Deciphering the molecular bases of<i>Mycobacterium tuberculosis</i>binding to the lectin DC-SIGN reveals an underestimated complexity

Pitarque, Sylvain; Herrmann, Jean-Louis; Duteyrat, Jean-Luc; Jackson, Mary; Stewart, Graham R.; Lecointe, François; Payré, Bruno; Schwartz, Olivier; Young, Douglas; Marchal, G; Lagrange, Philippe; Puzo, Germain; Gicquel, Brigitte; Nigou, Jérôme; Neyrolles, Olivier

doi:10.1042/bj20050709

Cited by 101 publications

(131 citation statements)

References 46 publications

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“…Nevertheless, the potential importance of DC-SIGN ligation during infection is illustrated by the large number of DC-SIGN ligands that (pathogenic) mycobacteria may express. Together with ManLAM (39), lipomannan (72), mannose-capped arabinomannan (72), two mannosylated glycoproteins (72), and the phosphatidylinositol mannosides (73), ␣-glucan represents the seventh documented mycobacterial ligand for DC-SIGN. Interestingly, it has been shown that in patients with TB up to 70% of alveolar macrophages show DC-SIGN expression (71).…”

Section: Discussionmentioning

confidence: 99%

Identification of Mycobacterial α-Glucan As a Novel Ligand for DC-SIGN: Involvement of Mycobacterial Capsular Polysaccharides in Host Immune Modulation

Geurtsen

Chedammi

Mesters

et al. 2009

The Journal of Immunology

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117

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Mycobacterium tuberculosis possesses a variety of immunomodulatory factors that influence the host immune response. When the bacillus encounters its target cell, the outermost components of its cell envelope are the first to interact. Mycobacteria, including M. tuberculosis, are surrounded by a loosely attached capsule that is mainly composed of proteins and polysaccharides. Although the chemical composition of the capsule is relatively well studied, its biological function is only poorly understood. The aim of this study was to further assess the functional role of the mycobacterial capsule by identifying host receptors that recognize its constituents. We focused on α-glucan, which is the dominant capsular polysaccharide. Here we demonstrate that M. tuberculosis α-glucan is a novel ligand for the C-type lectin DC-SIGN (dendritic cell-specific ICAM-3-grabbing nonintegrin). By using related glycogen structures, we show that recognition of α-glucans by DC-SIGN is a general feature and that the interaction is mediated by internal glucosyl residues. As for mannose-capped lipoarabinomannan, an abundant mycobacterial cell wall-associated glycolipid, binding of α-glucan to DC-SIGN stimulated the production of immunosuppressive IL-10 by LPS-activated monocyte-derived dendritic cells. By using specific inhibitors, we show that this IL-10 induction was DC-SIGN-dependent and also required acetylation of NF-κB. Finally, we demonstrate that purified M. tuberculosis α-glucan, in contrast to what has been reported for fungal α-glucan, was unable to activate TLR2.

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Section: Discussionmentioning

confidence: 99%

Identification of Mycobacterial α-Glucan As a Novel Ligand for DC-SIGN: Involvement of Mycobacterial Capsular Polysaccharides in Host Immune Modulation

Geurtsen

Chedammi

Mesters

et al. 2009

The Journal of Immunology

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117

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“…We recently described Mtb manno-proteins as an emerging class of bacterial adhesins that contribute to Mtb infectiousness through binding to host innate-immune system receptors, including lung surfactant protein A (SP-A) (1) and DC-SIGN (2), which are considered to be the receptors preferentially used by mycobacteria to enter target cells and evade host defense mechanisms (3). Here, we considered the systemic impact of protein mannosylation on the survival and virulence of Mtb.…”

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confidence: 99%

Bacterial protein-O-mannosylating enzyme is crucial for virulence ofMycobacterium tuberculosis

Liu

Tonini

Malaga

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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107

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A posttranslational protein O-mannosylation process resembling that found in fungi and animals has been reported in the major human pathogen Mycobacterium tuberculosis (Mtb) and related actinobacteria. However, the role and incidence of this process, which is essential in eukaryotes, have never been explored in Mtb. We thus analyzed the impact of interrupting O-mannosylation in the nonpathogenic saprophyte Mycobacterium smegmatis and in the human pathogen Mtb by inactivating the respective putative protein mannosyl transferase genes Msmeg_5447 and Rv1002c. Loss of protein O-mannosylation in both mutant strains was unambiguously demonstrated by efficient mass spectrometry-based glycoproteomics analysis. Unexpectedly, although the M. smegmatis phenotype was unaffected by the lack of manno-proteins, the Mtb mutant had severely impacted growth in vitro and in cellulo associated with a strong attenuation of its pathogenicity in immunocompromised mice. These data are unique in providing evidence of the biological significance of protein O-mannosylation in mycobacteria and demonstrate the crucial contribution of this protein posttranslational modification to Mtb virulence in the host.protein glycosylation | O-glycosylation | proteomics

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“…Several ligands have been studied so far: the mannosylated 19-kDa and 45-kDa antigens, mannose-capped lipoarabinomannan (ManLAM), arabinomannan (AM), lipomannan (LM), and phosphatidylinositol mannosides (PIMs) (27,46,59,67). The 19-and 45-kDa glycoproteins were shown to have an inhibitory effect on mycobacterial binding to DC-SIGN (59). However, M. tuberculosis mutants deficient in these glycoproteins bound DC-SIGN as well as the wild-type strain did (59).…”

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confidence: 99%

Role of Phosphatidylinositol Mannosides in the Interaction between Mycobacteria and DC-SIGN

et al. 2009

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The C-type lectin dendritic cell (DC)-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) is the major receptor on DCs for mycobacteria of the Mycobacterium tuberculosis complex. Recently, we have shown that although the mannose caps of the mycobacterial surface glycolipid lipoarabinomannan (ManLAM) are essential for the binding to DC-SIGN, genetic removal of these caps did not diminish the interaction of whole mycobacteria with DC-SIGN and DCs. Here we investigated the role of the structurally related glycolipids phosphatidylinositol mannosides (PIMs) as possible ligands for DC-SIGN. In a binding assay with both synthetic and natural PIMs, DC-SIGN exhibited a high affinity for hexamannosylated PIM 6 , which contains terminal ␣(132)-linked mannosyl residues identical to the mannose cap on ManLAM, but not for di-and tetramannosylated PIM 2 and PIM 4 , respectively. To determine the role of PIM 6 in the binding of whole mycobacteria to DC-SIGN, a mutant strain of M. bovis bacillus Calmette-Guérin deficient in the production of PIM 6 (⌬pimE) was created, as well as a double knockout deficient in the production of both PIM 6 and the mannose caps on LAM (⌬pimE ⌬capA). Compared to the wild-type strain, both mutant strains bound similarly well to DC-SIGN and DCs. Furthermore, the wild-type and mutant strains induced comparable levels of interleukin-10 and interleukin-12p40 when used to stimulate DCs. Hence, we conclude that, like ManLAM, PIM 6 represents a bona fide DC-SIGN ligand but that other, as-yet-unknown, ligands dominate in the interaction between mycobacteria and DCs.

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Deciphering the molecular bases ofMycobacterium tuberculosisbinding to the lectin DC-SIGN reveals an underestimated complexity

Cited by 101 publications

References 46 publications

Identification of Mycobacterial α-Glucan As a Novel Ligand for DC-SIGN: Involvement of Mycobacterial Capsular Polysaccharides in Host Immune Modulation

Identification of Mycobacterial α-Glucan As a Novel Ligand for DC-SIGN: Involvement of Mycobacterial Capsular Polysaccharides in Host Immune Modulation

Bacterial protein-O-mannosylating enzyme is crucial for virulence ofMycobacterium tuberculosis

Role of Phosphatidylinositol Mannosides in the Interaction between Mycobacteria and DC-SIGN

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