Microbial glycolipids: possible virulence factors that scavenge oxygen radicals.

Chan, John; Fujiwara, Tsuyoshi; Brennan, Patrick J.; McNeil, Michael; Turco, Salvatore J.; Sibille, Jean-Claude; Snapper, Marc L.; Aisen, Philip; Bloom, Barry R.

doi:10.1073/pnas.86.7.2453

Cited by 208 publications

(125 citation statements)

References 24 publications

Supporting

Mentioning

124

Contrasting

Order By: Relevance

“…It has been implicated in several processes at different steps of the infection cycle: tropism for Schwann cells or phagocytes; the resistance of the leprosy bacillus to intracellular killing; and immunomodulatory activities (18,50,14). However, analysis of the contribution of PGL-1 to the pathogenicity of M. leprae has been hampered by the failure of the bacterium to grow on laboratory media and its extremely slow growth in animal model.…”

Section: Discussionmentioning

confidence: 99%

“…The observation that p-HBAD are present in the culture fluids of all the strains of M. tuberculosis examined raises the question of their role in virulence of the tubercle bacillus. These compounds are properly located to interact with host cells and contain the oligosaccharide moiety of PGL, which seems to be essential for the various acitivities found for the PGL of M. leprae (18,50,14). Once again the best way to address this question will be the generation and characterization of M. tuberculosis mutants devoid of p-HBAD.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Role of the pks15/1 Gene in the Biosynthesis of Phenolglycolipids in the Mycobacterium tuberculosisComplex

Constant¹,

Pérez²,

Malaga

et al. 2002

Journal of Biological Chemistry

228

181

View full text Add to dashboard Cite

Diesters of phthiocerol and phenolphthiocerol are important virulence factors of Mycobacterium tuberculosis and Mycobacterium leprae, the two main mycobacterial pathogens in humans. They are both long-chain ␤-diols, and their biosynthetic pathway is beginning to be elucidated. Although the two classes of molecules share a common lipid core, phthiocerol diesters have been found in all the strains of the M. tuberculosis complex examined although phenolphthiocerol diesters are produced by only a few groups of strains. To address the question of the origin of this diversity 8 reference strains and 10 clinical isolates of M. tuberculosis were analyzed. We report the presence of glycosylated p-hydroxybenzoic acid methyl esters, structurally related to the type-specific phenolphthiocerol glycolipids, in the culture media of all reference strains of M. tuberculosis, suggesting that the strains devoid of phenolphthiocerol derivatives are unable to elongate the putative p-hydroxybenzoic acid precursor. We also show that all the strains of M. tuberculosis examined and deficient in the production of phenolphthiocerol derivatives are natural mutants with a frameshift mutation in pks15/1 whereas a single open reading frame for pks15/1 is found in Mycobacterium bovis BCG, M. leprae, and strains of M. tuberculosis that produce phenolphthiocerol derivatives. Complementation of the H37Rv strain of M. tuberculosis, which is devoid of phenolphthiocerol derivatives, with the fused pks15/1 gene from M. bovis BCG restored phenolphthiocerol glycolipids production. Conversely, disruption of the pks15/1 gene in M. bovis BCG led to the abolition of the synthesis of type-specific phenolphthiocerol glycolipid. These data indicate that Pks15/1 is involved in the elongation of p-hydroxybenzoic acid to give p-hydroxyphenylalkanoates, which in turn are converted, presumably by the PpsA-E synthase, to phenolphthiocerol derivatives.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Role of the pks15/1 Gene in the Biosynthesis of Phenolglycolipids in the Mycobacterium tuberculosisComplex

Constant¹,

Pérez²,

Malaga

et al. 2002

Journal of Biological Chemistry

228

181

View full text Add to dashboard Cite

show abstract

“…The xanthine-xanthine oxidase system (23,24) was used to generate oxidants in vitro. Logarithmic-phase promastigotes were washed with PBS and suspended in 150 M xanthine in PBS at 5 ϫ 10 6 cells per ml, and 0.5-5 units of xanthine oxidase per ml of cells.…”

Section: Methodsmentioning

confidence: 99%

“…The most abundant constituent is a large GPI-anchored phosphoglycan called lipophosphoglycan (LPG) (2)(3)(4). In all Leishmania species, the GPI anchor of LPG is composed of a 1-O-alkyl-2-lysophosphatidylinositol lipid anchor and a heptasaccharide core, to which is joined a long phosphoglycan (PG) polymer composed of [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] ] repeating units (substituted with other sugars in some species) and which is terminated by a capping oligosaccharide. These domains are shared with other molecules; the PG repeating units and caps occur on secreted proteins such as PPG or secreted acid phosphatase, and the core GPI anchor domains have similarities with those present in both GIPLs and GPI-anchored proteins (1,5,6).…”

mentioning

confidence: 99%

The role(s) of lipophosphoglycan (LPG) in the establishment ofLeishmania majorinfections in mammalian hosts

Späth

Garraway

Turco

et al. 2003

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

261

259

View full text Add to dashboard Cite

The abundant cell surface glycolipid lipophosphoglycan (LPG) was implicated in many steps of the Leishmania infectious cycle by biochemical tests. The presence of other abundant surface or secreted glycoconjugates sharing LPG domains, however, has led to uncertainty about the relative contribution of LPG in vivo. Here we used an Leishmania major lpg1 ؊ mutant, which lacks LPG alone and shows attenuated virulence, to dissect the role of LPG in the establishment of macrophage infections in vivo. lpg1 ؊ was highly susceptible to human complement, had lost the ability to inhibit phagolysosomal fusion transiently, and was oxidant sensitive. Studies of mouse mutants defective in relevant defense mechanisms confirmed the role of LPG in oxidant resistance but called into question the importance of transient inhibition of phagolysosomal fusion for Leishmania macrophage survival. Moreover, the limited lytic activity of mouse complement appears to be an ineffective pathogen defense mechanism in vitro and in vivo, unlike human hosts. In contrast, lpg1 ؊ parasites bound C3b and resisted low pH and proteases normally, entered macrophages efficiently and silently, and continued to inhibit host-signaling pathways. These studies illustrate the value of mechanistic approaches focusing on both parasite and host defense pathways in dissecting the specific biological roles of complex virulence factors such as LPG.phosphoglycans ͉ trypanosomatid protozoan parasite ͉ oxidant resistance ͉ inhibition of macrophage activation ͉ adhesin

show abstract

“…NO is reported to be microbicidal in vitro, which presumed to play a role in antimicrobial action. However, mycobacteria have developed the ability to resist ROI and RNI within the hostile environment of host phagocytes (32)(33)(34). In addition, NO represents as a crucial molecular signal, and we had previously reported that NO/iNOS-mediated regulation of proinflammatory gene expression involves multiple pathways in macrophages (18).…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Is Involved in Mycobacterium bovis Bacillus Calmette-Guérin–Activated Jagged1 and Notch1 Signaling

Kapoor

Narayana

Patil

et al. 2010

The Journal of Immunology

View full text Add to dashboard Cite

Pathogenic mycobacteria have evolved unique strategies to survive within the hostile environment of macrophages. Modulation of key signaling cascades by NO, generated by the host during infection, assumes critical importance in overall cell-fate decisions. We show that NO is a critical factor in Mycobacterium bovis bacillus Calmette-Guérin–mediated Notch1 activation, as the generation of activated Notch1 or expression of Notch1 target genes matrix metalloproteinase-9 (MMP-9) or Hes1 was abrogated in macrophages derived from inducible NO synthase (iNOS) knockout (iNOS−/−), but not from wild-type, mice. Interestingly, expression of the Notch1 ligand Jagged1 was compromised in M. bovis bacillus Calmette-Guérin–stimulated iNOS−/− macrophages, and loss of Jagged1 expression or Notch1 signaling could be rescued by NO donors. Signaling perturbations or genetic approaches implicated that robust expression of MMP-9 or Hes1 required synergy and cross talk between TLR2 and canonical Notch1-PI3K cascade. Further, CSL/RBP-Jk contributed to TLR2-mediated expression of MMP-9 or Hes1. Correlative evidence shows that, in a murine model for CNS tuberculosis, this mechanism operates in vivo only in brains derived from WT but not from iNOS−/− mice. Importantly, we demonstrate the activation of Notch1 signaling in vivo in granulomatous lesions in the brains of Mycobacterium tuberculosis-infected human patients with tuberculous meningitis. Current investigation identifies NO as a pathological link that modulates direct cooperation of TLR2 with Notch1-PI3K signaling or Jagged1 to regulate specific components of TLR2 responses. These findings provide new insights into mechanisms by which Notch1, TLR2, and NO signals are integrated in a cross talk that modulates a defined set of effector functions in macrophages.

show abstract

Microbial glycolipids: possible virulence factors that scavenge oxygen radicals.

Cited by 208 publications

References 24 publications

Role of the pks15/1 Gene in the Biosynthesis of Phenolglycolipids in the Mycobacterium tuberculosisComplex

Role of the pks15/1 Gene in the Biosynthesis of Phenolglycolipids in the Mycobacterium tuberculosisComplex

The role(s) of lipophosphoglycan (LPG) in the establishment ofLeishmania majorinfections in mammalian hosts

Nitric Oxide Is Involved in Mycobacterium bovis Bacillus Calmette-Guérin–Activated Jagged1 and Notch1 Signaling

Contact Info

Product

Resources

About