the color version of this figure.)
Cell signaling pathways triggered by PI-based lipoglycans. (A) LM ( Quesniaux et al., 2004 ; Vignal et al., 2003 ), and to a lesser extent PIM ( Gilleron et al., 2003 ), activate macrophages and DCs through a TLR2/TLR1-dependent but TLR6-independent pathway that requires MyD88 ( Quesniaux et al., 2004 ). Only Ac3 LM and Ac4LM are active ( Gilleron et al., 2006 ), whereas the residual PIM activity is independent of the acylation degree (from one to four fatty acids) ( Gilleron et al., 2003 ). It is not known whether lipoglycans are presented to the receptor in a monomeric or multimeric form. ManLAM and AraLAM do not signal through TLR2 as a consequence of steric hindrance: the arabinan domain masks the lipomannan moiety of the molecule ( Guerardel et al., 2003 ). The molecular bases of PILAM activity are not clear yet. (B) ManLAM inhibits IL-12 and TNF-α ( Nigou et al., 2001 ) and induces IL-10 production by LPS-stimulated DCs through DC-SIGN ligation ( Geijtenbeek et al., 2003 ). The signaling pathway involves activation of PI3K and ERK1/2 ( Caparros et al., 2006 ). In macrophages, ManLAM inhibits the LPS-induced production of TNF-α and IL-12 ( Knutson et al., 1998 ), independently of IL-10 production, through IRAK-M activation ( Pathak et al., 2005 ). ManLAM exerts other inhibitory activities on macrophages including inhibition of IFN-γ-mediated activation ( Sibley et al., 1988 ), M. tuberculosis-induced apoptosis ( Rojas et al., 2000 ), and phagolysosome biogenesis ( Fratti et al., 2003 ). Phagolysosome biogenesis is associated with ManLAM binding to MR ( Kang et al., 2005 ) and requires inhibition of both the cytosolic Ca2+ rise/calmodulin pathway and PI3K signaling ( Vergne et al., 2003 ). Inhibition of apoptosis ( Rojas et al., 2000 ) and possibly IFN-γ-mediated activation ( Briken et al., 2004 ) are also dependent on the alteration of Ca2+-dependent intracellular events, suggesting that they could be also both mediated by MR. LM and PIM also bind MR and DC-SIGN ( Pitarque et al., 2005 ; Torrelles et al., 2006 ); however, little is known about the functional consequences. LM induces a TLR2-dependent production of proinflammatory cytokines but concomitantly inhibits, most probably through C-type lectin binding, TLR4-mediated cytokine production ( Quesniaux et al., 2004 ). The net cytokine response is dependent on the receptor equipment of the cells as well as the LM used and their acylation degree ( Quesniaux et al., 2004 ). (See the color insert for the color version of this figure.)
Pathway of PIM presentation to T lymphocytes via CD1b. PIM are normally assembled in aqueous biological solutions in micelles or integrated into biological membranes. They have been provided to antigen-presenting cells (APCs) as membrane fragments (exosomes) ( Beatty et al., 2000 ; Rhoades et al., 2003 ), apoptotic bodies ( Schaible et al., 2003 ) or lipoprotein complexes ( van den Elzen et al., 2005 ). The uptake of PIM was shown to be mediated by host cell C-type lectins: the mannose receptor (MR), the dendritic-cell-specific intercellular adhesion molecule 3-grabbing nonintegrin receptor (DC-SIGN), and the complement receptor 3 (CR3). PIM are then segregated in late endosomes, where they meet CD1b, saposins and enzymes. PIM6 must be processed by a α-mannosidase to generate a structure (PIM2 in the diagram, but which could be even simpler than PIM2), that is presented by CD1b to stimulate the T lymphocytes. This phenomenon is CD1e-assisted ( De la Salle et al., 2005 ), but the exact role of the soluble CD1e protein (sCD1e) is still unknown (see text).