6 Structure, Biosynthesis, and Activities of the Phosphatidyl--Inositol-Based Lipoglycans

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bacilli are phagocytozed mostly by alveolar macrophages following entry into the lung. interactions with phagocytes are central to both host protective immunity and tuberculosis pathogenesis. The envelope lipids include phosphatidyl--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 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.

Citation: Gilleron M, Jackson M, Nigou J, Puzo G. 2008. 6 Structure, Biosynthesis, and Activities of the Phosphatidyl--Inositol-Based Lipoglycans, p 75-105. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch6
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Image of Figure 1.
Figure 1.

Schematic representation of mycobacterial LAM. Ara, arabinofuranose; Ins, -inositol; Man, mannopyranose; MPI, mannosyl-phosphatidyl--inositol; R, fatty acyl residue. The mean molecular mass of and BCG ManLAM is around 17 kDa, with a heterogeneity estimated at 6 kDa ( ). We estimate that these ManLAM contain approximately 60 Ara and 50 Man units. Man units are distributed between the mannose caps and the mannan core (30 to 35 Man units) ( ). The mannan domain of the ManLAM contains a low proportion of disaccharide side chains ( ). 5-Methylthiopentose (MTP) was identified as 5-deoxy-5-methylthio--furanose ( ) and has been described on the ManLAM of strains ( ) and ManLAM and LM of a clinical isolate ( ). Succ indicates succinyl residues located on the arabinan domain of ManLAM of BCG ( ) and of a clinical isolate ( ). One to four succinyl groups, depending on the BCG strain, esterify the 3,5-α-Ara units at position O-2 ( ), and an average of two succinic acids per LAM was found in the case of ManLAM ( ).

Citation: Gilleron M, Jackson M, Nigou J, Puzo G. 2008. 6 Structure, Biosynthesis, and Activities of the Phosphatidyl--Inositol-Based Lipoglycans, p 75-105. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch6
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Image of Figure 2.
Figure 2.

LAM biosynthesis schema. The biosynthesis of the triacylated forms of PIM and lipoglycans is shown. PimA is essential in ( ). Rv2611c appears to be essential in , but not in ( ; G. Stadthagen, M. Jackson, and B. Gicquel, unpublished results). AcylT, acyl-transferase; ManT(s), mannosyl-transferase(s); AraT(s), arabinosyl-transferase(s); C/C, polyprenol; C/C-P-Man, polyprenolmonophosphorylmannose; C/C-P-Ara, polyprenol-monophosphoryl-β-D-Ara.

Citation: Gilleron M, Jackson M, Nigou J, Puzo G. 2008. 6 Structure, Biosynthesis, and Activities of the Phosphatidyl--Inositol-Based Lipoglycans, p 75-105. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch6
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Image of Figure 3.
Figure 3.

Cell signaling pathways triggered by PI-based lipoglycans. (A) LM ( ), and to a lesser extent PIM ( ), activate macrophages and DCs through a TLR2/TLR1-dependent but TLR6-independent pathway that requires MyD88 ( ). Only Ac LM and AcLM are active ( ), whereas the residual PIM activity is independent of the acylation degree (from one to four fatty acids) ( ). 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 ( ). The molecular bases of PILAM activity are not clear yet. (B) ManLAM inhibits IL-12 and TNF-α ( ) and induces IL-10 production by LPS-stimulated DCs through DC-SIGN ligation ( ). The signaling pathway involves activation of PI3K and ERK1/2 ( ). In macrophages, ManLAM inhibits the LPS-induced production of TNF-α and IL-12 ( ), independently of IL-10 production, through IRAK-M activation ( ). ManLAM exerts other inhibitory activities on macrophages including inhibition of IFN-γ-mediated activation ( ), -induced apoptosis ( ), and phagolysosome biogenesis ( ). Phagolysosome biogenesis is associated with ManLAM binding to MR ( ) and requires inhibition of both the cytosolic Ca rise/calmodulin pathway and PI3K signaling ( ). Inhibition of apoptosis ( ) and possibly IFN-γ-mediated activation ( ) are also dependent on the alteration of Ca-dependent intracellular events, suggesting that they could be also both mediated by MR. LM and PIM also bind MR and DC-SIGN ( ); 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 ( ). The net cytokine response is dependent on the receptor equipment of the cells as well as the LM used and their acylation degree ( ).

Citation: Gilleron M, Jackson M, Nigou J, Puzo G. 2008. 6 Structure, Biosynthesis, and Activities of the Phosphatidyl--Inositol-Based Lipoglycans, p 75-105. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch6
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Figure 4.

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) ( ), apoptotic bodies ( ) or lipoprotein complexes ( ). 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. PIM must be processed by a α-mannosidase to generate a structure (PIM in the diagram, but which could be even simpler than PIM), that is presented by CD1b to stimulate the T lymphocytes. This phenomenon is CD1e-assisted ( ), but the exact role of the soluble CD1e protein (sCD1e) is still unknown (see text).

Citation: Gilleron M, Jackson M, Nigou J, Puzo G. 2008. 6 Structure, Biosynthesis, and Activities of the Phosphatidyl--Inositol-Based Lipoglycans, p 75-105. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch6
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