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

Martine Gilleron; Mary Jackson; Jérôme Nigou; Germain Puzo

doi:10.1128/9781555815783.ch6

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

Authors: Martine Gilleron¹, Mary Jackson², Jérôme Nigou³, Germain Puzo⁴

VIEW AFFILIATIONS HIDE AFFILIATIONS

Affiliations: 1: Department of Molecular Mechanisms of Mycobacterial Infections, Institut de Pharmacologie et de Biologie Structurale du Centre National de la Recherche Scientifique (CNRS) and Université Paul Sabatier, 205 route de Narbonne, 31077 Toulouse Cedex 4, France; 2: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523; 3: Department of Molecular Mechanisms of Mycobacterial Infections, Institut de Pharmacologie et de Biologie Structurale du Centre National de la Recherche Scientifique (CNRS) and Université Paul Sabatier, 205 route de Narbonne, 31077 Toulouse Cedex 4, France; 4: Department of Molecular Mechanisms of Mycobacterial Infections, Institut de Pharmacologie et de Biologie Structurale du Centre National de la Recherche Scientifique (CNRS) and Université Paul Sabatier, 205 route de Narbonne, 31077 Toulouse Cedex 4, France

Content Type: Monograph

Publication Year: 2008

Book DOI: 10.1128/9781555815783

Chapter DOI: 10.1128/9781555815783.ch6

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:

6 Structure, Biosynthesis, and Activities of the Phosphatidyl-myo-Inositol-Based Lipoglycans, Page 1 of 2

< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555815783/9781555814687_Chap06-1.gif /docserver/preview/fulltext/10.1128/9781555815783/9781555814687_Chap06-2.gif

Abstract:

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.

Citation: Gilleron M, Jackson M, Nigou J, Puzo G. 2008. 6 Structure, Biosynthesis, and Activities of the Phosphatidyl-myo-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

Highlighted Text: Show | Hide

Full text loading...

Figures

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

[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555815783.ch06-1,webId=/content/author/10.1128/9781555815783.ch06-1,properties={foaf_givenname=Martine, foaf_name=Martine Gilleron, foaf_surname=Gilleron, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555815783.ch06-aff1]]}], com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555815783.ch06-2,webId=/content/author/10.1128/9781555815783.ch06-2,properties={foaf_givenname=Mary, foaf_name=Mary Jackson, foaf_surname=Jackson, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555815783.ch06-aff2]]}], com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555815783.ch06-3,webId=/content/author/10.1128/9781555815783.ch06-3,properties={foaf_givenname=Jérôme, foaf_name=Jérôme Nigou, foaf_surname=Nigou, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555815783.ch06-aff3]]}], com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555815783.ch06-4,webId=/content/author/10.1128/9781555815783.ch06-4,properties={foaf_givenname=Germain, foaf_name=Germain Puzo, foaf_surname=Puzo, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555815783.ch06-aff4]]}]]

/content/10.1128/9781555815783.ch06.ch06fig01

Figure 1.

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.)

10.1128/9781555815783/f0077-01_thmb.gif

10.1128/9781555815783/f0077-01.gif

Figure 1.

/content/10.1128/9781555815783.ch06.ch06fig02

Figure 2.

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.)

10.1128/9781555815783/f0081-01_thmb.gif

10.1128/9781555815783/f0081-01.gif

Figure 2.

/content/10.1128/9781555815783.ch06.ch06fig03

Figure 3.

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.)

10.1128/9781555815783/f0089-01_thmb.gif

10.1128/9781555815783/f0089-01.gif

Figure 3.

/content/10.1128/9781555815783.ch06.ch06fig04

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) ( 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).

10.1128/9781555815783/f0094-01_thmb.gif

10.1128/9781555815783/f0094-01.gif

Figure 4.

References

/content/book/10.1128/9781555815783.ch06

1. Abdian, P. L.,, A. C. Lellouch,, C. Gautier,, L. Ielpi, and, R. A. Geremia. 2000. Identification of essential amino acids in the bacterial alpha-mannosyltransferase aceA. J. Biol. Chem. 275: 40568– 40575.

2. Ainge, G. D.,, J. Hudson,, D. S. Larsen,, G. F. Painter,, G. S. Gill, and, J. L. Harper. 2006. Phosphatidylinositol mannosides: Synthesis and suppression of allergic airway disease. Bioorg. Med. Chem. 14: 5632– 5642.

3. Akira, S. 2003. Mammalian Toll-like receptors. Curr. Opin. Immunol. 15: 5– 11.

4. Alderwick, L. J.,, V. Molle,, L. Kremer,, A. J. Cozzone,, T. R. Dafforn,, G. S. Besra, and, K. Futterer. 2006a. Molecular structure of EmbR, a response element of Ser/Thr kinase signaling in Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. USA 103: 2558– 2563.

5. Alderwick, L. J.,, E. Radmacher,, M. Seidel,, R. Gande,, P. G. Hitchen,, H. R. Morris,, A. Dell,, H. Sahm,, L. Eggeling, and, G. S. Besra. 2005. Deletion of Cg- emb in Corynebacterianeae leads to a novel truncated cell wall arabinogalactan, whereas inactivation of Cg- ubiA results in an arabinan-deficient mutant with a cell wall galactan core. J. Biol. Chem. 280: 32362– 32371.

6. Alderwick, L. J.,, M. Seidel,, H. Sahm,, G. S. Besra, and, L. Eggeling. 2006b. Identification of a novel arabinosyl transferase (AtfA) involved in cell wall arabinan biosynthesis in Mycobacterium tuberculosis. J. Biol. Chem. 281: 15653– 15661.

7. Alexander, D. C.,, J. R. W. Jones,, T. Tan,, J. M. Chen, and, J. Liu. 2004. PimF, a mannosyltransferase of Mycobacteria, is involved in the biosynthesis of phosphatidylinositol mannosides and lipoarabinomannan. J. Biol. Chem. 279: 18824– 18833.

8. Altare, F.,, A. Durandy,, D. Lammas,, J. F. Emile,, S. Lamhamedi,, F. Le Deist,, P. Drysdale,, E. Jouanguy,, R. Doffinger,, F. Bernaudin,, O. Jeppsson,, J. A. Gollob,, E. Meinl,, A. W. Segal,, A. Fischer,, D. Kumararatne, and, J. L. Casanova. 1998. Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency. Science 280: 1432– 1435.

9. Angenieux, C.,, V. Fraisier,, B. Maitre,, V. Racine,, N. van der Wel,, D. Fricker,, F. Proamer,, M. Sachse,, J. P. Cazenave,, P. Peters,, B. Goud,, D. Hanau,, J. B. Sibarita,, J. Salamero, and, H. de la Salle. 2005. The cellular pathway of CD1e in immature and maturing dendritic cells. Traffic 6: 286– 302.

10. Apostolou, I.,, A. Cumano,, G. Gachelin, and, P. Kourilsky. 2000. Evidence for two subgroups of CD4-CD8- NKT cells with distinct TCR alpha beta repertoires and differential distribution in lymphoid tissues. J. Immunol. 165: 2481– 2490.

11. Apostolou, I.,, Y. Takahama,, C. Belmant,, T. Kawano,, M. Huerre,, G. Marchal,, J. Cui,, M. Taniguchi,, H. Nakauchi,, J. J. Fournie,, P. Kourilsky, and, G. Gachelin. 1999. Murine natural killer T(NKT) cells [correction of natural killer cells] contribute to the granulomatous reaction caused by mycobacterial cell walls. Proc. Natl. Acad. Sci. USA 96: 5141– 5146.

12. Asselineau, C., and, J. Asselineau. 1984. Waxes, mycosides and related compounds, p. 345–360. In G. P. Kubica and, L. G. Wayne (ed.), The Mycobacteria—a Source Book, vol. 15. Marcel Dekker, Inc., New York, NY.

13. Astarie-Dequeker, C.,, E. N. N’Diaye,, V. Le Cabec,, M. G. Rittig,, J. Prandi, and, I. Maridonneau-Parini. 1999. The mannose receptor mediates uptake of pathogenic and nonpathogenic mycobacteria and bypasses bactericidal responses in human macrophages. Infect. Immun. 67: 469– 477.

14. Bachhawat, N., and, S. C. Mande. 1999. Identification of the INO1 gene of Mycobacterium tuberculosis H37Rv reveals a novel class of inositol-1-phosphate synthase enzyme. J. Mol. Biol. 291: 531– 536.

15. Ballou, C. E.,, E. Vilkas, and, E. Lederer. 1963. Structural studies on the myo-inositol phospholipids of Mycobacterium tuberculosis (var. bovis, strain BCG). J. Biol. Chem. 238: 69– 76.

16. Barreiro, L. B.,, O. Neyrolles,, C. L. Babb,, L. Tailleux,, H. Quach,, K. McElreavey,, P. D. Helden,, E. G. Hoal,, B. Gicquel, and, L. Quintana-Murci. 2006. Promoter variation in the DC-SIGN-encoding gene CD209 is associated with tuberculosis. PLoS Med. 3: e20.

17. Batuwangala, T.,, D. Shepherd,, S. D. Gadola,, K. J. Gibson,, N. R. Zaccai,, A. R. Fersht,, G. S. Besra,, V. Cerundolo, and, E. Y. Jones. 2004. The crystal structure of human CD1b with a bound bacterial glycolipid. J. Immunol. 172: 2382– 2388.

18. Beatty, W. L.,, E. R. Rhoades,, H. J. Ullrich,, D. Chatterjee,, J. E. Heuser, and, D. G. Russell. 2000. Trafficking and release of mycobacterial lipids from infected macrophages. Traffic 1: 235– 247.

19. Belanger, A. E.,, G. S. Besra,, M. E. Ford,, K. Mikusova,, J. T. Belisle,, P. J. Brennan, and, J. M. Inamine. 1996. The embAB genes of Mycobacterium avium encode an arabinosyl transferase involved in cell wall arabinan biosynthesis that is the target for the antimycobacterial drug ethambutol. Proc. Natl. Acad. Sci. USA 93: 11919– 11924.

20. Belanger, A. E., and, J. M. Inamine. 2000. Genetics of cell wall biosynthesis, p. 191–202. In G. F. Hatfull and, W. R. Jacobs (ed.), Molecular Genetics of Mycobacteria. ASM Press, Washington, DC.

21. Ben-Ali, M.,, M. R. Barbouche,, S. Bousnina,, A. Chabbou, and, K. Dellagi. 2004. Toll-like receptor 2 Arg677Trp polymorphism is associated with susceptibility to tuberculosis in Tunisian patients. Clin. Diagn. Lab. Immunol. 11: 625– 626.

22. Berg, S.,, J. Starbuck,, J. B. Torrelles,, V. D. Vissa,, D. C. Crick,, D. Chatterjee, and, P. J. Brennan. 2005. Roles of conserved proline and glycosyltransferase motifs of EmbC in biosynthesis of lipoarabinomannan. J. Biol. Chem. 280: 5651– 5663.

23. Besra, G. S.,, C. B. Morehouse,, C. M. Rittner,, C. J. Waechter and, P. J. Brennan. 1997. Biosynthesis of mycobacterial lipoarabinomannan. J. Biol. Chem. 272: 18460– 18466.

24. Braibant, M.,, P. Gilot, and, J. Content. 2000. The ATP binding cassette (ABC) transport systems of Mycobacterium tuberculosis. FEMS Microbiol. Rev. 24: 449– 467.

25. Brennan, P. J. 1984. Antigenic peptidoglycolipids, phospholipids and glycolipids, p. 467–490. In G. P. Kubica and, L. G. Wayne (ed.), The Mycobacteria—a Source Book, vol. 15. Marcel Dekker, Inc., New York, NY.

26. Brennan, P. J., and, C. E. Ballou. 1968. Biosynthesis of mannophosphoinositides by Mycobacterium phlei. Enzymatic acylation of the dimannophosphoinositides. J. Biol. Chem. 243: 2975– 2984.

27. Brennan, P. J., and, C. E. Ballou. 1967. Biosynthesis of mannophosphoinositides by Mycobacterium phlei. The family of dimannophosphoinositides. J. Biol. Chem. 242: 3046– 3056.

28. Brennan, P. J., and, H. Nikaido. 1995. The envelope of mycobacteria. Annu. Rev. Biochem. 64: 29– 63.

29. Brightbill, H. D.,, D. H. Libraty,, S. R. Krutzik,, R. B. Yang,, J. T. Belisle,, J. R. Bleharski,, M. Maitland,, M. V. Norgard,, S. E. Plevy,, S. T. Smale,, P. J. Brennan,, B. R. Bloom,, P. J. Godowski, and, R. L. Modlin. 1999. Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 285: 732– 736.

30. Brigl, M., and, M. B. Brenner. 2004. CD1: antigen presentation and T cell function. Annu. Rev. Immunol. 22: 817– 890.

31. Briken, V.,, S. A. Porcelli,, G. S. Besra, and, L. Kremer. 2004. Mycobacterial lipoarabinomannan and related lipoglycans: from biogenesis to modulation of the immune response. Mol. Microbiol. 53: 391– 403.

32. Burguière, A.,, P. G. Hitchen,, L. G. Dover,, L. Kremer,, M. Ridell,, D. C. Alexander,, J. Liu,, H. R. Morris,, D. E. Minnikin,, A. Dell, and, G. S. Besra. 2005. LosA, a key glycosyltransferase involved in the biosynthesis of a novel family of glycosylated acyl-trehalose lipooligosaccharides from Mycobacterium marinum. J. Biol. Chem. 280: 42124– 42133.

33. Caparros, E.,, P. Munoz,, E. Sierra-Filardi,, D. Serrano-Gomez,, A. Puig-Kroger,, J. L. Rodriguez-Fernandez,, M. Mellado,, J. Sancho,, M. Zubiaur, and, A. L. Corbi. 2006. DC-SIGN ligation on dendritic cells results in ERK and PI3K activation and modulates cytokine production. Blood 107: 3950– 3958.

34. Chatterjee, D.,, C. M. Bozic,, M. McNeil, and, P. J. Brennan. 1991. Structural features of the arabinan component of the lipoarabinomannan of Mycobacterium tuberculosis. J. Biol. Chem. 266: 9652– 9660.

35. Chatterjee, D.,, S. W. Hunter,, M. McNeil, and, P. J. Brennan. 1992a. Lipoarabinomannan. Multiglycosylated form of the mycobacterial mannosylphosphatidylinositols. J. Biol. Chem. 267: 6228– 6233.

36. Chatterjee, D., and, K. H. Khoo. 1998. Mycobacterial lipoarabinomannan: an extraordinary lipoheteroglycan with profound physiological effects. Glycobiology 8: 113– 120.

37. Chatterjee, D.,, K. H. Khoo,, M. R. McNeil,, A. Dell,, H. R. Morris, and, P. J. Brennan. 1993. Structural definition of the non-reducing termini of mannose-capped LAM from Mycobacterium tuberculosis through selective enzymatic degradation and fast atom bombardment-mass spectrometry. Glycobiology 3: 497– 506.

38. Chatterjee, D.,, K. Lowell,, B. Rivoire,, M. R. McNeil, and, P. J. Brennan. 1992b. Lipoarabinomannan of Mycobacterium tuberculosis. Capping with mannosyl residues in some strains. J. Biol. Chem. 267: 6234– 6239.

39. Chatterjee, D.,, A. D. Roberts,, K. Lowell,, P. J. Brennan, and, I. M. Orme. 1992c. Structural basis of capacity of lipoarabinomannan to induce secretion of tumor necrosis factor. Infect. Immun. 60: 1249– 1253.

40. Cheng, T. Y.,, M. Relloso,, I. Van Rhijn,, D. C. Young,, G. S. Besra,, V. Briken,, D. M. Zajonc,, I. A. Wilson,, S. Porcelli, and, D. B. Moody. 2006. Role of lipid trimming and CD1 groove size in cellular antigen presentation. EMBO J. 25: 2989– 2999.

41. Chieppa, M.,, G. Bianchi,, A. Doni,, A. Del Prete,, M. Sironi,, G. Laskarin,, P. Monti,, L. Piemonti,, A. Biondi,, A. Mantovani,, M. Introna, and, P. Allavena. 2003. Cross-linking of the mannose receptor on monocyte-derived dendritic cells activates an anti-inflammatory immunosuppressive program. J. Immunol. 171: 4552– 4560.

42. Cole, S. T.,, R. Brosch,, J. Parkhill,, T. Garnier,, C. Churcher,, D. Harris,, S. V. Gordon,, K. Eiglmeier,, S. Gas,, C. E. Barry, 3rd,, F. Tekaia,, K. Badcock,, D. Basham,, D. Brown,, T. Chillingworth,, R. Connor,, R. Davies,, K. Devlin,, T. Feltwell,, S. Gentles,, N. Hamlin,, S. Holroyd,, T. Hornsby,, K. Jagels,, A. Krogh,, J. McLean,, S. Moule,, L. Murphy,, K. Oliver,, J. Osborne,, M. A. Quail,, M. A. Rajandream,, J. Rogers,, S. Rutter,, K. Seeger,, J. Skelton,, R. Squares,, S. Squares,, J. E. Sulston,, K. Taylor,, S. Whitehead, and, B. G. Barrell. 1998. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393: 537– 544.

43. Cook, D. N.,, D. S. Pisetsky, and, D. A. Schwartz. 2004. Toll-like receptors in the pathogenesis of human disease. Nat. Immunol. 5: 975– 979.

44. Daffe, M., and, P. Draper. 1998. The envelope layers of mycobacteria with reference to their pathogenicity. Adv. Microb. Physiol. 39: 131– 203.

45. Dascher, C. C.,, K. Hiromatsu,, X. Xiong,, C. Morehouse,, G. Watts,, G. Liu,, D. N. McMurray,, K. P. LeClair,, S. A. Porcelli, and, M. B. Brenner. 2003. Immunization with a mycobacterial lipid vaccine improves pulmonary pathology in the guinea pig model of tuberculosis. Int. Immunol. 15: 915– 925.

46. De la Salle, H.,, S. Mariotti,, C. Angenieux,, M. Gilleron,, L. F. Garcia-Alles,, D. Malm,, T. Berg,, S. Paoletti,, B. Maitre,, L. Mourey,, J. Salamero,, J. P. Cazenave,, D. Hanau,, L. Mori,, G. Puzo, and, G. De Libero. 2005. Assistance of microbial glycolipid antigen processing by CD1e. Science 310: 1321– 1324.

47. De Libero, G., and, L. Mori. 2006a. How T lymphocytes recognize lipid antigens. FEBS Lett. 580: 5580– 5587.

48. De Libero, G., and, L. Mori. 2006b. Mechanisms of lipid-antigen generation and presentation to T cells. Trends Immunol. 27: 485– 492.

49. De Libero, G., and, L. Mori. 2005. Recognition of lipid antigens by T cells. Nat. Rev. Immunol. 5: 485– 496.

50. Delmas, C.,, M. Gilleron,, T. Brando,, A. Vercellone,, M. Gheorghui,, M. Rivière, and, G. Puzo. 1997. Comparative structural study of the mannosylated-lipoarabinomannans from Mycobacterium bovis BCG vaccine strains: characterization and localization of succinates. Glycobiology 7: 811– 817.

51. Deretic, V.,, S. Singh,, S. Master,, J. Harris,, E. Roberts,, G. Kyei,, A. Davis,, S. de Haro,, J. Naylor,, H. H. Lee, and, I. Vergne. 2006. Mycobacterium tuberculosis inhibition of phagolysosome biogenesis and autophagy as a host defence mechanism. Cell. Microbiol. 8: 719– 727.

52. Dhariwal, K. R.,, A. Chander, and, T. A. Venkitasubramanian. 1977. Environmental effects on lipids of Mycobacterium phlei ATCC 354. Can. J. Microbiol. 23: 7– 19.

53. Dinadayala, P.,, D. Kaur,, S. Berg,, A. G. Amin,, V. D. Vissa,, D. Chatterjee,, P. J. Brennan, and, D. C. Crick. 2006. Genetic basis for the synthesis of the immunomodulatory mannose caps of lipoarabinomannan in Mycobacterium tuberculosis. J. Biol. Chem. 281: 20027– 20035.

54. Dyer, B. S.,, J. D. Jones,, G. D. Ainge,, M. Denis,, D. S. Larsen, and, G. F. Painter. 2007. Synthesis and structure of phosphatidylinositol dimannoside. J. Org. Chem. 72: 3282– 3288.

55. Ehlers, M. R., and, Daffe. Daffe. 1998. Interactions between Mycobacterium tuberculosis and host cells: are mycobacterial sugars the key? Trends Microbiol. 6: 328– 335.

56. Ehlers, S. 2003. Role of tumour necrosis factor (TNF) in host defence against tuberculosis: implications for immunotherapies targeting TNF. Ann. Rheum. Dis. 62(Suppl 2): ii37– ii42.

57. Engering, A.,, T. B. Geijtenbeek, and, Y. van Kooyk. 2002. Immune escape through C-type lectins on dendritic cells. Trends Immunol. 23: 480– 485.

58. Ernst, J. D. 1998. Macrophage receptors for Mycobacterium tuberculosis. Infect. Immun. 66: 1277– 1281.

59. Escuyer, V. E.,, M.-A. Lety,, J. B. Torrelles,, K.-H. Khoo,, J.-B. Tang,, C. D. Rithner,, C. Frehel,, M. R. McNeil,, P. J. Brennan, and, D. Chatterjee. 2001. The role of the embA and embB gene products in the biosynthesis of the terminal hexaarabinofiuranosyl motif of Mycobacterium smegmatis arabinogalactan. J. Biol. Chem. 276: 48854– 48862.

60. Feinberg, H.,, D. A. Mitchell,, K. Drickamer, and, W. I. Weis. 2001. Structural basis for selective recognition of oligosaccharides by DC-SIGN and DC-SIGNR. Science 294: 2163– 2166.

61. Feinberg, H.,, S. Park-Snyder,, A. R. Kolatkar,, C. T. Heise,, M. E. Taylor, and, W. I. Weis. 2000. Structure of a C-type carbohydrate recognition domain from the macrophage mannose receptor. J. Biol. Chem. 275: 21539– 21548.

62. Fenton, M. J.,, L. W. Riley, and, L. S. Schlesinger. 2005. Receptor-mediated recognition of Mycobacterium tuberculosis by host cells, p. 405–426. In S. T. Cole,, K. D. Eisenach,, D. N. McMurray and, W. R. Jacobs, Jr. (ed.), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC.

63. Ferguson, J. S.,, D. R. Voelker,, F. X. McCormack and, L. S. Schlesinger. 1999. Surfactant protein D binds to Mycobacterium tuberculosis bacilli and lipoarabinomannan via carbohydratelectin interactions resulting in reduced phagocytosis of the bacteria by macrophages. J. Immunol. 163: 312– 321.

64. Figdor, C. G.,, Y. van Kooyk, and, G. J. Adema. 2002. C-type lectin receptors on dendritic cells and Langerhans cells. Nat. Rev. Immunol. 2: 77– 84.

65. Fischer, K.,, E. Scotet,, M. Niemeyer,, H. Koebernick,, J. Zerrahn,, S. Maillet,, R. Hurwitz,, M. Kursar,, M. Bonneville,, S. H. Kaufmann, and, U. E. Schaible. 2004. Mycobacterial phosphatidylinositol mannoside is a natural antigen for CD1d-restricted T cells. Proc. Natl. Acad. Sci. USA 101: 10685– 10690.

66. Fratti, R. A.,, J. Chua,, I. Vergne, and, V. Deretic. 2003. Mycobacterium tuberculosis glycosylated phosphatidylinositol causes phagosome maturation arrest. Proc. Natl. Acad. Sci. USA 100: 5437– 5442.

67. Fukao, T., and, S. Koyasu. 2003. PI3K and negative regulation of TLR signaling. Trends Immunol. 24: 358– 363.

68. Gadola, S. D.,, N. R. Zaccai,, K. Harlos,, D. Shepherd,, J. C. Castro-Palomino,, G. Ritter,, R. R. Schmidt,, E. Y. Jones, and, V. Cerundolo. 2002. Structure of human CD1b with bound ligands at 2.3 A, a maze for alkyl chains. Nat. Immunol. 3: 721– 726.

69. Garton, N. J.,, M. Gilleron,, T. Brando,, H. H. Dan,, S. Giguere,, G. Puzo,, J. F. Prescott and, I. C. Sutcliffe. 2002. A novel lipoarabinomannan from the equine pathogen Rhodococcus equi: structure and effect on macrophage cytokine production. J. Biol. Chem. 277: 31722– 31733.

70. Gaylord, H., and, P. J. Brennan. 1987. Leprosy and the leprosy bacillus: recent developments in characterization of antigens and immunology of the disease. Annu. Rev. Microbiol. 41: 645– 675.

71. Gehring, A. J.,, K. M. Dobos,, J. T. Belisle,, C. V. Harding, and, W. H. Boom. 2004. Mycobacterium tuberculosis LprG (Rv1411c): a novel TLR-2 ligand that inhibits human macrophage class II MHC antigen processing. J. Immunol. 173: 2660– 2668.

72. Geijtenbeek, T. B.,, S. J. Van Vliet,, E. A. Koppel,, M. Sanchez-Hernandez,, C. M. Vandenbroucke-Grauls,, B. Appelmelk, and, Y. Van Kooyk. 2003. Mycobacteria target DC-SIGN to suppress dendritic cell function. J. Exp. Med. 197: 7– 17.

73. Geremia, R. A.,, E. A. Petroni,, L. Ielpi, and, B. Henrissat. 1996. Towards a classification of glycosyltransferases based on amino acid sequence similarities: prokaryotic alpha-mannosyltransferases. Biochem. J. 318: 133– 138.

74. Giabbai, B.,, S. Sidobre,, M. D. Crispin,, Y. Sanchez-Ruiz,, A. Bachi,, M. Kronenberg,, I. A. Wilson, and, M. Degano. 2005. Crystal structure of mouse CD1d bound to the self ligand phosphatidylcholine: a molecular basis for NKT cell activation. J. Immunol. 175: 977– 984.

75. Gibson, K. J.,, M. Gilleron,, P. Constant,, T. Brando,, G. Puzo,, G. S. Besra, and, J. Nigou. 2004. Tsukamurella paurometabola lipoglycan: a new lipoarabinomannan variant with proinflammatory activity. J. Biol. Chem. 279: 22973– 22982.

76. Gibson, K. J.,, M. Gilleron,, P. Constant,, G. Puzo,, J. Nigou, and, G. S. Besra. 2003a. Structural and functional features of Rhodococcus ruber lipoarabinomannan. Microbiology 149: 1437– 1445.

77. Gibson, K. J.,, M. Gilleron,, P. Constant,, G. Puzo,, J. Nigou, and, G. S. Besra. 2003b. Identification of a novel mannose-capped lipoarabinomannan from Amycolatopsis sulphurea. Biochem. J. 372: 821– 829.

78. Gibson, K. J.,, M. Gilleron,, P. Constant,, B. Sichi,, G. Puzo,, G. S. Besra, and, J. Nigou. 2005. A lipomannan variant with strong TLR-2-dependent proinflammatory activity in Saccharothrix aerocolonigenes. J. Biol. Chem. 280: 28347– 28356.

79. Gibson, K. J. C.,, L. Eggeling,, W. N. Maughan,, K. Krumbach,, S. S. Gurcha,, J. Nigou,, G. Puzo,, H. Sahm, and, G. S. Besra. 2003c. Disruption of Cg-Ppm1, a polyprenyl monophosphomannose synthase, and the generation of lipoglycan-less mutants in Corynebacterium glutamicum. J. Biol. Chem. 278: 40842– 40850.

80. Gilleron, M.,, L. Bala,, T. Brando,, A. Vercellone, and, G. Puzo. 2000. Mycobacterium tuberculosis H37Rv parietal and cellular lipoarabinomannans. Characterization of the acyl- and glyco-forms. J. Biol. Chem. 275: 677– 684.

81. Gilleron, M.,, N. J. Garton,, J. Nigou,, T. Brando,, G. Puzo, and, I. C. Sutcliffe. 2005. Characterization of a truncated lipoarabinomannan from the actinomycete Turicella otitidis. J. Bacteriol. 187: 854– 861.

82. Gilleron, M.,, N. Himoudi,, O. Adam,, P. Constant,, A. Venisse,, M. Riviere, and, G. Puzo. 1997. Mycobacterium smegmatis phosphoinositols-glyceroarabinomannans. Structure and localization of alkali-labile and alkali-stable phosphoinositides. J. Biol. Chem. 272: 117– 124.

83. Gilleron, M.,, J. Nigou,, B. Cahuzac, and, G. Puzo. 1999. Structural study of the lipomannans from Mycobacterium bovis BCG: characterisation of multiacylated forms of the phosphatidyl- myo-inositol anchor. J. Mol. Biol. 285: 2147– 2160.

84. Gilleron, M.,, J. Nigou,, D. Nicolle,, V. Quesniaux, and, G. Puzo. 2006. The acylation state of mycobacterial lipomannans modulates innate immunity response through toll-like receptor 2. Chem. Biol. 13: 39– 47.

85. Gilleron, M.,, V. F. Quesniaux, and, G. Puzo. 2003. Acylation state of the phosphatidylinositol hexamannosides from Mycobacterium bovis bacillus Calmette Guerin and mycobacterium tuberculosis H37Rv and its implication in Toll-like receptor response. J. Biol. Chem. 278: 29880– 29889.

86. Gilleron, M.,, M. Riviere, and, G. Puzo. 2001a. Role of glycans in the bacterial infections: interaction host-mycobacteria, p. 113–140. In M. Aubery (ed.), Glycans in Cell Interaction and Recognition: Therapeutic Aspects. Harwood Academic, Amsterdam, The Netherlands.

87. Gilleron, M.,, C. Ronet,, M. Mempel,, B. Monsarrat,, G. Gachelin and, G. Puzo. 2001b. Acylation state of the phosphatidylinositol mannosides from Mycobacterium bovis bacillus Calmette Guerin and ability to induce granuloma and recruit natural killer T cells. J. Biol. Chem. 276: 34896– 34904.

88. Gilleron, M.,, S. Stenger,, Z. Mazorra,, F. Wittke,, S. Mariotti,, G. Bohmer,, J. Prandi,, L. Mori,, G. Puzo, and, G. De Libero. 2004. Diacylated sulfoglycolipids are novel mycobacterial antigens stimulating CD1-restricted T Cells during infection with Mycobacterium tuberculosis. J. Exp. Med. 199: 649– 659.

89. Goren, M. B. 1984. Biosynthesis and structures of phospholipids and sulfatides, p. 379–415. In G. P. Kubica and, L. G. Wayne (ed.), The Mycobacteria—a Source Book, vol. 1. Marcel Dekker, Inc., New York, NY.

90. Gu, X.,, M. Chen,, Q. Wang,, M. Zhang,, B. Wang, and, H. Wang. 2005. Expression and purification of a functionally active recombinant GDP-mannosyltransferase (PimA) from Mycobacterium tuberculosis H37Rv. Protein Expr. Purif. 42: 47– 53.

91. Guerardel, Y.,, E. Maes,, V. Briken,, F. Chirat,, Y. Leroy,, C. Locht,, G. Strecker, and, L. Kremer. 2003. Lipomannan and lipoarabinomannan from a clinical isolate of Mycobacterium kansasii: novel structural features and apoptosis-inducing properties. J. Biol. Chem. 278: 36637– 36651.

92. Guerardel, Y.,, E. Maes,, E. Elass,, Y. Leroy,, P. Timmerman,, G. S. Besra,, C. Locht,, G. Strecker, and, L. Kremer. 2002. Structural study of lipomannan and lipoarabinomannan from Mycobacterium chelonae. Presence of unusual components with alpha 1,3-mannopyranose side chains. J. Biol. Chem. 277: 30635– 30648.

93. Gurcha, S. S.,, A. R. Baulard,, L. Kremer,, C. Locht,, D. B. Moody,, W. Muhlecker,, C. E. Costellos,, D. C. Crick,, P. J. Brennan, and, G. S. Besra. 2002. Ppm1, a novel polyprenol monophosphomannose synthase from Mycobacterium tuberculosis. Biochem. J. 365: 441– 450.

94. Haites, R. E.,, Y. S. Morita,, M. J. McConville, and, H. BillmanJacobe. 2005. Function of phosphatidylinositol in mycobacteria. J. Biol. Chem. 280: 10981– 10987.

95. Herrmann, J. L.,, L. Tailleux,, J. Nigou,, B. Giquel,, G. Puzo,, P. H. Lagrange, and, O. Neyrolles. 2006. The role of human dendritic cells in tuberculosis: protector or non-protector? Rev. Mal. Respir. 23: 21– 28.

96. Hill, D. L., and, C. E. Ballou. 1966. Biosynthesis of mannophospholipids by Mycobacterium phlei. J. Biol. Chem. 241: 895– 902.

97. Hong, X., and, A. J. Hopfinger. 2004. Construction, molecular modeling, and simulation of Mycobacterium tuberculosis cell walls. Biomacromolecules 5: 1052– 1065.

98. Hoppe, H. C.,, B. J. de Wet,, C. Cywes,, M. Daffe, and, M. R. Ehlers. 1997. Identification of phosphatidylinositol mannoside as a mycobacterial adhesin mediating both direct and opsonic binding to nonphagocytic mammalian cells. Infect. Immun. 65: 3896– 3905.

99. Huang, H.,, M. S. Scherman,, W. D’Haeze,, D. Vereecke,, M. Holsters,, D. C. Crick, and, M. R. McNeil. 2005. Identification and active expression of the Mycobacterium tuberculosis gene encoding 5-phospho-α-D-ribose-1-diphosphate: decaprenyl-phosphate 5-phosphoribosyltransferase, the first enzyme committed to decaprenylphosphoryl-D-arabinose synthesis. J. Biol. Chem. 280: 24539– 24543.

100. Hunger, R. E.,, P. A. Sieling,, M. T. Ochoa,, M. Sugaya,, A. E. Burdick,, T. H. Rea,, P. J. Brennan,, J. T. Belisle,, A. Blauvelt,, S. A. Porcelli, and, R. L. Modlin. 2004. Langerhans cells utilize CD1a and langerin to efficiently present nonpeptide antigens to T cells. J. Clin. Investig. 113: 701– 708.

101. Hunter, S. W., and, P. J. Brennan. 1990. Evidence for the presence of a phosphatidylinositol anchor on the lipoarabinomannan and lipomannan of Mycobacterium tuberculosis. J. Biol. Chem. 265: 9272– 9279.

102. Hunter, S. W.,, H. Gaylord, and, P. J. Brennan. 1986. Structure and antigenicity of the phosphorylated lipopolysaccharide antigens from the leprosy and tubercle bacilli. J. Biol. Chem. 261: 12345– 12351.

103. Jackson, M.,, D. C. Crick, and, P. J. Brennan. 2000. Phosphatidylinositol is an essential phospholipid of mycobacteria. J. Biol. Chem. 275: 30092– 30099.

104. Jayaprakash, K. N.,, J. Lu, and, B. Fraser-Reid. 2005. Synthesis of a lipomannan component of the cell-wall complex of Mycobacterium tuberculosis is based on Paulsen’s concept of donor/acceptor “match.” Angew. Chem. Int. Ed. Engl. 44: 5894– 5898.

105. Joe, M.,, D. Sun,, H. Taha,, G. C. Completo,, J. E. Croudace,, D. A. Lammas,, G. S. Besra, and, T. L. Lowary. 2006. The 5-deoxy-5-methylthio-xylofuranose residue in mycobacterial lipoarabinomannan. Absolute stereochemistry, linkage position, conformation, and immunomodulatory activity. J. Am. Chem. Soc. 128: 5059– 5072.

106. Jones, B. W.,, T. K. Means,, K. A. Heldwein,, M. A. Keen,, P. J. Hill,, J. T. Belisle, and, M. J. Fenton. 2001. Different Toll-like receptor agonists induce distinct macrophage responses. J. Leukoc. Biol. 69: 1036– 1044.

107. Jung, S. B.,, C. S. Yang,, J. S. Lee,, A. R. Shin,, S. S. Jung,, J. W. Son,, C. V. Harding,, H. J. Kim,, J. K. Park,, T. H. Paik,, C. H. Song, and, E. K. Jo. 2006. The mycobacterial 38-kilodalton glycolipoprotein antigen activates the mitogen-activated protein kinase pathway and release of proinflammatory cytokines through Toll-like receptors 2 and 4 in human monocytes. Infect. Immun. 74: 2686– 2696.

108. Kang, P. B.,, A. K. Azad,, J. B. Torrelles,, T. M. Kaufman,, A. Beharka,, E. Tibesar,, L. E. DesJardin, and, L. S. Schlesinger. 2005. The human macrophage mannose receptor directs Mycobacterium tuberculosis lipoarabinomannan-mediated phagosome biogenesis. J. Exp. Med. 202: 987– 999.

109. Kang, S. J., and, Cresswell. Cresswell. 2004. Saposins facilitate CD1d-restricted presentation of an exogenous lipid antigen to T cells. Nat. Immunol. 5: 175– 181.

110. Kaufmann, S. H. 2001. How can immunology contribute to the control of tuberculosis? Nat. Rev. Immunol. 1: 20– 30.

111. Kaufmann, S. H. 2005. Recent findings in immunology give tuberculosis vaccines a new boost. Trends Immunol. 26: 660– 667.

112. Kaur, D.,, S. Berg,, P. Dinadayala,, B. Gicquel,, D. Chatterjee,, M. R. McNeil,, V. D. Vissa,, D. C. Crick,, M. Jackson, and, P. J. Brennan. 2006. Biosynthesis of mycobacterial lipoarabinomannan: role of a branching mannosyltransferase. Proc. Natl Acad. Sci. USA 103: 13664– 13669.

113. Khoo, K. H.,, A. Dell,, H. R. Morris,, P. J. Brennan. and, D. Chatterjee. 1995a. Inositol phosphate capping of the nonreducing termini of lipoarabinomannan from rapidly growing strains of Mycobacterium. J. Biol. Chem. 270: 12380– 12389.

114. Khoo, K.-H.,, A. Dell,, H. R. Morris,, P. J. Brennan, and, D. Chatterjee. 1995b. Structural definition of acylated phosphatidylinositol mannosides from Mycobacterium tuberculosis: definition of a common anchor for lipomannan and lipoarabinomannan. Glycobiology 5: 117– 127.

115. Khoo, K. H.,, E. Douglas,, P. Azadi,, J. M. Inamine,, G. S. Besra,, K. Mikusova,, P. J. Brennan, and, D. Chatterjee. 1996. Truncated structural variants of lipoarabinomannan in ethambutol drug-resistant strains of Mycobacterium smegmatis. Inhibition of arabinan biosynthesis by ethambutol. J. Biol. Chem. 271: 28682– 28690.

116. Khoo, K. H.,, J. B. Tang, and, D. Chatterjee. 2001. Variation in mannose-capped terminal arabinan motifs of lipoarabinomannans from clinical isolates of Mycobacterium tuberculosis and Mycobacterium avium complex. J. Biol. Chem. 276: 3863– 3871.

117. Knutson, K. L.,, Z. Hmama,, P. Herrera-Velit,, R. Rochford, and, N. E. Reiner. 1998. Lipoarabinomannan of Mycobacterium tuberculosis promotes protein tyrosine dephosphorylation and inhibition of mitogen-activated protein kinase in human mononuclear phagocytes. Role of the Src homology 2 containing tyrosine phosphatase 1. J. Biol. Chem. 273: 645– 652.

118. Koch, M.,, V. S. Stronge,, D. Shepherd,, S. D. Gadola,, B. Mathew,, G. Ritter,, A. R. Fersht,, G. S. Besra,, R. R. Schmidt,, E. Y. Jones, and, V. Cerundolo. 2005. The crystal structure of human CD1d with and without alpha-galactosylceramide. Nat. Immunol. 6: 819– 826.

119. Koppel, E. A.,, I. S. Ludwig,, M. S. Hernandez,, T. L. Lowary,, R. R. Gadikota,, A. B. Tuzikov,, C. M. Vandenbroucke-Grauls,, Y. van Kooyk,, B. J. Appelmelk, and, T. B. Geijtenbeek. 2004. Identification of the mycobacterial carbohydrate structure that binds the C-type lectins DC-SIGN, L-SIGN and SIGNR1. Immunobiology 209: 117– 127.

120. Kordulakova, J.,, M. Gilleron,, K. Mikusova,, G. Puzo,, P. J. Brennan,, B. Gicquel and, M. Jackson. 2002. Definition of the first mannosylation step in phosphatidylinositol synthesis: PimA is essential for growth of mycobacteria. J. Biol. Chem. 277: 31335– 31344.

121. Kordulakova, J.,, M. Gilleron,, G. Puzo,, P. J. Brennan,, B. Gicquel,, K. Mikusova, and, M. Jackson. 2003. Identification of the required acyltransferase step in the biosynthesis of the phosphatidylinositol mannosides of Mycobacterium species. J. Biol. Chem. 278: 36285– 36295.

122. Koul, A.,, T. Herget,, B. Klebl, and, A. Ullrich. 2004. Interplay between mycobacteria and host signalling pathways. Nat. Rev. Microbiol. 2: 189– 202.

123. Kovacevic, S.,, D. Anderson,, Y. S. Morita,, J. H. Patterson,, R. E. Haites,, B. N. I. McMillan,, R. Coppel,, M. J. McConville, and, H. Billman-Jacobe. 2006. Identification of a novel protein with a role in lipoarabinomannan biosynthesis in mycobacteria. J. Biol. Chem. 281: 9011– 9017.

124. Kremer, L.,, S. S. Gurcha,, P. Bifani,, P. G. Hitchen,, A. Baulard,, H. R. Morris,, A. Dell,, P. J. Brennan, and, G. S. Besra. 2002. Characterization of a putative α-mannosyltransferase involved in phosphatidylinositol trimannoside biosynthesis in Mycobacterium tuberculosis. Biochem. J. 363: 437– 447.

125. Krishnegowda, G.,, A. M. Hajjar,, J. Zhu,, E. J. Douglass,, S. Uematsu,, S. Akira,, A. S. Woods, and, D. C. Gowda. 2005. Induction of proinflammatory responses in macrophages by the glycosylphosphatidylinositols of Plasmodium falciparum: cell signaling receptors, glycosylphosphatidylinositol (GPI) structural requirement, and regulation of GPI activity. J. Biol. Chem. 280: 8606– 8616.

126. Krutzik, S. R.,, B. Tan,, H. Li,, M. T. Ochoa,, P. T. Liu,, S. E. Sharfstein,, T. G. Graeber,, P. A. Sieling,, Y. J. Liu,, T. H. Rea,, B. R. Bloom, and, R. L. Modlin. 2005. TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cells. Nat. Med. 11: 653– 660.

127. Lawton, A. P., and, M. Kronenberg. 2004. The Third Way: Progress on pathways of antigen processing and presentation by CD1. Immunol. Cell. Biol. 82: 295– 306.

128. Lee, Y. C., and, C. E. Ballou. 1965. Complete structures of the glycophospholipids of mycobacteria. Biochemistry 4: 1395– 1404.

129. Liew, F. Y.,, D. Xu,, E. K. Brint, and, L. A. O’Neill. 2005. Negative regulation of toll-like receptor-mediated immune responses. Nat. Rev. Immunol. 5: 446– 458.

130. Liu, J., and, Mushegian. Mushegian. 2003. Three monophyletic superfamilies account for the majority of the known glycosyltransferases. Protein Sci. 12: 1418– 1431.

131. Liu, P. T.,, S. Stenger,, H. Li,, L. Wenzel,, B. H. Tan,, S. R. Krutzik,, M. T. Ochoa,, J. Schauber,, K. Wu,, C. Meinken,, D. L. Kamen,, M. Wagner,, R. Bals,, A. Steinmeyer,, U. Zugel,, R. L. Gallo,, D. Eisenberg,, M. Hewison,, B. W. Hollis,, J. S. Adams,, B. R. Bloom, and, R. L. Modlin. 2006a. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311: 1770– 1773.

132. Liu, X.,, B. L. Stocker, and, P. H. Seeberger. 2006b. Total synthesis of phosphatidylinositol mannosides of Mycobacterium tuberculosis. J. Am. Chem. Soc. 128: 3638– 3648.

133. Lucas, M.,, X. Zhang,, V. Prasanna, and, D. M. Mosser. 2005. ERK activation following macrophage FcgammaR ligation leads to chromatin modifications at the IL-10 locus. J. Immunol. 175: 469– 477.

134. Ludwiczak, P.,, M. Gilleron,, Y. Bordat,, C. Martin,, B. Gicquel, and, G. Puzo. 2002. Mycobacterium tuberculosis phoP mutant: lipoarabinomannan molecular structure. Microbiology 148: 3029– 3037.

135. Ma, Y.,, R. J. Stern,, M. S. Scherman,, V. D. Vissa,, W. Yan,, V. C. Jones,, F. Zhang,, S. G. Franzblau,, W. H. Lewis, and, M. R. McNeil. 2001. Drug targeting Mycobacterium tuberculosis cell wall synthesis: genetics of dTDP-rhamnose synthetic enzymes and development of a microtiter plate-based screen for inhibitors of conversion of dTDP-glucose to dTDP-rhamnose. Antimicrob. Agents Chemother. 45: 1407– 1416.

136. Maeda, N.,, J. Nigou,, J. L. Herrmann,, M. Jackson,, A. Amara,, P. H. Lagrange,, G. Puzo,, B. Gicquel, and, O. Neyrolles. 2002. The cell surface receptor DC-SIGN discriminates between Mycobacterium species through selective recognition of the mannose caps on lipoarabinomannan. J. Biol. Chem. 278: 5513– 5516.

137. Marland, Z.,, T. Beddoe,, L. Zaker-Tabrizi,, R. L. Coppel,, P. K. Crellin, and, J. Rossjohn. 2005. Expression, purification, crystallization and preliminary X-ray diffraction analysis of an essential lipoprotein implicated in cell-wall biosynthesis in mycobacteria. Acta Crystallogr. Sect. F 61: 1081– 1083.

138. Marland, Z.,, T. Beddoe,, L. Zaker-Tabrizi,, I. S. Lucet,, R. Brammananth,, J. C. Whisstock,, M. C. J. Wilce,, R. L. Coppel,, P. K. Crellin, and, J. Rossjohn. 2006. Hijacking of a substrate-binding protein scaffold for use in mycobacterial cell wall biosynthesis. J. Mol. Biol. 359: 983– 997.

139. Martin, C. 2005. The dream of a vaccine against tuberculosis; new vaccines improving or replacing BCG? Eur. Respir. J. 26: 162– 167.

140. McCarthy, T. R.,, J. B. Torrelles,, A. S. MacFarlane,, M. Katawczik,, B. Kutzbach,, L. E. DesJardin,, S. Clegg,, J. B. Goldberg, and, L. S. Schlesinger. 2005. Overexpression of Mycobacterium tuberculosis manB, a phosphomannomutase that increases phosphatidylinositol mannoside biosynthesis in Mycobacterium smegmatis and mycobacterial association with human macrophages. Mol. Microbiol. 58: 774– 790.

141. McNeil, M. R., and, P. J. Brennan. 1991. Structure, function and biogenesis of the cell envelope of mycobacteria in relation to bacterial physiology, pathogenesis and drug resistance; some thoughts and possibilities arising from recent structural information. Res. Microbiol. 142: 451– 463.

142. Means, T. K.,, E. Lien,, A. Yoshimura,, S. Wang,, D. T. Golenbock, and, M. J. Fenton. 1999. The CD14 ligands lipoarabinomannan and lipopolysaccharide differ in their requirement for Toll-like receptors. J. Immunol. 163: 6748– 6755.

143. Mikusova, K.,, H. Huang,, T. Yagi,, M. Holsters,, D. Vereecke,, W. D’Haeze,, M. S. Scherman,, P. J. Brennan,, M. R. McNeil, and, D. C. Crick. 2005. Decaprenylphosphoryl arabinofuranose, the donor of the D-arabinofuranosyl residues of mycobacterial arabinan, is formed via a two-step epimerization of decaprenylphosphoryl ribose. J. Bacteriol. 187: 8020– 8025.

144. Minnikin, D. E. 1982. Lipids: complex lipids, their chemistry, biosynthesis and role, p. 95–184. In C. Ratledge and, J. Standford (ed.), The Biology of the Mycobacteria, vol. 1. Academic Press Ltd., London, United Kingdom.

145. Molle, V.,, L. Kremer,, C. Girard-Blanc,, G. S. Besra,, A. J. Cozzone, and, J. F. Prost. 2003. An FHA phosphoprotein recognition domain mediates protein EmbR phosphorylation by PknH, a Ser/Thr protein kinase from Mycobacterium tuberculosis. Biochemistry 42: 15300– 15309.

146. Moody, D. B. 2006. TLR gateways to CD1 function. Nat. Immunol. 7: 811– 817.

147. Moody, D. B.,, V. Briken,, T. Y. Cheng,, C. Roura-Mir,, M. R. Guy,, D. H. Geho,, M. L. Tykocinski,, G. S. Besra, and, S. A. Porcelli. 2002. Lipid length controls antigen entry into endosomal and nonendosomal pathways for CD1b presentation. Nat. Immunol. 3: 435– 442.

148. Moody, D. B., and, S. A. Porcelli. 2003. Intracellular pathways of CD1 antigen presentation. Nat. Rev. Immunol. 3: 11– 22.

149. Moody, D. B.,, B. B. Reinhold,, V. N. Reinhold,, G. S. Besra, and, S. A. Porcelli. 1999. Uptake and processing of glycosylated mycolates for presentation to CD1b-restricted T cells. Immunol. Lett. 65: 85– 91.

150. Moody, D. B.,, T. Ulrichs,, W. Muhlecker,, D. C. Young,, S. S. Gurcha,, E. Grant,, J. P. Rosat,, M. B. Brenner,, C. E. Costello,, G. S. Besra, and, S. A. Porcelli. 2000. CD1c-mediated T-cell recognition of isoprenoid glycolipids in Mycobacterium tuberculosis infection. Nature 404: 884– 888.

151. Moody, D. B.,, D. M. Zajonc, and, I. A. Wilson. 2005. Anatomy of CD1-lipid antigen complexes. Nat. Rev. Immunol. 5: 387– 399.

152. Morita, Y. S.,, J. H. Patterson,, H. Billman-Jacobe, and, M. J. McConville. 2004. Biosynthesis of mycobacterial phosphatidylinositol mannosides. Biochem. J. 378: 589– 597.

153. Morita, Y. S.,, C. B. C. Sena,, R. F. Waller,, K. Kurokawa,, M. F. Sernee,, F. Nakatani,, R. E. Haites,, H. Billman-Jacobe,, M. J. McConville,, Y. Maeda, and, T. Kinoshita. 2006. PimE is a polyprenol-phosphate-mannose-dependent mannosyltransferase that transfers the fifth mannose of phosphatidylinositol mannoside in mycobacteria. J. Biol. Chem. 281: 25143– 25155.

154. Morita, Y. S.,, R. Velasquez,, E. Taig,, R. F. Waller,, J. H. Patterson,, D. Tull,, S. J. Williams,, H. Billman-Jacobe, and, M. J. McConville. 2005. Compartmentalization of lipid biosynthesis in mycobacteria. J. Biol. Chem. 280: 21645– 21652.

155. Morona, R.,, L. Van Den Bosch, and, C. Daniels. 2000. Evaluation of Wzz/MPA1/MPA2 proteins based on the presence of coiled coil regions. Microbiology 146: 1– 4.

156. Movahedzadeh, F.,, D. A. Smith,, R. A. Norman,, P. Dinadayala,, J. Murray-Rust,, D. G. Russell,, S. L. Kendall,, S. C. G. Rison,, M. S. B. McAlister,, G. J. Bancroft,, N. Q. McDonald,, M. Daffé,, Y. Av-Gay, and, N. G. Stocker. 2004. The Mycobacterium tuberculosis ino1 gene is essential for growth and virulence. Mol. Microbiol. 51: 1003– 1014.

157. Mukherjee, S.,, T. T. Soe, and, F. R. Maxfield. 1999. Endocytic sorting of lipid analogues differing solely in the chemistry of their hydrophobic tails. J. Cell. Biol. 144: 1271– 1284.

158. Neyrolles, O.,, B. Gicquel, and, L. Quintana-Murci. 2006. Towards a crucial role for DC-SIGN in tuberculosis and beyond. Trends Microbiol. 14: 383– 387.

159. Nigou, J., and, G. S. Besra. 2002a. Characterization and regulation of inositol monophosphatase activity in Mycobacterium smegmatis. Biochem. J. 361: 385– 390.

160. Nigou, J., and, G. S. Besra. 2002b. Cytidine diphosphate-diacylglycerol synthesis in Mycobacterium smegmatis. Biochem. J. 367: 157– 162.

161. Nigou, J.,, L. G. Dover, and, G. S. Besra. 2002a. Purification and biochemical characterization of Mycobacterium tuberculosis SuhB, an inositol monophosphatase involved in inositol biosynthesis. Biochemistry 41: 4392– 4398.

162. Nigou, J.,, M. Gilleron,, T. Brando,, A. Vercellone, and, G. Puzo. 1999a. Structural definition of arabinomannans from Mycobacterium bovis BCG. Glycoconj. J. 16: 257– 264.

163. Nigou, J.,, M. Gilleron, and, G. Puzo. 1999b. Lipoarabinomannans: characterization of the multiacylated forms of the phosphatidyl-myo-inositol anchor by NMR spectroscopy. Biochem. J. 337: 453– 460.

164. Nigou, J.,, M. Gilleron, and, G. Puzo. 2003. Lipoarabinomannans: from structure to biosynthesis. Biochimie 85: 153– 166.

165. Nigou, J.,, M. Gilleron,, M. Rojas,, L. F. Garcia,, M. Thurnher, and, G. Puzo. 2002b. Mycobacterial lipoarabinomannans: modulators of dendritic cell function and the apoptotic response. Microbes Infect. 4: 945– 953.

166. Nigou, J.,, A. Vercellone, and, G. Puzo. 2000. New structural insights into the molecular deciphering of mycobacterial lipoglycan binding to C-type lectins: lipoarabinomannan glycoform characterization and quantification by capillary electrophoresis at the subnanomole level. J. Mol. Biol. 299: 1353– 1362.

167. Nigou, J.,, C. Zelle-Rieser,, M. Gilleron,, M. Thurnher, and, G. Puzo. 2001. Mannosylated lipoarabinomannans inhibit IL-12 production by human dendritic cells: evidence for a negative signal delivered through the mannose receptor. J. Immunol. 166: 7477– 7485.

168. Ning, B., and, A. D. Elbein. 1999. Purification and properties of mycobacterial GDP-mannose pyrophosphorylase. Arch. Biochem. Biophys. 362: 339– 345.

169. Norman, R. A.,, M. S. McAlister,, J. Murray-Rust,, F. Movahedzadeh,, N. G. Stocker, and, N. Q. McDonald. 2002. Crystal structure of inositol 1-phosphate synthase from Mycobacterium tuberculosis, a key enzyme in phosphatidylinositol synthesis. Structure 10: 393– 402.

170. Noss, E. H.,, R. K. Pai,, T. J. Sellati,, J. D. Radolf,, J. Belisle,, D. T. Golenbock,, W. H. Boom, and, C. V. Harding. 2001. Toll-like receptor 2-dependent inhibition of macrophage class II MHC expression and antigen processing by 19-kDa lipoprotein of Mycobacterium tuberculosis. J. Immunol. 167: 910– 918.

171. Oriol, R.,, I. Martinez-Duncker,, I. Chantret,, R. Mollicone, and, P. Codogno. 2002. Common origin and evolution of glycosyltransferases using Dol-P-monosaccharides as donor substrate. Mol. Biol. Evol. 19: 1451– 1463.

172. Orme, I. M. 2005. The use of animal models to guide rational vaccine design. Microbes Infect. 7: 905– 910.

173. Ortalo-Magne, A.,, A. B. Andersen, and, M. Daffe. 1996a. The outermost capsular arabinomannans and other mannoconjugates of virulent and avirulent tubercle bacilli. Microbiology 142: 927– 935.

174. Ortalo-Magne, A.,, M. A. Dupont,, A. Lemassu,, A. B. Andersen,, P. Gounon, and, M. Daffe. 1995. Molecular composition of the outermost capsular material of the tubercle bacillus. Microbiology 141: 1609– 1620.

175. Ortalo-Magne, A.,, A. Lemassu,, M. A. Laneelle,, F. Bardou,, G. Silve,, P. Gounon,, G. Marchal, and, M. Daffe. 1996b. Identification of the surface-exposed lipids on the cell envelopes of Mycobacterium tuberculosis and other mycobacterial species. J. Bacteriol. 178: 456– 461.

176. Owens, R. M.,, F. F. Hsu,, B. C. VanderVen,, G. E. Purdy,, E. Hesteande,, P. Giannakas,, J. C. Sacchettini,, J. D. McKinney,, P. J. Hill,, J. T. Belisle,, B. A. Butcher,, K. Pethe, and, D. G. Russell. 2006. M. tuberculosis Rv2252 encodes a diacylglycerol kinase involved in the biosynthesis of phosphatidylinositol mannosides (PIMs). Mol. Microbiol. 60: 1152– 1163.

177. Parish, T.,, J. Liu,, H. Nikaido, and, N. G. Stoker. 1997. A Mycobacterium smegmatis mutant with a defective inositol monophosphate phosphatase gene homolog has altered cell envelope permeability. J. Bacteriol. 179: 7827– 7833.

178. Pathak, S. K.,, S. Basu,, A. Bhattacharyya,, S. Pathak,, M. Kundu, and, J. Basu. 2005. Mycobacterium tuberculosis lipoarabinomannan-mediated IRAK-M induction negatively regulates Toll-like receptor-dependent interleukin-12 p40 production in macrophages. J. Biol. Chem. 280: 42794– 42800.

179. Patterson, J. H.,, R. F. Waller,, D. Jeevarajah,, H. Billman-Jacobe, and, M. J. McConville. 2003. Mannose metabolism is required for mycobacterial growth. Biochem. J. 372: 77– 86.

180. Paul, T. R., and, T. J. Beveridge. 1994. Preservation of surface lipids and determination of ultrastructure of Mycobacterium kansasii by freeze-substitution. Infect. Immun. 62: 1542– 1550.

181. Paul, T. R., and, T. J. Beveridge. 1992. Reevaluation of envelope profiles and cytoplasmic ultrastructure of mycobacteria processed by conventional embedding and freeze-substitution protocols. J. Bacteriol. 174: 6508– 6517.

182. Pecora, N. D.,, A. J. Gehring,, D. H. Canaday,, W. H. Boom, and, C. V. Harding. 2006. Mycobacterium tuberculosis LprA is a lipoprotein agonist of TLR2 that regulates innate immunity and APC function. J. Immunol. 177: 422– 429.

183. Penumarti, N., and, G. K. Khuller. 1983. Subcellular distribution of mannophosphoinositides in Mycobacterium smegmatis during growth. Experientia 39: 882– 884.

184. Petit, J. F., and, E. Lederer. 1984. The structure of the mycobacterial cell wall, p. 301–314. In G. P. Kubica and, L. G. Wayne (ed.), The Mycobacteria—a Source Book, vol. 15. Marcel Dekker, Inc., New York, NY.

185. Pitarque, S.,, J. L. Herrmann,, J. L. Duteyrat,, M. Jackson,, G. R. Stewart,, F. Lecointe,, B. Payre,, O. Schwartz,, D. B. Young,, G. Marchal,, P. H. Lagrange,, G. Puzo,, B. Gicquel,, J. Nigou, and, O. Neyrolles. 2005. Deciphering the molecular bases of Mycobacterium tuberculosis binding to the lectin DC-SIGN reveals an underestimated complexity. Biochem. J. 392: 615– 624.

186. Polotsky, V. Y.,, J. T. Belisle,, K. Mikusova,, R. A. Ezekowitz, and, K. A. Joiner. 1997. Interaction of human mannose-binding protein with Mycobacterium avium. J. Infect. Dis. 175: 1159– 1168.

187. Porcelli, S. A. 1995. The CD1 family: a third lineage of antigen-presenting molecules. Adv. Immunol. 59: 1– 98.

188. Prigozy, T. I.,, O. Naidenko,, P. Qasba,, D. Elewaut,, L. Brossay,, A. Khurana,, T. Natori,, Y. Koezuka,, A. Kulkarni, and, M. Kronenberg. 2001. Glycolipid antigen processing for presentation by CD1d molecules. Science 291: 664– 667.

189. Prigozy, T. I.,, P. A. Sieling,, D. Clemens,, P. L. Stewart,, S. M. Behar,, S. A. Porcelli,, M. B. Brenner,, R. L. Modlin, and, M. Kronenberg. 1997. The mannose receptor delivers lipoglycan antigens to endosomes for presentation to T cells by CD1b molecules. Immunity 6: 187– 197.

190. Prinzis, S.,, D. Chatterjee, and, P. J. Brennan. 1993. Structure and antigenicity of lipoarabinomannan from Mycobacterium bovis BCG. J. Gen. Microbiol. 139: 2649– 2658.

191. Puig-Kroger, A.,, D. Serrano-Gomez,, E. Caparros,, A. DominguezSoto,, M. Relloso,, M. Colmenares,, L. Martinez-Munoz,, N. Longo,, N. Sanchez-Sanchez,, M. Rincon,, L. Rivas,, P. Sanchez-Mateos,, E. Fernandez-Ruiz, and, A. L. Corbi. 2004. Regulated expression of the pathogen receptor dendritic cell-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin in THP-1 human leukemic cells, monocytes, and macrophages. J. Biol. Chem 279: 25680– 25688.

192. Puzo, G. 1993. La paroi mycobactérienne: structure et organisation des glycoconjugués majeurs. Ann. Inst. Pasteur 4: 225– 238.

193. Quesniaux, V. J.,, D. M. Nicolle,, D. Torres,, L. Kremer,, Y. Guerardel,, J. Nigou,, G. Puzo,, F. Erard, and, B. Ryffel. 2004. Toll-like receptor 2 (TLR2)-dependent-positive and TLR2-independentnegative regulation of proinflammatory cytokines by mycobacterial lipomannans. J. Immunol. 172: 4425– 4434.

194. Rastogi, N. 1991. Recent observations concerning structure and function relationships in the mycobacterial cell envelope: elaboration of a model in terms of mycobacterial pathogenicity, virulence and drug-resistance. Res. Microbiol. 142: 464– 476.

195. Rhoades, E.,, F. Hsu,, J. B. Torrelles,, J. Turk,, D. Chatterjee, and, D. G. Russell. 2003. Identification and macrophage-activating activity of glycolipids released from intracellular Mycobacterium bovis BCG. Mol. Microbiol. 48: 875– 888.

196. Riviere, M.,, A. Moisand,, A. Lopez, and, G. Puzo. 2004. Highly ordered supra-molecular organization of the mycobacterial lipoarabinomannans in solution. Evidence of a relationship between supra-molecular organization and biological activity. J. Mol. Biol. 344: 907– 918.

197. Rojas, M.,, L. F. Garcia,, J. Nigou,, G. Puzo, and, M. Olivier. 2000. Mannosylated lipoarabinomannan antagonizes Mycobacterium tuberculosis-induced macrophage apoptosis by altering Ca 2-dependent cell signaling. J. Infect. Dis. 182: 240– 251.

198. Rojas, M.,, M. Olivier, and, L. F. Garcia. 2002. Activation of JAK2/STAT1-alpha-dependent signaling events during Mycobacterium tuberculosis-induced macrophage apoptosis. Cell. Immunol. 217: 58– 66.

199. Ronet, C.,, M. Mempel,, N. Thieblemont,, A. Lehuen,, P. Kourilsky, and, G. Gachelin. 2001. Role of the complementarity-determining region 3 (CDR3) of the TCR-beta chains associated with the Valpha14 semi-invariant TCR alpha-chain in the selection of CD4(+) NK T cells. J. Immunol. 166: 1755– 1762.

200. Roura-Mir, C.,, L. Wang,, T. Y. Cheng,, I. Matsunaga,, C. C. Dascher,, S. L. Peng,, M. J. Fenton,, C. Kirschning, and, D. B. Moody. 2005. Mycobacterium tuberculosis regulates CD1 antigen presentation pathways through TLR-2. J. Immunol. 175: 1758– 1766.

201. Russell, D. G. 2003. Phagosomes, fatty acids and tuberculosis. Nat. Cell. Biol. 5: 776– 778.

202. Salman, M.,, J. T. Lonsdale,, G. S. Besra, and, P. J. Brennan. 1999. Phosphatidylinositol synthesis in mycobacteria. Biochim. Biophys. Acta 1436: 437– 450.

203. Schaeffer, M. L.,, K.-H. Khoo,, G. S. Besra,, D. Chatterjee,, P. J. Brennan,, J. T. Belisle, and, J. M. Inamine. 1999. The pimB gene of Mycobacterium tuberculosis encodes a mannosyltransferase involved in lipoarabinomannan biosynthesis. J. Biol. Chem. 274: 31625– 31631.

204. Schaible, U. E.,, F. Winau,, P. A. Sieling,, K. Fischer,, H. L. Collins,, K. Hagens,, R. L. Modlin,, V. Brinkmann, and, S. H. Kaufmann. 2003. Apoptosis facilitates antigen presentation to T lymphocytes through MHC-I and CD1 in tuberculosis. Nat. Med. 9: 1039– 1046.

205. Scherman, M. S.,, L. Kalbe-Bournonville,, D. Bush,, Y. Xin,, L. Deng, and, M. R. McNeil. 1996. Polyprenylphosphate-pentoses in mycobacteria are synthesized from 5-phosphoribose pyrophosphate. J. Biol. Chem. 271: 29652– 29658.

206. Schlesinger, L. S. 1993. Macrophage phagocytosis of virulent but not attenuated strains of Mycobacterium tuberculosis is mediated by mannose receptors in addition to complement receptors. J. Immunol. 150: 2920– 2930.

207. Schlesinger, L. S.,, S. R. Hull, and, T. M. Kaufman. 1994. Binding of the terminal mannosyl units of lipoarabinomannan from a virulent strain of Mycobacterium tuberculosis to human macrophages. J. Immunol. 152: 4070– 4079.

208. Schlesinger, L. S.,, T. M. Kaufman,, S. Iyer,, S. R. Hull, and, L. K. Marchiando. 1996. Differences in mannose receptor-mediated uptake of lipoarabinomannan from virulent and attenuated strains of Mycobacterium tuberculosis by human macrophages. J. Immunol. 157: 4568– 4575.

209. Sharma, K.,, M. Gupta,, A. Krupa,, N. Srinivasan, and, Y. Singh. 2006a. EmbR, a regulatory protein with ATPase activity, is a substrate of multiple serine/threonine kinases and phosphatase in Mycobacterium tuberculosis. FEBS J. 273: 2711– 2721.

210. Sharma, K.,, M. Gupta,, M. Pathak,, N. Gupta,, A. Koul,, S. Sarangi,, R. Baweja, and, Y. Singh. 2006b. Transcriptional control of the mycobacterial embCAB operon by PknH through a regulatory protein, EmbR, in vivo. J. Bacteriol. 188: 2936– 2944.

211. Shi, L.,, S. Berg,, A. Lee,, J. S. Spencer,, J. Zhang,, V. Vissa,, M. R. McNeil,, K.-H. Khoo, and, Chatterjee. Chatterjee. 2006. The carboxy terminus of EmbC from Mycobacterium smegmatis mediates chain length extension of the arabinan in lipoarabinomannan. J. Biol. Chem. 281: 19542– 19546.

212. Sibley, L. D.,, S. W. Hunter,, P. J. Brennan, and, J. L. Krahenbuhl. 1988. Mycobacterial lipoarabinomannan inhibits gamma interferon-mediated activation of macrophages. Infect. Immun. 56: 1232– 1236.

213. Sidobre, S.,, J. Nigou,, G. Puzo, and, M. Riviere. 2000. Lipoglycans are putative ligands for the human pulmonary surfactant protein A attachment to mycobacteria. Critical role of the lipids for lectin-carbohydrate recognition. J. Biol. Chem. 275: 2415– 2422.

214. Sidobre, S.,, G. Puzo, and, M. Riviere. 2002. Lipid-restricted recognition of mycobacterial lipoglycans by human pulmonary surfactant protein A: a surface-plasmon-resonance study. Biochem. J. 365: 89– 97.

215. Sieling, P. A.,, D. Chatterjee,, S. A. Porcelli,, T. I. Prigozy,, R. J. Mazzaccaro,, T. Soriano,, B. R. Bloom,, M. B. Brenner,, M. Kronenberg,, P. J. Brennan, et al. 1995. CD1-restricted T cell recognition of microbial lipoglycan antigens. Science 269: 227– 230.

216. Skeiky, Y. A., and, J. C. Sadoff. 2006. Advances in tuberculosis vaccine strategies. Nat. Rev. Microbiol. 4: 469– 476.

217. Skold, M., and, S. M. Behar. 2005. The role of group 1 and group 2 CD1-restricted T cells in microbial immunity. Microbes Infect. 7: 544– 551.

218. Stadelmaier, A., and, R. R. Schmidt. 2003. Synthesis of phosphatidylinositol mannosides (PIMs). Carbohydr. Res. 338: 2557– 2569.

219. Stenger, S., and, R. L. Modlin. 2002. Control of Mycobacterium tuberculosis through mammalian Toll-like receptors. Curr. Opin. Immunol. 14: 452– 427.

220. Sulzenbacher, G.,, S. Canaan,, Y. Bordat,, O. Neyrolles,, G. Stadthagen,, V. Roig-Zamboni,, J. Rauzier,, D. Maurin,, F. Laval,, M. Daffe,, C. Cambillau,, B. Gicquel,, Y. Bourne, and, M. Jackson. 2006. LppX is a lipoprotein required for the translocation of phthiocerol dimycocerosates to