Lymphocyte suppression in leprosy induced by unique M. leprae glycolipid

Mehra, Vishu; Brennan, Patrick J.; Rada, Elsa; Convit, J; Bloom, Barry R.

doi:10.1038/308194a0

Cited by 198 publications

(93 citation statements)

References 15 publications

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“…Defective IFN-␥ mediated activation has been reported in mouse macrophages heavily infected with live M. leprae (21,22). Possible inhibitory molecules present in the cell wall of M. leprae include phenolic glycolipid 1 (PGL-1) (23,24). PGL-1 has been implicated in dampening the allogeneic response caused by M. leprae-infected DCs (18).…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium leprae Inhibits Dendritic Cell Activation and Maturation

Murray¹,

Siddiqui

Mendillo

et al. 2007

The Journal of Immunology

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Leprosy presents with a clinical spectrum of skin lesions that span from strong Th1-mediated cellular immunity and control of bacillary growth at one pole to poor Ag-specific T cell immunity with extensive bacillary load and Th2 cytokine-expressing lesions at the other. To understand how the immune response to Mycobacterium leprae is regulated, human dendritic cells (DC), potent inducers of adaptive immune responses, exposed to M. leprae, Mycobacterium tuberculosis (Mtb), and Mycobacterium bovis bacillus Calmette-Guerin (BCG) were studied for their ability to be activated and to prime T cell proliferation. In contrast with Mtb and BCG, M. leprae did not induce DC activation/maturation as measured by the expression of selected surface markers and proinflammatory cytokine production. In MLR, T cells did not proliferate in response to M. leprae-stimulated DC. Interestingly, M. leprae-exposed MLR cells secreted increased Th2 cytokines as well as similar Th1 cytokine levels as compared with Mtb- and BCG-exposed cells. Gene expression analysis revealed a reduction in levels of mRNA of DC activation and maturation markers following exposure to M. leprae. Our data suggest that M. leprae does not induce and probably suppresses in vitro DC maturation/activation, whereas Mtb and BCG are stimulatory.

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Section: Discussionmentioning

confidence: 99%

Mycobacterium leprae Inhibits Dendritic Cell Activation and Maturation

Murray¹,

Siddiqui

Mendillo

et al. 2007

The Journal of Immunology

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“…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%

“…In addition some of these glycolipids exhibit biological activities in vitro that may be relevant to the pathogenesis of mycobacterial infections. For instance, PGL-1 from M. leprae has been reported to inhibit the proliferation of T lymphocytes after stimulation with concanavalin A (14); this observation has been extended to PGLs produced by other mycobacterial species (15). Furthermore, PGL-1 seems to be associated with resistance to intracellular killing by macrophages (16) and promotes phagocytosis of M. leprae by macrophages and Schwann cells through binding, respectively, to complement component C3 or laminin-2 (17,18).…”

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confidence: 97%

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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

227

181

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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.

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“…However, there are three reports on increased number of T regulatory cells in leprosy patients [15][16][17], two of them reported increased T regulatory cells in lepromatous leprosy patients and one reported increased T regulatory cells in tuberculoid leprosy patients. PGL-1 is M. leprae specific lipid which has been reported to be immunosuppressive [18] and highest rate of leprosy cases was detected in PGL-1 seropositive BCG unvaccinated contacts [19], therefore, we designed the present study to evaluate the percentage of T regulatory cells in different categories of leprosy patients and healthy controls to delineate their role in T cell suppression in leprosy. Further, frequency of T regulatory cells was detected in PBMCs after stimulation with M. leprae antigens to evaluate role of these antigens, especially PGL-1 in the induction of T regulatory cells.…”

Section: Introductionmentioning

confidence: 99%