Mycobacterial Phosphatidylinositol Mannosides Negatively Regulate Host Toll-like Receptor 4, MyD88-dependent Proinflammatory Cytokines, and TRIF-dependent Co-stimulatory Molecule Expression

Doz, Emilie; Rose, Stéphanie; Court, Nathalie; Front, Sophie; Vasseur, Virginie; Charron, Sabine; Gilleron, Martine; Puzo, Germain; Frémaux, Isabelle; Delneste, Yves; Erard, François; Ryffel, Bernhard; Martin, Olivier R.; Quesniaux, Valérie

doi:10.1074/jbc.m109.037846

Cited by 57 publications

(90 citation statements)

References 57 publications

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“…LAM mediates entry in to macrophages via the mannose receptor aiding the bacilli in avoiding phagosome-lysosome fusion, oxidative burst and altered calcium and cytokine responses (3,23,42,43,48). LAM has also been shown to bind to Toll-like receptors and induce signaling events important in the host response in tuberculosis (15,16). Thus, LAM is generally considered to be a crucial factor in mycobacterial pathogenesis.…”

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confidence: 99%

Lipoarabinomannan Localization and Abundance during Growth of Mycobacterium smegmatis

et al. 2011

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Lipoarabinomannan (LAM) is a structurally heterogeneous amphipathic lipoglycan present in Mycobacterium spp. and other actinomycetes, which constitutes a major component of the cell wall and exhibits a wide spectrum of immunomodulatory effects. Analysis of Mycobacterium smegmatis subcellular fractions and spheroplasts showed that LAM and lipomannan (LM) were primarily found in a cell wall-enriched subcellular fraction and correlated with the presence (or absence) of the mycolic acids in spheroplast preparations, suggesting that LAM and LM are primarily associated with the putative outer membrane of mycobacteria. During the course of these studies significant changes in the LAM/LM content of the cell wall were noted relative to the age of the culture. The LAM content of the M. smegmatis cell wall was dramatically reduced as the bacilli approached stationary phase, whereas LM, mycolic acid, and arabinogalactan content appeared to be unchanged. In addition, cell morphology and acid-fast staining characteristics showed variations with growth phase of the bacteria. In the logarithmic phase, the bacteria were found to be classic rod-shaped acid-fast bacilli, while in the stationary phase M. smegmatis lost the characteristic rod shape and developed a punctate acid-fast staining pattern with carbolfuchsin. The number of viable bacteria was independent of LAM content and phenotype. Taken together, the results presented here suggest that LAM is primarily localized with the mycolic acids in the cell wall and that the cellular concentration of LAM in M. smegmatis is selectively modulated with the growth phase.

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Lipoarabinomannan Localization and Abundance during Growth of Mycobacterium smegmatis

et al. 2011

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“…founding to several studies where PIM 2 was found to be proinflammatory in its function (10,12), several members of PIM family that are TLR2 agonists are majorly anti-inflammatory in nature and can suppress pro-inflammatory responses mediated by other PRRs (13)(14)(15). We sought to analyze the cross-regulation, if any, between PIM-induced TLR2 signaling and another PRR signaling like NOD2 pathway.…”

Section: Ac 2 Pim Inflects Nod2-induced Immunomodulators-con-mentioning

confidence: 99%

“…Functional consequences of PIM-induced TLR2 signaling span both pro-and anti-inflammatory capacities (10,(12)(13)(14)(15). Importantly, stimulation of PIM-TLR2 pathway down-regulates TLR4-induced pro-inflammatory signals (13).…”

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confidence: 99%

Ac2PIM-responsive miR-150 and miR-143 Target Receptor-interacting Protein Kinase 2 and Transforming Growth Factor Beta-activated Kinase 1 to Suppress NOD2-induced Immunomodulators

Prakhar¹,

Holla²,

Ghorpade³

et al. 2015

Journal of Biological Chemistry

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Background: Ac 2 PIM signals via TLR2 to direct both pro-and anti-inflammatory responses. Results: Ac 2 PIM induces miR-150/143 via SRC-FAK-PYK2-CREB-P300 signaling to target RIP2 and TAK1 and subdues MDPstimulated PI3K-PKC-MAPK-␤-catenin axis. Conclusion: Ac 2 PIM-mediated TLR2 signaling suppresses the NOD2-induced immunomodulators viz. COX-2, SOCS-3, and MMP-9. Significance: TLR2-NOD2 crosstalk accentuated the utilities of Ac 2 PIM and MDP as vaccine adjuvant.

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“…Mycobacterial lipids have long been implicated in the induction of responses in both the innate and adaptive cell-mediated immune responses (17)(18)(19)(20)(21). Although one strategy has been published which allows the isolation of PIMs from the avirulent M. bovis BCG strain (18,(22)(23)(24) and M. tuberculosis H37Rv (22) and certain synthetic molecules (17,19,21), in this study we successfully developed a novel method for extracting and subsequently highly purifying and characterizing individual PIM species from the polar fraction of virulent M. tuberculosis H37Rv.…”

Section: Discussionmentioning

confidence: 99%

“…Although one strategy has been published which allows the isolation of PIMs from the avirulent M. bovis BCG strain (18,(22)(23)(24) and M. tuberculosis H37Rv (22) and certain synthetic molecules (17,19,21), in this study we successfully developed a novel method for extracting and subsequently highly purifying and characterizing individual PIM species from the polar fraction of virulent M. tuberculosis H37Rv. The method developed here improves upon the previously published protocols primarily by using a French press to disrupt the bacterial cells, thereby increasing PIM yield.…”

Section: Discussionmentioning

confidence: 99%

Highly Purified Mycobacterial Phosphatidylinositol Mannosides Drive Cell-Mediated Responses and Activate NKT Cells in Cattle

Pirson¹,

Engel²,

Gj³

et al. 2014

Clin. Vaccine Immunol.

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M embers of the mycobacterial genus are renowned for their waxy, lipid-rich outer envelope. Under physiological conditions, this outer layer is likely to be the first point of contact between the bacterial cell and the host's immune system, and the outcome of this interaction is pivotal in the establishment of infection. One of the most important groups of membrane bound lipids consists of the phosphatidylinositol mannosides (PIMs). Interest in PIMs was stimulated since it was shown that phosphatidylinositol dimannoside (PIM 2 ) forms the phosphoglycolipid anchor which tethers a large array of glycolipids and lipoglycans, including lipomannan (LM) and lipoarabinomannan (LAM), to the cellular membrane (1). PIMs have been shown to interact with a variety of immune components and mediate significant effects on the host. Ever since the realization that NKT cells could respond to lipid antigens (2-4) and the subsequent discovery of the CD1d-restricted lipid antigen ␣-galactosylceramide (␣-GalCer) (5, 6), much research effort has been concentrated on understanding lipid antigens. Although work was initially focused on invariant NKT cells, it has since been shown that great diversity exists in the lipid-responsive T cell receptor (TCR) repertoire (7-9) and that these diverse NKT cells contribute to the Th1/Th2 balance (7, 10). It has been shown that CD1d-restricted NKT cells are capable of recognizing a variety of lipid antigens, including phospholipids (11). More recently, a CD1b-restricted subset of T cells has been found (12). Similarly to CD1d-restricted invariant NKT (iNKT) cells, the CD1b-restricted variant cells require CD1B for their development and produce proinflammatory cytokines in response to CD1b-expressing dendritic cells (DCs) (12). It is clear that NKT-like cells have a significant role to play in lipid-mediated responses, and the hunt for their antigens has continued (13-15).Given the ability of lipid molecules to generate responses in peripheral blood mononuclear cells (PBMC), we decided to assess the ability of individual, highly purified natural PIMs to activate bovine lymphocytes. In this study, we developed a novel extraction method which allowed us to extract and highly purify a variety of PIM molecules from virulent Mycobacterium tuberculosis H37Rv. The ability of these molecules to induce lymphocyte responses in Mycobacterium bovis-infected cattle was investigated by measuring lymphocyte proliferation and gamma interferon (IFN-␥) production. Furthermore, flow cytometry techniques were utilized to characterize responding cell populations. MATERIALS AND METHODS Extraction of PIMs.Using the novel methodology outlined below, highly pure phosphatidylinositol dimannoside (PIM 2 ), acylphosphatidylinositol dimannoside (AcPIM 2 ), diacyl-phosphatidylinositol dimannoside (Ac 2 PIM 2 ), acylphosphatidylinositol hexamannoside (AcPIM 6 ), and diacylphosphatidylinositol hexamannoside (Ac 2 PIM 6 ) were successfully isolated. Individual PIM molecules were analyzed by electrospray ionization mass spectrometr...

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Mycobacterial Phosphatidylinositol Mannosides Negatively Regulate Host Toll-like Receptor 4, MyD88-dependent Proinflammatory Cytokines, and TRIF-dependent Co-stimulatory Molecule Expression

Cited by 57 publications

References 57 publications

Lipoarabinomannan Localization and Abundance during Growth of Mycobacterium smegmatis

Lipoarabinomannan Localization and Abundance during Growth of Mycobacterium smegmatis

Ac2PIM-responsive miR-150 and miR-143 Target Receptor-interacting Protein Kinase 2 and Transforming Growth Factor Beta-activated Kinase 1 to Suppress NOD2-induced Immunomodulators

Highly Purified Mycobacterial Phosphatidylinositol Mannosides Drive Cell-Mediated Responses and Activate NKT Cells in Cattle

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