Ishikawa, E. et al. Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle. J. Exp. Med. 206, 2879-2888

Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
Journal of Experimental Medicine (Impact Factor: 12.52). 12/2009; 206(13):2879-88. DOI: 10.1084/jem.20091750
Source: PubMed


Tuberculosis remains a fatal disease caused by Mycobacterium tuberculosis, which contains various unique components that affect the host immune system. Trehalose-6,6'-dimycolate (TDM; also called cord factor) is a mycobacterial cell wall glycolipid that is the most studied immunostimulatory component of M. tuberculosis. Despite five decades of research on TDM, its host receptor has not been clearly identified. Here, we demonstrate that macrophage inducible C-type lectin (Mincle) is an essential receptor for TDM. Heat-killed mycobacteria activated Mincle-expressing cells, but the activity was lost upon delipidation of the bacteria; analysis of the lipid extracts identified TDM as a Mincle ligand. TDM activated macrophages to produce inflammatory cytokines and nitric oxide, which are completely suppressed in Mincle-deficient macrophages. In vivo TDM administration induced a robust elevation of inflammatory cytokines in sera and characteristic lung inflammation, such as granuloma formation. However, no TDM-induced lung granuloma was formed in Mincle-deficient mice. Whole mycobacteria were able to activate macrophages even in MyD88-deficient background, but the activation was significantly diminished in Mincle/MyD88 double-deficient macrophages. These results demonstrate that Mincle is an essential receptor for the mycobacterial glycolipid, TDM.

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Available from: Taroh Kinoshita, Oct 02, 2015
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    • "Dectin-1 was found to play a role in dendritic cell IL-12 production in response to mycobacteria in vitro; however , loss of this receptor did not alter susceptibility to infection in vivo (Marakalala et al., 2011). Mincle recognizes trehalose- 6,6 0 -dimycolate (TDM or cord factor) and was found to mediate robust responses to this mycobacterial cell wall glycolipid both in vitro and in vivo (Ishikawa et al., 2009; Schoenen et al., 2010). However, the role of Mincle in vivo is controversial, with some studies describing no clear role for this receptor during mycobacterial infection (Behler et al., 2012; Heitmann et al., 2013). "
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    ABSTRACT: The interaction of microbes with pattern recognition receptors (PRRs) is essential for protective immunity. While many PRRs that recognize mycobacteria have been identified, none is essentially required for host defense in vivo. Here, we have identified the C-type lectin receptor CLECSF8 (CLEC4D, MCL) as a key molecule in anti-mycobacterial host defense. Clecsf8(-/-) mice exhibit higher bacterial burdens and increased mortality upon M. tuberculosis infection. Additionally, Clecsf8 deficiency is associated with exacerbated pulmonary inflammation, characterized by enhanced neutrophil recruitment. Clecsf8(-/-) mice show reduced mycobacterial uptake by pulmonary leukocytes, but infection with opsonized bacteria can restore this phagocytic defect as well as decrease bacterial burdens. Notably, a CLECSF8 polymorphism identified in humans is associated with an increased susceptibility to pulmonary tuberculosis. We conclude that CLECSF8 plays a non-redundant role in anti-mycobacterial immunity in mouse and in man. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Host & Microbe 02/2015; 17(2):252-259. DOI:10.1016/j.chom.2015.01.004 · 12.33 Impact Factor
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    • "Mycobacterium tuberculosis and all other species of mycobacteria, many of which are opportunistic intracellular pathogens, owe much of their resilience to a distinctive lipid-rich cell envelope that not only protects the cells against harsh environments, but also contains many molecules that are immune effectors crucial in evading the host immune response (Briken et al. 2004; Ishikawa et al. 2009; Schafer et al. 2009; Court et al. 2010; Ehlers 2010; Philips and Ernst 2012; Lang 2013; Nobre et al. 2014). Besides glycolipids and glucans that constitute most of M. tuberculosis cell envelope, several secreted proteins have been identified and shown to also play fundamental roles in M. tuberculosis survival and proliferation within the host (Abdallah et al. 2007; Philips 2008; Philips and Ernst 2012). "
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    DNA and cell biology 01/2015; 34(4):1-15. DOI:10.1089/dna.2014.2745 · 2.06 Impact Factor
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    • "TMM is the common donor of mycolyl chain in the synthesis of mAGP and TDM (Belisle et al., 1997; Takayama et al., 2005). TDM has long been studied as a cord factor, conferring a cord-like appearance to Mtb in vitro, with strong immunomodulatory activities (Hunter et al., 2006; Ishikawa et al., 2009; Rao et al., 2006). However, recent studies suggest that TDM could be a structural component of MoM (Ojha et al., 2010; Yang et al., 2013). "
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    ABSTRACT: Chronic tuberculosis in an immunocompetent host is a consequence of the delicately balanced growth of Mycobacterium tuberculosis (Mtb) in the face of host defense mechanisms. We identify an Mtb enzyme (TdmhMtb) that hydrolyzes the mycobacterial glycolipid trehalose dimycolate and plays a critical role in balancing the intracellular growth of the pathogen. TdmhMtb is induced under nutrient-limiting conditions and remodels the Mtb envelope to increase nutrient influx but concomitantly sensitizes Mtb to stresses encountered in the host. Consistent with this, a ΔtdmhMtb mutant is more resilient to stress and grows to levels higher than those of wild-type in immunocompetent mice. By contrast, mutant growth is retarded in MyD88(-/-) mice, indicating that TdmhMtb provides a growth advantage to intracellular Mtb in an immunocompromised host. Thus, the effects and countereffects of TdmhMtb play an important role in balancing intracellular growth of Mtb in a manner that is directly responsive to host innate immunity.
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