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1805.Full.Pdf Fine Discrimination in the Recognition of Individual Species of Phosphatidyl- myo -Inositol Mannosides from Mycobacterium tuberculosis by C-Type Lectin Pattern This information is current as Recognition Receptors of September 29, 2021. Jordi B. Torrelles, Abul K. Azad and Larry S. Schlesinger J Immunol 2006; 177:1805-1816; ; doi: 10.4049/jimmunol.177.3.1805 http://www.jimmunol.org/content/177/3/1805 Downloaded from References This article cites 50 articles, 34 of which you can access for free at: http://www.jimmunol.org/content/177/3/1805.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 29, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Fine Discrimination in the Recognition of Individual Species of Phosphatidyl-myo-Inositol Mannosides from Mycobacterium tuberculosis by C-Type Lectin Pattern Recognition Receptors1 Jordi B. Torrelles, Abul K. Azad, and Larry S. Schlesinger2 The Mycobacterium tuberculosis (M.tb) envelope is highly mannosylated with phosphatidyl-myo-inositol mannosides (PIMs), lipo- mannan, and mannose-capped lipoarabinomannan (ManLAM). Little is known regarding the interaction between specific PIM types and host cell C-type lectin pattern recognition receptors. The macrophage mannose receptor (MR) and dendritic cell-specific ICAM-3-grabbing nonintegrin on dendritic cells engage ManLAM mannose caps and regulate several host responses. In this study, we analyzed the association of purified PIM families (f, separated by carbohydrate number) and individual PIM species (further separated by fatty acid number) from M.tb H R with human monocyte-derived macrophages (MDMs) and lectin- 37 v Downloaded from expressing cell lines using an established bead model. Higher-order PIMs preferentially associated with the MR as demonstrated by their reduced association with MDMs upon MR blockade and increased binding to COS-1-MR. In contrast, the lower-order PIM2f associated poorly with MDMs and did not bind to COS-1-MR. Triacylated PIM species were recognized by MDM lectins better than tetra-acylated species and the degree of acylation influenced higher-order PIM association with the MR. Moreover, only higher-order PIMs that bind the MR showed a significant increase in phagosome-lysosome fusion upon MR blockade. In contrast with the MR, the PIM2f and lipomannan were recognized by DC-SIGN comparable to higher-order PIMs and ManLAM, http://www.jimmunol.org/ and the association was independent of their degree of acylation. Thus, recognition of M.tb PIMs by host cell C-type lectins is dependent on both the nature of the terminal carbohydrates and degree of acylation. Subtle structural differences among the PIMs impact host cell recognition and response and are predicted to influence the intracellular fate of M.tb. The Journal of Immu- nology, 2006, 177: 1805–1816. ycobacterium tuberculosis (M.tb)3 is an intracellular capped lipoarabinomannan (ManLAM) (Fig. 1) (5, 6). They are pathogen that survives within the macrophage. It has thought to be both incorporated into the M.tb membrane and also developed multiple strategies to enhance its entry into exposed on its cell surface (7–9). In this regard, M.tb ManLAM M by guest on September 29, 2021 human mononuclear phagocytes by interaction of its surface-ex- with its well-defined structure comprised of a carbohydrate core posed cell wall components with specific host pattern recognition (i.e., D-mannan and D-arabinan), a mannosyl-phosphatidyl-myo- receptors (PRRs) and through these interactions, modulates diverse inositol anchor and various terminal mannose-capping motifs (Fig. biological functions (reviewed in Refs. 1 and 2). 1), has been shown to bind to the macrophage mannose receptor The complex outermost components of the mycobacterial cell (MR) mediating phagocytosis of M.tb by human macrophages wall, comprised predominantly of lipids and carbohydrates, are the (10). ManLAMs from different M.tb strains vary in the degree to first to contact host cellular constituents, and therefore play a major which they bind to the MR pointing to a potential relationship role in facilitating host cell entry and modulating the host cell between the length and/or presentation of the mannose caps and response (2, 3). The M.tb cell wall is dominated by a group of their affinity for the MR (11). Importantly, our recent studies biosynthetically related mannosylated lipoglycoconjugates (3, 4) showed that engagement of the MR by M.tb ManLAM during the including phosphatidylinositol mannosides (PIMs) and their hy- phagocytic process directs M.tb to its initial phagosomal niche permannosylated derivatives, lipomannan (LM) and the mannose- (12). ManLAM caps also bind to dendritic cell-specific ICAM-3- grabbing nonintegrin (DC-SIGN) on dendritic cells (13, 14). Thus, terminal components of ManLAM are very important in host cell Departments of Medicine and Molecular Virology, Immunology, and Medical Ge- recognition. The role of ManLAM in MR- and DC-SIGN-depen- netics, Center for Microbial Interface Biology, and Division of Infectious Diseases, 2ϩ Ohio State University, Columbus, OH 43210 dent cytokine and Ca responses has also been reported (14–16). The PIMs are the major phospholipid components of the my- Received for publication December 9, 2005. Accepted for publication May 1, 2006. cobacterial cell wall. They are a heterogeneous mixture of families The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance (Fig. 1), which differ by the number of mannosyl residues in their ϭ with 18 U.S.C. Section 1734 solely to indicate this fact. structure (PIMxf, x number of mannoses). Each family is com- 1 This work was supported by the National Institutes of Health Grant AI-052458. posed of several species that differ in their fatty acid content 2 ϭ Address correspondence and reprint requests to Dr. Larry S. Schlesinger, Depart- (AcyPIMx, y number of fatty acids where 0, 1, or 2 denotes di-, ment of Internal Medicine, Ohio State University, 420 West 12th Avenue, 200 Med- tri-, or tetra-acylated species, respectively). As shown in Fig. 1, ical Research Facility, Columbus, OH 43210. E-mail address: Larry.Schlesinger@ osumc.edu PIM structures consist of a phosphatidylinositol anchor with a mannosyl unit attached to position C2 of the myo-inositol. Addi- 3 Abbreviations used in this paper: M.tb, Mycobacterium tuberculosis; PRR, pattern recognition receptor; PIM, phosphatidyl-myo-inositol mannoside; LM, lipomannan; tional substitutions at the C6 position of the myo-inositol by one, ManLAM, mannose-capped lipoarabinomannan; MR, mannose receptor; DC-SIGN, two, or three mannosyl units define the PIM2f, PIM3f, and PIM4f, dendritic cell-specific ICAM-3 grabbing non-integrin; P-L, phagosome-lysosome; HSA, human serum albumin; MDM, monocyte-derived macrophage; WT, wild type; respectively. The terminal mannose of the PIM4f may be further CRD, carbohydrate recognition domain; TBST, tuberculostearic acid. substituted at position C2 by one or two mannosyl units leading to Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 1806 RECOGNITION OF PIMs BY MACROPHAGE C-TYPE LECTINS Downloaded from http://www.jimmunol.org/ by guest on September 29, 2021 FIGURE 1. Structure of the M.tb cell envelope mannose-containing glycoconjugates. Diagram depicting structures of PI - PIM6, LM, and ManLAM from M.tb. PIMs as well as LM and ManLAM have four potential sites for fatty acid additions. Commonly, the C1 and C2 positions of the ns-glycerol of the PI anchor are substituted by a tuberculostearic and palmitic acid, respectively (PIMy). Further acylation may occur in position C6 of the mannose ␣ 3 attached to the C2 position of the myo-inositol (Ac1PIMy) and to the C3 position of the myo-inositol (Ac2PIMy). LM is characterized by an (1 6)-mannan core, which has substitutions at the C2 position of some of its mannoses. ManLAM is characterized by its terminal mono-, di-, and trimannoside caps, which interact with the MR and DC-SIGN during M.tb phagocytosis. PIM5f and PIM6f contain mono- and dimannoside cap-like structures, respectively. the formation of PIM5forPIM6f, respectively. The latter two fam- uate the association of highly purified M.tb PIM families and spe- ilies are the highest ones present in M.tb (Fig. 1) and their nonre- cies with the human macrophage MR. In addition, by comparing ducing termini resemble the mono- and dimannosyl cap present in the PIM association pattern between the MR and DC-SIGN using ManLAM, respectively, raising the possibility that along with mammalian cell lines expressing each of these C-type lectins, we ManLAM, PIMs participate in the phagocytic process. Multiacy- establish the importance of PIM composition in host cell recogni- lated forms (di- to tetra-acylated) of PIMs exist in M.tb. Diacylated tion by these lectins that play a role in tuberculosis pathogenesis. forms have been reported to have both fatty acids located in their Finally, we determine the degree to which the MR is involved in ns-glycerol (denoted PIMx), triacylated forms have an additional phagosome-lysosome (P-L) fusion events for phagosomes contain- fatty acid at the C6 position of their 2-mannosyl unit attached to ing PIM-coated beads.
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