Mycobacterial trehalose-containing glycolipid with immunomodulatory activity on human CD4+ and CD8+ T-cells

Saavedra, Rafael; Segura, Erika; Tenorio, Eda Patricia; López-Marı́n, Luz M.

doi:10.1016/j.micinf.2005.08.005

Cited by 34 publications

(25 citation statements)

References 24 publications

(55 reference statements)

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“…Inhibitory effects of DAT on proliferation and cytokine production had been previously observed in both naïve mice and tuberculin-sensitive healthy individuals (Saavedra et al 2001(Saavedra et al , 2006. We herein show that DAT is able to inhibit one of the main pathways, leading to protective response against intracellular pathogens.…”

Section: Dat Inhibits Cytokine Gene Expression In Antigenstimulated Csupporting

confidence: 66%

“…Mycobacterial DAT is known to down-modulate mitogen-and antigen-driven blastogenesis of T cells as well as cytokine production (Saavedra et al 2006). In order to study the molecular events involved in inhibition, we used the DAG analog phorbol 12-myristate 13-acetate (PMA) and the calcium ionophore ionomycin, to bypass the requirements for early signals derived from TCR ligation.…”

Section: Inhibitory Effects Of Mycobacterial Dat Involve Ca 2+ -And Dmentioning

confidence: 99%

“…Previously, we found that mycobacterial di-O-acyltrehalose (DAT) suppressed murine and human immune cells (Saavedra et al 2001(Saavedra et al , 2006. To gain insights into the molecular aspects of immune suppression by DAT, we looked for alterations in intracellular pathways leading to protective response against intracellular pathogens, namely the Protein Kinase C (PKC) and the mitogen-activated protein kinase (MAPK) pathway.…”

Section: Introductionmentioning

confidence: 99%

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Mycobacterial di-O-acyl trehalose inhibits Th-1 cytokine gene expression in murine cells by down-modulation of MAPK signaling

et al. 2010

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Section: Dat Inhibits Cytokine Gene Expression In Antigenstimulated Csupporting

confidence: 66%

Section: Inhibitory Effects Of Mycobacterial Dat Involve Ca 2+ -And Dmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mycobacterial di-O-acyl trehalose inhibits Th-1 cytokine gene expression in murine cells by down-modulation of MAPK signaling

et al. 2010

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“…Diacyltrehaloses inhibit proliferation of naive T cells and downregulate cytokine production in activated monocytes, indicative of an immunosuppressive function (9)(10)(11). Also, impairment of acyltrehalose production in M. tuberculosis is associated with acidification of M. tuberculosis-containing phagosomes (12).…”

mentioning

confidence: 99%

The rv1184c Locus Encodes Chp2, an Acyltransferase in Mycobacterium tuberculosis Polyacyltrehalose Lipid Biosynthesis

et al. 2015

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Trehalose glycolipids are found in many bacteria in the suborder Corynebacterineae, but methyl-branched acyltrehaloses are exclusive to virulent species such as the human pathogen Mycobacterium tuberculosis. In M. tuberculosis, the acyltransferase PapA3 catalyzes the formation of diacyltrehalose (DAT), but the enzymes responsible for downstream reactions leading to the final product, polyacyltrehalose (PAT), have not been identified. The PAT biosynthetic gene locus is similar to that of another trehalose glycolipid, sulfolipid 1. Recently, Chp1 was characterized as the terminal acyltransferase in sulfolipid 1 biosynthesis. Here we provide evidence that the homologue Chp2 (Rv1184c) is essential for the final steps of PAT biosynthesis. Disruption of chp2 led to the loss of PAT and a novel tetraacyltrehalose species, TetraAT, as well as the accumulation of DAT, implicating Chp2 as an acyltransferase downstream of PapA3. Disruption of the putative lipid transporter MmpL10 resulted in a similar phenotype. Chp2 activity thus appears to be regulated by MmpL10 in a relationship similar to that between Chp1 and MmpL8 in sulfolipid 1 biosynthesis. Chp2 is localized to the cell envelope fraction, consistent with its role in DAT modification and possible regulatory interactions with MmpL10. Labeling of purified Chp2 by an activity-based probe was dependent on the presence of the predicted catalytic residue Ser141 and was inhibited by the lipase inhibitor tetrahydrolipstatin (THL). THL treatment of M. tuberculosis resulted in selective inhibition of Chp2 over PapA3, confirming Chp2 as a member of the serine hydrolase superfamily. Efforts to produce in vitro reconstitution of acyltransferase activity using straight-chain analogues were unsuccessful, suggesting that Chp2 has specificity for native methyl-branched substrates.

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“…paratuberculosis within lesion granulomas typically lack expression of inducible nitric oxide synthase, a marker of classic macrophage activation [1]. Released bacterial products and host cytokine responses are factors that can interfere with monocyte/macrophage activation both within the microenvironment of the infection site and systemically [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Mycobacterium avium subspecies paratuberculosis infection of cattle does not diminish peripheral blood-derived macrophage mycobactericidal activity

2006

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Mycobacterial trehalose-containing glycolipid with immunomodulatory activity on human CD4+ and CD8+ T-cells

Cited by 34 publications

References 24 publications

Mycobacterial di-O-acyl trehalose inhibits Th-1 cytokine gene expression in murine cells by down-modulation of MAPK signaling

Mycobacterial di-O-acyl trehalose inhibits Th-1 cytokine gene expression in murine cells by down-modulation of MAPK signaling

The rv1184c Locus Encodes Chp2, an Acyltransferase in Mycobacterium tuberculosis Polyacyltrehalose Lipid Biosynthesis

Mycobacterium avium subspecies paratuberculosis infection of cattle does not diminish peripheral blood-derived macrophage mycobactericidal activity

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