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Vol. 1, No. 3, 2009
Issue release date: April 2009
J Innate Immun 2009;1:231–243
(DOI:10.1159/000173703)

Non-Opsonic Recognition of Mycobacterium tuberculosis by Phagocytes

Schäfer G.a · Jacobs M.a · Wilkinson R.J.a–c · Brown G.D.a
aInstitute for Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, South Africa; bNational Institute for Medical Research, and cDivision of Medicine, Imperial College London, London, UK
email Corresponding Author

Abstract

The interactions between Mycobacterium tuberculosis and host phagocytes such as macrophages and dendritic cells are central to both immunity and pathogenesis. Many receptors have been implicated in recognition and binding of M. tuberculosis such as the mannose receptor, dendritic-cell-specific intercellular adhesion molecule-3 grabbing nonintegrin, dectin-1 and complement receptor 3 as well as Toll-like receptors, scavenger receptors and CD14. While in vitro studies have demonstrated clear roles for particular recep- tor(s), in vivo work in receptor-deficient animals often revealed only a minor, or no role, in infection with M. tuberculosis. The initial encounter of phagocytic cells with myco- bacteria appears to be complex and depends on various parameters. It seems likely that infection with M. tuberculosis does not occur via a single receptor-mediated pathway. Rather, multiple receptors play different roles in M. tuberculosis infection, and the overall effect depends on the expression and availability of a particular receptor on a particular cell type and its triggered downstream responses. Moreover, the role of membrane cholesterol for M. tuberculosis interactions with phagocytes adds to the complexity of mycobacterial recognition and response. This review summarizes current knowledge on non-opsonic receptors involved in binding of mycobacteria and discusses the contribution of individual receptors to the recognition process.


 goto top of outline Key Words

  • Innate immune receptors
  • Non-opsonic receptors
  • Mycobacteria

 goto top of outline Abstract

The interactions between Mycobacterium tuberculosis and host phagocytes such as macrophages and dendritic cells are central to both immunity and pathogenesis. Many receptors have been implicated in recognition and binding of M. tuberculosis such as the mannose receptor, dendritic-cell-specific intercellular adhesion molecule-3 grabbing nonintegrin, dectin-1 and complement receptor 3 as well as Toll-like receptors, scavenger receptors and CD14. While in vitro studies have demonstrated clear roles for particular recep- tor(s), in vivo work in receptor-deficient animals often revealed only a minor, or no role, in infection with M. tuberculosis. The initial encounter of phagocytic cells with myco- bacteria appears to be complex and depends on various parameters. It seems likely that infection with M. tuberculosis does not occur via a single receptor-mediated pathway. Rather, multiple receptors play different roles in M. tuberculosis infection, and the overall effect depends on the expression and availability of a particular receptor on a particular cell type and its triggered downstream responses. Moreover, the role of membrane cholesterol for M. tuberculosis interactions with phagocytes adds to the complexity of mycobacterial recognition and response. This review summarizes current knowledge on non-opsonic receptors involved in binding of mycobacteria and discusses the contribution of individual receptors to the recognition process.

Copyright © 2008 S. Karger AG, Basel


 goto top of outline References
  1. van Crevel R, Ottenhoff TH, van der Meer JW: Innate immunity to Mycobacterium tuberculosis. Clin Microbiol Rev 2002;15:294–309.
  2. Gatfield J, Pieters J: Essential role for cholesterol in entry of mycobacteria into macrophages. Science 2000;288:1647–1650.
  3. Ehlers MR, Daffe M: Interactions between Mycobacterium tuberculosis and host cells: are mycobacterial sugars the key? Trends Microbiol 1998;6:328–335.
  4. Ernst JD: Macrophage receptors for Mycobacterium tuberculosis. Infect Immun 1998;66:1277–1281.
  5. Means TK, Wang S, Lien E, Yoshimura A, Golenbock DT, Fenton MJ: Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. J Immunol 1999;163:3920–3927.
  6. Vergne I, Chua J, Singh SB, Deretic V: Cell biology of Mycobacterium tuberculosis phagosome. Annu Rev Cell Dev Biol 2004;20:367–394.
  7. Jayachandran R, Sundaramurthy V, Combaluzier B, Mueller P, Korf H, Huygen K, Miyazaki T, Albrecht I, Massner J, Pieters J: Survival of mycobacteria in macrophages is mediated by coronin 1-dependent activation of calcineurin. Cell 2007;130:37–50.
  8. Ferrari G, Langen H, Naito M, Pieters J: A coat protein on phagosomes involved in the intracellular survival of mycobacteria. Cell 1999;97:435–447.
  9. van der Wel N, Hava D, Houben D, Fluitsma D, van Zon M, Pierson J, Brenner M, Peters PJ: M. tuberculosis and M. leprae translocate from the phagolysosome to the cytosol in myeloid cells. Cell 2007;129:1287–1298.
  10. Jordao L, Bleck CK, Mayorga L, Griffiths G, Anes E: On the killing of mycobacteria by macrophages. Cell Microbiol 2008;10:529–548.
  11. Ehlers S, Reiling N, Gangloff S, Woltmann A, Goyert S: Mycobacterium avium infection in CD14-deficient mice fails to substantiate a significant role for CD14 in antimycobacterial protection or granulomatous inflammation. Immunology 2001;103:113–121.
  12. Hu C, Mayadas-Norton T, Tanaka K, Chan J, Salgame P: Mycobacterium tuberculosis infection in complement receptor 3-deficient mice. J Immunol 2000;165:2596–2602.
  13. Zimmerli S, Edwards S, Ernst JD: Selective receptor blockade during phagocytosis does not alter the survival and growth of Mycobacterium tuberculosis in human macrophages. Am J Respir Cell Mol Biol 1996;15:760–770.
  14. Schluger NW: Recent advances in our understanding of human host responses to tuberculosis. Respir Res 2001;2:157–163.
  15. Torrelles JB, Azad AK, Henning LN, Carlson TK, Schlesinger LS: Role of C-type lectins in mycobacterial infections. Curr Drug Targets 2008;9:102–112.
  16. Stokes RW, Haidl ID, Jefferies WA, Speert DP: Mycobacteria-macrophage interactions. Macrophage phenotype determines the nonopsonic binding of Mycobacterium tuberculosis to murine macrophages. J Immunol 1993;151:7067–7076.
  17. Stokes RW, Thorson LM, Speert DP: Nonopsonic and opsonic association of Mycobacterium tuberculosis with resident alveolar macrophages is inefficient. J Immunol 1998;160:5514–5521.
  18. Jo EK: Mycobacterial interaction with innate receptors: TLRs, C-type lectins, and NLRs. Curr Opin Infect Dis 2008;21:279–286.
  19. Zelensky AN, Gready JE: The C-type lectin-like domain superfamily. FEBS J 2005;272:6179–6217.
  20. Taylor PR, Gordon S, Martinez-Pomares L: The mannose receptor: linking homeostasis and immunity through sugar recognition. Trends Immunol 2005;26:104–110.
  21. Taylor ME: Structure and function of the macrophage mannose receptor. Results Probl Cell Differ 2001;33:105–121.
  22. Reiling N, Klug K, Krallmann-Wenzel U, Laves R, Goyert S, Taylor ME, Lindhorst TK, Ehlers S: Complex encounters at the macrophage-mycobacterium interface: studies on the role of the mannose receptor and CD14 in experimental infection models with Mycobacterium avium. Immunobiology 2001;204:558–571.
  23. Schlesinger LS, Hull SR, Kaufman TM: Binding of the terminal mannosyl units of lipoarabinomannan from a virulent strain of Mycobacterium tuberculosis to human macrophages. J Immunol 1994;152:4070–4079.
  24. Schlesinger LS: Macrophage phagocytosis of virulent but not attenuated strains of Mycobacterium tuberculosis is mediated by mannose receptors in addition to complement receptors. J Immunol 1993;150:2920–2930.
  25. Torrelles JB, Azad AK, Schlesinger LS: Fine discrimination in the recognition of individual species of phosphatidyl-myo-inositol mannosides from Mycobacterium tuberculosis by C-type lectin pattern recognition receptors. J Immunol 2006;177:1805–1816.
  26. Nigou J, Zelle-Rieser C, Gilleron M, Thurnher M, Puzo G: Mannosylated lipoarabinomannans inhibit IL-12 production by human dendritic cells: evidence for a negative signal delivered through the mannose receptor. J Immunol 2001;166:7477–7485.
  27. Kang PB, Azad AK, Torrelles JB, Kaufman TM, Beharka A, Tibesar E, DesJardin LE, Schlesinger LS: The human macrophage mannose receptor directs Mycobacterium tuberculosis lipoarabinomannan-mediated phagosome biogenesis. J Exp Med 2005;202:987–999.
  28. Bernhard OK, Lai J, Wilkinson J, Sheil MM, Cunningham AL: Proteomic analysis of DC-SIGN on dendritic cells detects tetramers required for ligand binding but no association with CD4. J Biol Chem 2004;279:51828–51835.
  29. Soilleux EJ, Morris LS, Leslie G, Chehimi J, Luo Q, Levroney E, Trowsdale J, Montaner LJ, Doms RW, Weissman D, et al: Constitutive and induced expression of DC-SIGN on dendritic cell and macrophage subpopulations in situ and in vitro. J Leukoc Biol 2002;71:445–457.
  30. Tailleux L, Pham-Thi N, Bergeron-Lafaurie A, Herrmann JL, Charles P, Schwartz O, Scheinmann P, Lagrange PH, de Blic J, Tazi A, et al: DC-SIGN induction in alveolar macrophages defines privileged target host cells for mycobacteria in patients with tuberculosis. PLoS Med 2005;2:e381.
  31. van Kooyk Y, Geijtenbeek TB: DC-SIGN: escape mechanism for pathogens. Nat Rev Immunol 2003;3:697–709.
  32. Kaufmann SH, Schaible UE: A dangerous liaison between two major killers: Mycobacterium tuberculosis and HIV target dendritic cells through DC-SIGN. J Exp Med 2003;197:1–5.
  33. Geijtenbeek TB, Van Vliet SJ, Koppel EA, Sanchez-Hernandez M, Vandenbroucke-Grauls CM, Appelmelk B, Van Kooyk Y: Mycobacteria target DC-SIGN to suppress dendritic cell function. J Exp Med 2003;197:7–17.
  34. Tailleux L, Schwartz O, Herrmann JL, Pivert E, Jackson M, Amara A, Legres L, Dreher D, Nicod LP, Gluckman JC, et al: DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells. J Exp Med 2003;197:121–127.
  35. Maeda N, Nigou J, Herrmann JL, Jackson M, Amara A, Lagrange PH, Puzo G, Gicquel B, Neyrolles O: The cell surface receptor DC-SIGN discriminates between Mycobacterium species through selective recognition of the mannose caps on lipoarabinomannan. J Biol Chem 2003;278:5513–5516.
  36. Herrmann JL, Lagrange PH: Dendritic cells and Mycobacterium tuberculosis: which is the Trojan horse? Pathol Biol (Paris) 2005;53:35–40.
  37. Vannberg FO, Chapman SJ, Khor CC, Tosh K, Floyd S, Jackson-Sillah D, Crampin A, Sichali L, Bah B, Gustafson P, et al: CD209 genetic polymorphism and tuberculosis disease. PLoS ONE 2008;3:e1388.
  38. Barreiro LB, Neyrolles O, Babb CL, Tailleux L, Quach H, McElreavey K, Helden PD, Hoal EG, Gicquel B, Quintana-Murci L: Promoter variation in the DC-SIGN-encoding gene CD209 is associated with tuberculosis. PLoS Med 2006;3:e20.
  39. Wieland CW, Koppel EA, den Dunnen J, Florquin S, McKenzie AN, van Kooyk Y, van der Poll T, Geijtenbeek TB: Mice lacking SIGNR1 have stronger T helper 1 responses to Mycobacterium tuberculosis. Microbes Infect 2007;9:134–141.
  40. Brown GD: Dectin-1:a signalling non-TLR pattern-recognition receptor. Nat Rev Immunol 2006;6:33–43.
  41. Taylor PR, Tsoni SV, Willment JA, Dennehy KM, Rosas M, Findon H, Haynes K, Steele C, Botto M, Gordon S, Brown GD: Dectin-1 is required for β-glucan recognition and control of fungal infection. Nat Immunol 2007;8:31–38.
  42. Yadav M, Schorey JS: The β-glucan receptor dectin-1 functions together with TLR2 to mediate macrophage activation by mycobacteria. Blood 2006;108:3168–3175.
  43. Rothfuchs AG, Bafica A, Feng CG, Egen JG, Williams DL, Brown GD, Sher A: Dectin-1 interaction with Mycobacterium tuberculosis leads to enhanced IL-12p40 production by splenic dendritic cells. J Immunol 2007;179:3463–3471.
  44. Shin DM, Yang CS, Yuk JM, Lee JY, Kim KH, Shin SJ, Takahara K, Lee SJ, Jo EK: Mycobacterium abscessus activates the macrophage innate immune response via a physical and functional interaction between TLR2 and dectin-1. Cell Microbiol 2008;10:1608–1621.
  45. Appelberg R, Sarmento A, Castro AG: Tumour necrosis factor-α (TNF-α) in the host resistance to mycobacteria of distinct virulence. Clin Exp Immunol 1995;101:308–313.
  46. Anderson ST, Williams AJ, Brown JR, Newton SM, Simsova M, Nicol MP, Sebo P, Levin M, Wilkinson RJ, Wilkinson KA: Transmission of Mycobacterium tuberculosis undetected by tuberculin skin testing. Am J Respir Crit Care Med 2006;173:1038–1042.
  47. Newton SM, Smith RJ, Wilkinson KA, Nicol MP, Garton NJ, Staples KJ, Stewart GR, Wain JR, Martineau AR, Fandrich S, et al: A deletion defining a common Asian lineage of Mycobacterium tuberculosis associates with immune subversion. Proc Natl Acad Sci USA 2006;103:15594–15598.
  48. Dennehy KM, Ferwerda G, Faro-Trindade I, Pyz E, Willment JA, Taylor PR, Kerrigan A, Tsoni SV, Gordon S, Meyer-Wentrup F, et al: Syk kinase is required for collaborative cytokine production induced through dectin-1 and Toll-like receptors. Eur J Immunol 2008;38:500–506.
  49. Dinadayala P, Lemassu A, Granovski P, Cerantola S, Winter N, Daffe M: Revisiting the structure of the anti-neoplastic glucans of Mycobacterium bovis Bacille Calmette-Guérin. Structural analysis of the extracellular and boiling water extract-derived glucans of the vaccine substrains. J Biol Chem 2004;279:12369–12378.
  50. Ariizumi K, Shen GL, Shikano S, Xu S, Ritter R 3rd, Kumamoto T, Edelbaum D, Morita A, Bergstresser PR, Takashima A: Identification of a novel, dendritic cell-associated molecule, dectin-1, by subtractive cDNA cloning. J Biol Chem 2000;275:20157–20167.
  51. Schlesinger LS, Bellinger-Kawahara CG, Payne NR, Horwitz MA: Phagocytosis of Mycobacterium tuberculosis is mediated by human monocyte complement receptors and complement component C3. J Immunol 1990;144:2771–2780.
  52. Schorey JS, Carroll MC, Brown EJ: A macrophage invasion mechanism of pathogenic mycobacteria. Science 1997;277:1091–1093.
  53. Velasco-Velazquez MA, Barrera D, Gonzalez-Arenas A, Rosales C, Agramonte-Hevia J: Macrophage-Mycobacterium tuberculosis interactions: role of complement receptor 3. Microb Pathog 2003;35:125–131.
  54. Thornton BP, Vetvicka V, Pitman M, Goldman RC, Ross GD: Analysis of the sugar specificity and molecular location of the β-glucan-binding lectin site of complement receptor type 3 (CD11b/CD18). J Immunol 1996;156:1235–1246.
  55. Villeneuve C, Gilleron M, Maridonneau-Parini I, Daffe M, Astarie-Dequeker C, Etienne G: Mycobacteria use their surface-exposed glycolipids to infect human macrophages through a receptor-dependent process. J Lipid Res 2005;46:475–483.
  56. Rooyakkers AW, Stokes RW: Absence of complement receptor 3 results in reduced binding and ingestion of Mycobacterium tuberculosis but has no significant effect on the induction of reactive oxygen and nitrogen intermediates or on the survival of the bacteria in resident and interferon-γ activated macrophages. Microb Pathog 2005;39:57–67.
  57. Kaisho T, Akira S: Toll-like receptor function and signaling. J Allergy Clin Immunol 2006;117:979–987; quiz 988.
  58. Chang JS, Huggett JF, Dheda K, Kim LU, Zumla A, Rook GA: Myobacterium tuberculosis induces selective up-regulation of TLRs in the mononuclear leukocytes of patients with active pulmonary tuberculosis. J Immunol 2006;176:3010–3018.
  59. Quesniaux V, Fremond C, Jacobs M, Parida S, Nicolle D, Yeremeev V, Bihl F, Erard F, Botha T, Drennan M, et al: Toll-like receptor pathways in the immune responses to mycobacteria. Microbes Infect 2004;6:946–959.
  60. Doz E, Rose S, Nigou J, Gilleron M, Puzo G, Erard F, Ryffel B, Quesniaux VF: Acylation determines the toll-like receptor (TLR)-dependent positive versus TLR2-, mannose receptor-, and SIGNR1-independent negative regulation of pro-inflammatory cytokines by mycobacterial lipomannan. J Biol Chem 2007;282:26014–26025.
  61. Pathak SK, Basu S, Basu KK, Banerjee A, Pathak S, Bhattacharyya A, Kaisho T, Kundu M, Basu J: Direct extracellular interaction between the early secreted antigen ESAT-6 of Mycobacterium tuberculosis and TLR2 inhibits TLR signaling in macrophages. Nat Immunol 2007;8:610–618.
  62. Garlanda C, Di Liberto D, Vecchi A, La Manna MP, Buracchi C, Caccamo N, Salerno A, Dieli F, Mantovani A: Damping excessive inflammation and tissue damage in Mycobacterium tuberculosis infection by Toll IL-1 receptor 8/single Ig IL-1-related receptor, a negative regulator of IL-1/TLR signaling. J Immunol 2007;179:3119–3125.
  63. Mukhopadhyay S, Herre J, Brown GD, Gordon S: The potential for Toll-like receptors to collaborate with other innate immune receptors. Immunology 2004;112:521–530.
  64. Schierloh P, Yokobori N, Aleman M, Landoni V, Geffner L, Musella RM, Castagnino J, Baldini M, Abbate E, de la Barrera SS, Sasiain MC: Mycobacterium tuberculosis-induced γ-interferon production by natural killer cells requires cross-talk with antigen-presenting cells involving Toll-like receptors 2 and 4 and the mannose receptor in tuberculous pleurisy. Infect Immun 2007;75:5325–5337.
  65. Jo EK, Yang CS, Choi CH, Harding CV: Intracellular signalling cascades regulating innate immune responses to Mycobacteria: branching out from Toll-like receptors. Cell Microbiol 2007;9:1087–1098.
  66. Means TK, Jones BW, Schromm AB, Shurtleff BA, Smith JA, Keane J, Golenbock DT, Vogel SN, Fenton MJ: Differential effects of a Toll-like receptor antagonist on Mycobacterium tuberculosis-induced macrophage responses. J Immunol 2001;166:4074–4082.
  67. Bafica A, Scanga CA, Feng CG, Leifer C, Cheever A, Sher A: TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis. J Exp Med 2005;202:1715–1724.
  68. Abel B, Thieblemont N, Quesniaux VJ, Brown N, Mpagi J, Miyake K, Bihl F, Ryffel B: Toll-like receptor 4 expression is required to control chronic Mycobacterium tuberculosis infection in mice. J Immunol 2002;169:3155–3162.
  69. Drennan MB, Nicolle D, Quesniaux VJ, Jacobs M, Allie N, Mpagi J, Fremond C, Wagner H, Kirschning C, Ryffel B: Toll-like receptor 2-deficient mice succumb to Mycobacterium tuberculosis infection. Am J Pathol 2004;164:49–57.
  70. Reiling N, Holscher C, Fehrenbach A, Kroger S, Kirschning CJ, Goyert S, Ehlers S: Cutting edge: Toll-like receptor (TLR)2- and TLR4-mediated pathogen recognition in resistance to airborne infection with Mycobacterium tuberculosis. J Immunol 2002;169:3480–3484.
  71. Feng CG, Scanga CA, Collazo-Custodio CM, Cheever AW, Hieny S, Caspar P, Sher A: Mice lacking myeloid differentiation factor 88 display profound defects in host resistance and immune responses to Mycobacterium avium infection not exhibited by Toll-like receptor 2 (TLR2)- and TLR4-deficient animals. J Immunol 2003;171:4758–4764.
  72. Holscher C, Reiling N, Schaible UE, Holscher A, Bathmann C, Korbel D, Lenz I, Sonntag T, Kroger S, Akira S, et al: Containment of aerogenic Mycobacterium tuberculosis infection in mice does not require MyD88 adaptor function for TLR2, -4 and -9. Eur J Immunol 2008;38:680–694.
  73. Sugawara I, Yamada H, Li C, Mizuno S, Takeuchi O, Akira S: Mycobacterial infection in TLR2 and TLR6 knockout mice. Microbiol Immunol 2003;47:327–336.
  74. Thuong NT, Hawn TR, Thwaites GE, Chau TT, Lan NT, Quy HT, Hieu NT, Aderem A, Hien TT, Farrar JJ, Dunstan SJ: A polymorphism in human TLR2 is associated with increased susceptibility to tuberculous meningitis. Genes Immun 2007;8:422–428.
  75. Peiser L, Gordon S: The function of scavenger receptors expressed by macrophages and their role in the regulation of inflammation. Microbes Infect 2001;3:149–159.
  76. Neyrolles O, Hernandez-Pando R, Pietri-Rouxel F, Fornes P, Tailleux L, Barrios Payan JA, Pivert E, Bordat Y, Aguilar D, Prevost MC, et al: Is adipose tissue a place for Mycobacterium tuberculosis persistence? PLoS ONE 2006;1:e43.
  77. Philips JA, Rubin EJ, Perrimon N: Drosophila RNAi screen reveals CD36 family member required for mycobacterial infection. Science 2005;309:1251–1253.
  78. Hoebe K, Georgel P, Rutschmann S, Du X, Mudd S, Crozat K, Sovath S, Shamel L, Hartung T, Zahringer U, Beutler B: CD36 is a sensor of diacylglycerides. Nature 2005;433:523–527.
  79. Dziarski R, Ulmer AJ, Gupta D: Interactions of CD14 with components of Gram-positive bacteria. Chem Immunol 2000;74:83–107.
  80. Pugin J, Heumann ID, Tomasz A, Kravchenko VV, Akamatsu Y, Nishijima M, Glauser MP, Tobias PS, Ulevitch RJ: CD14 is a pattern recognition receptor. Immunity 1994;1:509–516.
  81. Lewthwaite JC, Coates AR, Tormay P, Singh M, Mascagni P, Poole S, Roberts M, Sharp L, Henderson B: Mycobacterium tuberculosis chaperonin 60.1 is a more potent cytokine stimulator than chaperonin 60.2 (Hsp 65) and contains a CD14-binding domain. Infect Immun 2001;69:7349–7355.
  82. Peterson PK, Gekker G, Hu S, Sheng WS, Anderson WR, Ulevitch RJ, Tobias PS, Gustafson KV, Molitor TW, Chao CC: CD14 receptor-mediated uptake of nonopsonized Mycobacterium tuberculosis by human microglia. Infect Immun 1995;63:1598–1602.
  83. Kaisho T, Akira S: Critical roles of Toll-like receptors in host defense. Crit Rev Immunol 2000;20:393–405.
  84. Hoheisel G, Zheng L, Teschler H, Striz I, Costabel U: Increased soluble CD14 levels in BAL fluid in pulmonary tuberculosis. Chest 1995;108:1614–1616.
  85. Rosas-Taraco AG, Revol A, Salinas-Carmona MC, Rendon A, Caballero-Olin G, Arce-Mendoza AY: CD14 C(-159)T polymorphism is a risk factor for development of pulmonary tuberculosis. J Infect Dis 2007;196:1698–1706.
  86. Wieland CW, van der Windt GJ, Wiersinga WJ, Florquin S, van der Poll T: CD14 contributes to pulmonary inflammation and mortality during murine tuberculosis. Immunology 2008;125:272–279.
  87. Lazarevic V, Myers AJ, Scanga CA, Flynn JL: CD40, but not CD40L, is required for the optimal priming of T cells and control of aerosol M. tuberculosis infection. Immunity 2003;19:823–835.
  88. Demangel C, Palendira U, Feng CG, Heath AW, Bean AG, Britton WJ: Stimulation of dendritic cells via CD40 enhances immune responses to Mycobacterium tuberculosis infection. Infect Immun 2001;69:2456–2461.
  89. Fratazzi C, Manjunath N, Arbeit RD, Carini C, Gerken TA, Ardman B, Remold-O’Donnell E, Remold HG: A macrophage invasion mechanism for mycobacteria implicating the extracellular domain of CD43. J Exp Med 2000;192:183–192.
  90. Randhawa AK, Ziltener HJ, Stokes RW: CD43 controls the intracellular growth of Mycobacterium tuberculosis through the induction of TNF-α-mediated apoptosis. Cell Microbiol 2008;10:2105–2017.
  91. Leemans JC, Florquin S, Heikens M, Pals ST, van der Neut R, Van Der Poll T: CD44 is a macrophage binding site for Mycobacterium tuberculosis that mediates macrophage recruitment and protective immunity against tuberculosis. J Clin Invest 2003;111:681–689.
  92. Kipnis A, Basaraba RJ, Turner J, Orme IM: Increased neutrophil influx but no impairment of protective immunity to tuberculosis in mice lacking the CD44 molecule. J Leukoc Biol 2003;74:992–997.
  93. de Chastellier C, Thilo L: Cholesterol depletion in Mycobacterium avium-infected macrophages overcomes the block in phagosome maturation and leads to the reversible sequestration of viable mycobacteria in phagolysosome-derived autophagic vacuoles. Cell Microbiol 2006;8:242–256.
  94. Peyron P, Bordier C, N’Diaye EN, Maridonneau-Parini I: Nonopsonic phagocytosis of Mycobacterium kansasii by human neutrophils depends on cholesterol and is mediated by CR3 associated with glycosylphosphatidylinositol-anchored proteins. J Immunol 2000;165:5186–5191.
  95. Perez-Guzman C, Vargas MH: Hypocholesterolemia: a major risk factor for developing pulmonary tuberculosis? Med Hypotheses 2006;66:1227–1230.
  96. Martens GW, Arikan MC, Lee J, Ren F, Vallerskog T, Kornfeld H: Hypercholesterolemia impairs immunity to tuberculosis. Infect Immun 2008;76:3464–3472.
  97. Van der Geize R, Yam K, Heuser T, Wilbrink MH, Hara H, Anderton MC, Sim E, Dijkhuizen L, Davies JE, Mohn WW, Eltis LD: A gene cluster encoding cholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages. Proc Natl Acad Sci USA 2007;104:1947–1952.
  98. Stokes RW, Norris-Jones R, Brooks DE, Beveridge TJ, Doxsee D, Thorson LM: The glycan-rich outer layer of the cell wall of Mycobacterium tuberculosis acts as an antiphagocytic capsule limiting the association of the bacterium with macrophages. Infect Immun 2004;72:5676–5686.
  99. Hall-Stoodley L, Watts G, Crowther JE, Balagopal A, Torrelles JB, Robison-Cox J, Bargatze RF, Harmsen AG, Crouch EC, Schlesinger LS: Mycobacterium tuberculosis binding to human surfactant proteins A and D, fibronectin, and small airway epithelial cells under shear conditions. Infect Immun 2006;74:3587–3596.
  100. North RJ: Mycobacterium tuberculosis is strikingly more virulent for mice when given via the respiratory than via the intravenous route. J Infect Dis 1995;172:1550–1553.

 goto top of outline Author Contacts

Dr. Gordon D. Brown, Institute of Infectious Disease and Molecular Medicine
Division of Immunology, CLS, Faculty of Health Sciences
University of Cape Town, Lower Ground Floor, Wernher & Beit Building South
Groote Schuur Campus, Observatory, 7925 Cape Town (South Africa)
Tel. +27 21 406 6684, Fax +27 21 406 6029, E-Mail gordon.brown@mweb.co.za


 goto top of outline Article Information

Received: August 26, 2008
Accepted after revision: September 8, 2008
Published online: November 12, 2008
Number of Print Pages : 13
Number of Figures : 1, Number of Tables : 0, Number of References : 100


 goto top of outline Publication Details

Journal of Innate Immunity

Vol. 1, No. 3, Year 2009 (Cover Date: April 2009)

Journal Editor: Herwald H. (Lund), Egesten A. (Lund)
ISSN: 1662-811X (Print), eISSN: 1662-8128 (Online)

For additional information: http://www.karger.com/JIN


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Abstract

The interactions between Mycobacterium tuberculosis and host phagocytes such as macrophages and dendritic cells are central to both immunity and pathogenesis. Many receptors have been implicated in recognition and binding of M. tuberculosis such as the mannose receptor, dendritic-cell-specific intercellular adhesion molecule-3 grabbing nonintegrin, dectin-1 and complement receptor 3 as well as Toll-like receptors, scavenger receptors and CD14. While in vitro studies have demonstrated clear roles for particular recep- tor(s), in vivo work in receptor-deficient animals often revealed only a minor, or no role, in infection with M. tuberculosis. The initial encounter of phagocytic cells with myco- bacteria appears to be complex and depends on various parameters. It seems likely that infection with M. tuberculosis does not occur via a single receptor-mediated pathway. Rather, multiple receptors play different roles in M. tuberculosis infection, and the overall effect depends on the expression and availability of a particular receptor on a particular cell type and its triggered downstream responses. Moreover, the role of membrane cholesterol for M. tuberculosis interactions with phagocytes adds to the complexity of mycobacterial recognition and response. This review summarizes current knowledge on non-opsonic receptors involved in binding of mycobacteria and discusses the contribution of individual receptors to the recognition process.



 goto top of outline Author Contacts

Dr. Gordon D. Brown, Institute of Infectious Disease and Molecular Medicine
Division of Immunology, CLS, Faculty of Health Sciences
University of Cape Town, Lower Ground Floor, Wernher & Beit Building South
Groote Schuur Campus, Observatory, 7925 Cape Town (South Africa)
Tel. +27 21 406 6684, Fax +27 21 406 6029, E-Mail gordon.brown@mweb.co.za


 goto top of outline Article Information

Received: August 26, 2008
Accepted after revision: September 8, 2008
Published online: November 12, 2008
Number of Print Pages : 13
Number of Figures : 1, Number of Tables : 0, Number of References : 100


 goto top of outline Publication Details

Journal of Innate Immunity

Vol. 1, No. 3, Year 2009 (Cover Date: April 2009)

Journal Editor: Herwald H. (Lund), Egesten A. (Lund)
ISSN: 1662-811X (Print), eISSN: 1662-8128 (Online)

For additional information: http://www.karger.com/JIN


Copyright / Drug Dosage

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Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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References

  1. van Crevel R, Ottenhoff TH, van der Meer JW: Innate immunity to Mycobacterium tuberculosis. Clin Microbiol Rev 2002;15:294–309.
  2. Gatfield J, Pieters J: Essential role for cholesterol in entry of mycobacteria into macrophages. Science 2000;288:1647–1650.
  3. Ehlers MR, Daffe M: Interactions between Mycobacterium tuberculosis and host cells: are mycobacterial sugars the key? Trends Microbiol 1998;6:328–335.
  4. Ernst JD: Macrophage receptors for Mycobacterium tuberculosis. Infect Immun 1998;66:1277–1281.
  5. Means TK, Wang S, Lien E, Yoshimura A, Golenbock DT, Fenton MJ: Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. J Immunol 1999;163:3920–3927.
  6. Vergne I, Chua J, Singh SB, Deretic V: Cell biology of Mycobacterium tuberculosis phagosome. Annu Rev Cell Dev Biol 2004;20:367–394.
  7. Jayachandran R, Sundaramurthy V, Combaluzier B, Mueller P, Korf H, Huygen K, Miyazaki T, Albrecht I, Massner J, Pieters J: Survival of mycobacteria in macrophages is mediated by coronin 1-dependent activation of calcineurin. Cell 2007;130:37–50.
  8. Ferrari G, Langen H, Naito M, Pieters J: A coat protein on phagosomes involved in the intracellular survival of mycobacteria. Cell 1999;97:435–447.
  9. van der Wel N, Hava D, Houben D, Fluitsma D, van Zon M, Pierson J, Brenner M, Peters PJ: M. tuberculosis and M. leprae translocate from the phagolysosome to the cytosol in myeloid cells. Cell 2007;129:1287–1298.
  10. Jordao L, Bleck CK, Mayorga L, Griffiths G, Anes E: On the killing of mycobacteria by macrophages. Cell Microbiol 2008;10:529–548.
  11. Ehlers S, Reiling N, Gangloff S, Woltmann A, Goyert S: Mycobacterium avium infection in CD14-deficient mice fails to substantiate a significant role for CD14 in antimycobacterial protection or granulomatous inflammation. Immunology 2001;103:113–121.
  12. Hu C, Mayadas-Norton T, Tanaka K, Chan J, Salgame P: Mycobacterium tuberculosis infection in complement receptor 3-deficient mice. J Immunol 2000;165:2596–2602.
  13. Zimmerli S, Edwards S, Ernst JD: Selective receptor blockade during phagocytosis does not alter the survival and growth of Mycobacterium tuberculosis in human macrophages. Am J Respir Cell Mol Biol 1996;15:760–770.
  14. Schluger NW: Recent advances in our understanding of human host responses to tuberculosis. Respir Res 2001;2:157–163.
  15. Torrelles JB, Azad AK, Henning LN, Carlson TK, Schlesinger LS: Role of C-type lectins in mycobacterial infections. Curr Drug Targets 2008;9:102–112.
  16. Stokes RW, Haidl ID, Jefferies WA, Speert DP: Mycobacteria-macrophage interactions. Macrophage phenotype determines the nonopsonic binding of Mycobacterium tuberculosis to murine macrophages. J Immunol 1993;151:7067–7076.
  17. Stokes RW, Thorson LM, Speert DP: Nonopsonic and opsonic association of Mycobacterium tuberculosis with resident alveolar macrophages is inefficient. J Immunol 1998;160:5514–5521.
  18. Jo EK: Mycobacterial interaction with innate receptors: TLRs, C-type lectins, and NLRs. Curr Opin Infect Dis 2008;21:279–286.
  19. Zelensky AN, Gready JE: The C-type lectin-like domain superfamily. FEBS J 2005;272:6179–6217.
  20. Taylor PR, Gordon S, Martinez-Pomares L: The mannose receptor: linking homeostasis and immunity through sugar recognition. Trends Immunol 2005;26:104–110.
  21. Taylor ME: Structure and function of the macrophage mannose receptor. Results Probl Cell Differ 2001;33:105–121.
  22. Reiling N, Klug K, Krallmann-Wenzel U, Laves R, Goyert S, Taylor ME, Lindhorst TK, Ehlers S: Complex encounters at the macrophage-mycobacterium interface: studies on the role of the mannose receptor and CD14 in experimental infection models with Mycobacterium avium. Immunobiology 2001;204:558–571.
  23. Schlesinger LS, Hull SR, Kaufman TM: Binding of the terminal mannosyl units of lipoarabinomannan from a virulent strain of Mycobacterium tuberculosis to human macrophages. J Immunol 1994;152:4070–4079.
  24. Schlesinger LS: Macrophage phagocytosis of virulent but not attenuated strains of Mycobacterium tuberculosis is mediated by mannose receptors in addition to complement receptors. J Immunol 1993;150:2920–2930.
  25. Torrelles JB, Azad AK, Schlesinger LS: Fine discrimination in the recognition of individual species of phosphatidyl-myo-inositol mannosides from Mycobacterium tuberculosis by C-type lectin pattern recognition receptors. J Immunol 2006;177:1805–1816.
  26. Nigou J, Zelle-Rieser C, Gilleron M, Thurnher M, Puzo G: Mannosylated lipoarabinomannans inhibit IL-12 production by human dendritic cells: evidence for a negative signal delivered through the mannose receptor. J Immunol 2001;166:7477–7485.
  27. Kang PB, Azad AK, Torrelles JB, Kaufman TM, Beharka A, Tibesar E, DesJardin LE, Schlesinger LS: The human macrophage mannose receptor directs Mycobacterium tuberculosis lipoarabinomannan-mediated phagosome biogenesis. J Exp Med 2005;202:987–999.
  28. Bernhard OK, Lai J, Wilkinson J, Sheil MM, Cunningham AL: Proteomic analysis of DC-SIGN on dendritic cells detects tetramers required for ligand binding but no association with CD4. J Biol Chem 2004;279:51828–51835.
  29. Soilleux EJ, Morris LS, Leslie G, Chehimi J, Luo Q, Levroney E, Trowsdale J, Montaner LJ, Doms RW, Weissman D, et al: Constitutive and induced expression of DC-SIGN on dendritic cell and macrophage subpopulations in situ and in vitro. J Leukoc Biol 2002;71:445–457.
  30. Tailleux L, Pham-Thi N, Bergeron-Lafaurie A, Herrmann JL, Charles P, Schwartz O, Scheinmann P, Lagrange PH, de Blic J, Tazi A, et al: DC-SIGN induction in alveolar macrophages defines privileged target host cells for mycobacteria in patients with tuberculosis. PLoS Med 2005;2:e381.
  31. van Kooyk Y, Geijtenbeek TB: DC-SIGN: escape mechanism for pathogens. Nat Rev Immunol 2003;3:697–709.
  32. Kaufmann SH, Schaible UE: A dangerous liaison between two major killers: Mycobacterium tuberculosis and HIV target dendritic cells through DC-SIGN. J Exp Med 2003;197:1–5.
  33. Geijtenbeek TB, Van Vliet SJ, Koppel EA, Sanchez-Hernandez M, Vandenbroucke-Grauls CM, Appelmelk B, Van Kooyk Y: Mycobacteria target DC-SIGN to suppress dendritic cell function. J Exp Med 2003;197:7–17.
  34. Tailleux L, Schwartz O, Herrmann JL, Pivert E, Jackson M, Amara A, Legres L, Dreher D, Nicod LP, Gluckman JC, et al: DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells. J Exp Med 2003;197:121–127.
  35. Maeda N, Nigou J, Herrmann JL, Jackson M, Amara A, Lagrange PH, Puzo G, Gicquel B, Neyrolles O: The cell surface receptor DC-SIGN discriminates between Mycobacterium species through selective recognition of the mannose caps on lipoarabinomannan. J Biol Chem 2003;278:5513–5516.
  36. Herrmann JL, Lagrange PH: Dendritic cells and Mycobacterium tuberculosis: which is the Trojan horse? Pathol Biol (Paris) 2005;53:35–40.
  37. Vannberg FO, Chapman SJ, Khor CC, Tosh K, Floyd S, Jackson-Sillah D, Crampin A, Sichali L, Bah B, Gustafson P, et al: CD209 genetic polymorphism and tuberculosis disease. PLoS ONE 2008;3:e1388.
  38. Barreiro LB, Neyrolles O, Babb CL, Tailleux L, Quach H, McElreavey K, Helden PD, Hoal EG, Gicquel B, Quintana-Murci L: Promoter variation in the DC-SIGN-encoding gene CD209 is associated with tuberculosis. PLoS Med 2006;3:e20.
  39. Wieland CW, Koppel EA, den Dunnen J, Florquin S, McKenzie AN, van Kooyk Y, van der Poll T, Geijtenbeek TB: Mice lacking SIGNR1 have stronger T helper 1 responses to Mycobacterium tuberculosis. Microbes Infect 2007;9:134–141.
  40. Brown GD: Dectin-1:a signalling non-TLR pattern-recognition receptor. Nat Rev Immunol 2006;6:33–43.
  41. Taylor PR, Tsoni SV, Willment JA, Dennehy KM, Rosas M, Findon H, Haynes K, Steele C, Botto M, Gordon S, Brown GD: Dectin-1 is required for β-glucan recognition and control of fungal infection. Nat Immunol 2007;8:31–38.
  42. Yadav M, Schorey JS: The β-glucan receptor dectin-1 functions together with TLR2 to mediate macrophage activation by mycobacteria. Blood 2006;108:3168–3175.
  43. Rothfuchs AG, Bafica A, Feng CG, Egen JG, Williams DL, Brown GD, Sher A: Dectin-1 interaction with Mycobacterium tuberculosis leads to enhanced IL-12p40 production by splenic dendritic cells. J Immunol 2007;179:3463–3471.
  44. Shin DM, Yang CS, Yuk JM, Lee JY, Kim KH, Shin SJ, Takahara K, Lee SJ, Jo EK: Mycobacterium abscessus activates the macrophage innate immune response via a physical and functional interaction between TLR2 and dectin-1. Cell Microbiol 2008;10:1608–1621.
  45. Appelberg R, Sarmento A, Castro AG: Tumour necrosis factor-α (TNF-α) in the host resistance to mycobacteria of distinct virulence. Clin Exp Immunol 1995;101:308–313.
  46. Anderson ST, Williams AJ, Brown JR, Newton SM, Simsova M, Nicol MP, Sebo P, Levin M, Wilkinson RJ, Wilkinson KA: Transmission of Mycobacterium tuberculosis undetected by tuberculin skin testing. Am J Respir Crit Care Med 2006;173:1038–1042.
  47. Newton SM, Smith RJ, Wilkinson KA, Nicol MP, Garton NJ, Staples KJ, Stewart GR, Wain JR, Martineau AR, Fandrich S, et al: A deletion defining a common Asian lineage of Mycobacterium tuberculosis associates with immune subversion. Proc Natl Acad Sci USA 2006;103:15594–15598.
  48. Dennehy KM, Ferwerda G, Faro-Trindade I, Pyz E, Willment JA, Taylor PR, Kerrigan A, Tsoni SV, Gordon S, Meyer-Wentrup F, et al: Syk kinase is required for collaborative cytokine production induced through dectin-1 and Toll-like receptors. Eur J Immunol 2008;38:500–506.
  49. Dinadayala P, Lemassu A, Granovski P, Cerantola S, Winter N, Daffe M: Revisiting the structure of the anti-neoplastic glucans of Mycobacterium bovis Bacille Calmette-Guérin. Structural analysis of the extracellular and boiling water extract-derived glucans of the vaccine substrains. J Biol Chem 2004;279:12369–12378.
  50. Ariizumi K, Shen GL, Shikano S, Xu S, Ritter R 3rd, Kumamoto T, Edelbaum D, Morita A, Bergstresser PR, Takashima A: Identification of a novel, dendritic cell-associated molecule, dectin-1, by subtractive cDNA cloning. J Biol Chem 2000;275:20157–20167.
  51. Schlesinger LS, Bellinger-Kawahara CG, Payne NR, Horwitz MA: Phagocytosis of Mycobacterium tuberculosis is mediated by human monocyte complement receptors and complement component C3. J Immunol 1990;144:2771–2780.
  52. Schorey JS, Carroll MC, Brown EJ: A macrophage invasion mechanism of pathogenic mycobacteria. Science 1997;277:1091–1093.
  53. Velasco-Velazquez MA, Barrera D, Gonzalez-Arenas A, Rosales C, Agramonte-Hevia J: Macrophage-Mycobacterium tuberculosis interactions: role of complement receptor 3. Microb Pathog 2003;35:125–131.
  54. Thornton BP, Vetvicka V, Pitman M, Goldman RC, Ross GD: Analysis of the sugar specificity and molecular location of the β-glucan-binding lectin site of complement receptor type 3 (CD11b/CD18). J Immunol 1996;156:1235–1246.
  55. Villeneuve C, Gilleron M, Maridonneau-Parini I, Daffe M, Astarie-Dequeker C, Etienne G: Mycobacteria use their surface-exposed glycolipids to infect human macrophages through a receptor-dependent process. J Lipid Res 2005;46:475–483.
  56. Rooyakkers AW, Stokes RW: Absence of complement receptor 3 results in reduced binding and ingestion of Mycobacterium tuberculosis but has no significant effect on the induction of reactive oxygen and nitrogen intermediates or on the survival of the bacteria in resident and interferon-γ activated macrophages. Microb Pathog 2005;39:57–67.
  57. Kaisho T, Akira S: Toll-like receptor function and signaling. J Allergy Clin Immunol 2006;117:979–987; quiz 988.
  58. Chang JS, Huggett JF, Dheda K, Kim LU, Zumla A, Rook GA: Myobacterium tuberculosis induces selective up-regulation of TLRs in the mononuclear leukocytes of patients with active pulmonary tuberculosis. J Immunol 2006;176:3010–3018.
  59. Quesniaux V, Fremond C, Jacobs M, Parida S, Nicolle D, Yeremeev V, Bihl F, Erard F, Botha T, Drennan M, et al: Toll-like receptor pathways in the immune responses to mycobacteria. Microbes Infect 2004;6:946–959.
  60. Doz E, Rose S, Nigou J, Gilleron M, Puzo G, Erard F, Ryffel B, Quesniaux VF: Acylation determines the toll-like receptor (TLR)-dependent positive versus TLR2-, mannose receptor-, and SIGNR1-independent negative regulation of pro-inflammatory cytokines by mycobacterial lipomannan. J Biol Chem 2007;282:26014–26025.
  61. Pathak SK, Basu S, Basu KK, Banerjee A, Pathak S, Bhattacharyya A, Kaisho T, Kundu M, Basu J: Direct extracellular interaction between the early secreted antigen ESAT-6 of Mycobacterium tuberculosis and TLR2 inhibits TLR signaling in macrophages. Nat Immunol 2007;8:610–618.
  62. Garlanda C, Di Liberto D, Vecchi A, La Manna MP, Buracchi C, Caccamo N, Salerno A, Dieli F, Mantovani A: Damping excessive inflammation and tissue damage in Mycobacterium tuberculosis infection by Toll IL-1 receptor 8/single Ig IL-1-related receptor, a negative regulator of IL-1/TLR signaling. J Immunol 2007;179:3119–3125.
  63. Mukhopadhyay S, Herre J, Brown GD, Gordon S: The potential for Toll-like receptors to collaborate with other innate immune receptors. Immunology 2004;112:521–530.
  64. Schierloh P, Yokobori N, Aleman M, Landoni V, Geffner L, Musella RM, Castagnino J, Baldini M, Abbate E, de la Barrera SS, Sasiain MC: Mycobacterium tuberculosis-induced γ-interferon production by natural killer cells requires cross-talk with antigen-presenting cells involving Toll-like receptors 2 and 4 and the mannose receptor in tuberculous pleurisy. Infect Immun 2007;75:5325–5337.
  65. Jo EK, Yang CS, Choi CH, Harding CV: Intracellular signalling cascades regulating innate immune responses to Mycobacteria: branching out from Toll-like receptors. Cell Microbiol 2007;9:1087–1098.
  66. Means TK, Jones BW, Schromm AB, Shurtleff BA, Smith JA, Keane J, Golenbock DT, Vogel SN, Fenton MJ: Differential effects of a Toll-like receptor antagonist on Mycobacterium tuberculosis-induced macrophage responses. J Immunol 2001;166:4074–4082.
  67. Bafica A, Scanga CA, Feng CG, Leifer C, Cheever A, Sher A: TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis. J Exp Med 2005;202:1715–1724.
  68. Abel B, Thieblemont N, Quesniaux VJ, Brown N, Mpagi J, Miyake K, Bihl F, Ryffel B: Toll-like receptor 4 expression is required to control chronic Mycobacterium tuberculosis infection in mice. J Immunol 2002;169:3155–3162.
  69. Drennan MB, Nicolle D, Quesniaux VJ, Jacobs M, Allie N, Mpagi J, Fremond C, Wagner H, Kirschning C, Ryffel B: Toll-like receptor 2-deficient mice succumb to Mycobacterium tuberculosis infection. Am J Pathol 2004;164:49–57.
  70. Reiling N, Holscher C, Fehrenbach A, Kroger S, Kirschning CJ, Goyert S, Ehlers S: Cutting edge: Toll-like receptor (TLR)2- and TLR4-mediated pathogen recognition in resistance to airborne infection with Mycobacterium tuberculosis. J Immunol 2002;169:3480–3484.
  71. Feng CG, Scanga CA, Collazo-Custodio CM, Cheever AW, Hieny S, Caspar P, Sher A: Mice lacking myeloid differentiation factor 88 display profound defects in host resistance and immune responses to Mycobacterium avium infection not exhibited by Toll-like receptor 2 (TLR2)- and TLR4-deficient animals. J Immunol 2003;171:4758–4764.
  72. Holscher C, Reiling N, Schaible UE, Holscher A, Bathmann C, Korbel D, Lenz I, Sonntag T, Kroger S, Akira S, et al: Containment of aerogenic Mycobacterium tuberculosis infection in mice does not require MyD88 adaptor function for TLR2, -4 and -9. Eur J Immunol 2008;38:680–694.
  73. Sugawara I, Yamada H, Li C, Mizuno S, Takeuchi O, Akira S: Mycobacterial infection in TLR2 and TLR6 knockout mice. Microbiol Immunol 2003;47:327–336.
  74. Thuong NT, Hawn TR, Thwaites GE, Chau TT, Lan NT, Quy HT, Hieu NT, Aderem A, Hien TT, Farrar JJ, Dunstan SJ: A polymorphism in human TLR2 is associated with increased susceptibility to tuberculous meningitis. Genes Immun 2007;8:422–428.
  75. Peiser L, Gordon S: The function of scavenger receptors expressed by macrophages and their role in the regulation of inflammation. Microbes Infect 2001;3:149–159.
  76. Neyrolles O, Hernandez-Pando R, Pietri-Rouxel F, Fornes P, Tailleux L, Barrios Payan JA, Pivert E, Bordat Y, Aguilar D, Prevost MC, et al: Is adipose tissue a place for Mycobacterium tuberculosis persistence? PLoS ONE 2006;1:e43.
  77. Philips JA, Rubin EJ, Perrimon N: Drosophila RNAi screen reveals CD36 family member required for mycobacterial infection. Science 2005;309:1251–1253.
  78. Hoebe K, Georgel P, Rutschmann S, Du X, Mudd S, Crozat K, Sovath S, Shamel L, Hartung T, Zahringer U, Beutler B: CD36 is a sensor of diacylglycerides. Nature 2005;433:523–527.
  79. Dziarski R, Ulmer AJ, Gupta D: Interactions of CD14 with components of Gram-positive bacteria. Chem Immunol 2000;74:83–107.
  80. Pugin J, Heumann ID, Tomasz A, Kravchenko VV, Akamatsu Y, Nishijima M, Glauser MP, Tobias PS, Ulevitch RJ: CD14 is a pattern recognition receptor. Immunity 1994;1:509–516.
  81. Lewthwaite JC, Coates AR, Tormay P, Singh M, Mascagni P, Poole S, Roberts M, Sharp L, Henderson B: Mycobacterium tuberculosis chaperonin 60.1 is a more potent cytokine stimulator than chaperonin 60.2 (Hsp 65) and contains a CD14-binding domain. Infect Immun 2001;69:7349–7355.
  82. Peterson PK, Gekker G, Hu S, Sheng WS, Anderson WR, Ulevitch RJ, Tobias PS, Gustafson KV, Molitor TW, Chao CC: CD14 receptor-mediated uptake of nonopsonized Mycobacterium tuberculosis by human microglia. Infect Immun 1995;63:1598–1602.
  83. Kaisho T, Akira S: Critical roles of Toll-like receptors in host defense. Crit Rev Immunol 2000;20:393–405.
  84. Hoheisel G, Zheng L, Teschler H, Striz I, Costabel U: Increased soluble CD14 levels in BAL fluid in pulmonary tuberculosis. Chest 1995;108:1614–1616.
  85. Rosas-Taraco AG, Revol A, Salinas-Carmona MC, Rendon A, Caballero-Olin G, Arce-Mendoza AY: CD14 C(-159)T polymorphism is a risk factor for development of pulmonary tuberculosis. J Infect Dis 2007;196:1698–1706.
  86. Wieland CW, van der Windt GJ, Wiersinga WJ, Florquin S, van der Poll T: CD14 contributes to pulmonary inflammation and mortality during murine tuberculosis. Immunology 2008;125:272–279.
  87. Lazarevic V, Myers AJ, Scanga CA, Flynn JL: CD40, but not CD40L, is required for the optimal priming of T cells and control of aerosol M. tuberculosis infection. Immunity 2003;19:823–835.
  88. Demangel C, Palendira U, Feng CG, Heath AW, Bean AG, Britton WJ: Stimulation of dendritic cells via CD40 enhances immune responses to Mycobacterium tuberculosis infection. Infect Immun 2001;69:2456–2461.
  89. Fratazzi C, Manjunath N, Arbeit RD, Carini C, Gerken TA, Ardman B, Remold-O’Donnell E, Remold HG: A macrophage invasion mechanism for mycobacteria implicating the extracellular domain of CD43. J Exp Med 2000;192:183–192.
  90. Randhawa AK, Ziltener HJ, Stokes RW: CD43 controls the intracellular growth of Mycobacterium tuberculosis through the induction of TNF-α-mediated apoptosis. Cell Microbiol 2008;10:2105–2017.
  91. Leemans JC, Florquin S, Heikens M, Pals ST, van der Neut R, Van Der Poll T: CD44 is a macrophage binding site for Mycobacterium tuberculosis that mediates macrophage recruitment and protective immunity against tuberculosis. J Clin Invest 2003;111:681–689.
  92. Kipnis A, Basaraba RJ, Turner J, Orme IM: Increased neutrophil influx but no impairment of protective immunity to tuberculosis in mice lacking the CD44 molecule. J Leukoc Biol 2003;74:992–997.
  93. de Chastellier C, Thilo L: Cholesterol depletion in Mycobacterium avium-infected macrophages overcomes the block in phagosome maturation and leads to the reversible sequestration of viable mycobacteria in phagolysosome-derived autophagic vacuoles. Cell Microbiol 2006;8:242–256.
  94. Peyron P, Bordier C, N’Diaye EN, Maridonneau-Parini I: Nonopsonic phagocytosis of Mycobacterium kansasii by human neutrophils depends on cholesterol and is mediated by CR3 associated with glycosylphosphatidylinositol-anchored proteins. J Immunol 2000;165:5186–5191.
  95. Perez-Guzman C, Vargas MH: Hypocholesterolemia: a major risk factor for developing pulmonary tuberculosis? Med Hypotheses 2006;66:1227–1230.
  96. Martens GW, Arikan MC, Lee J, Ren F, Vallerskog T, Kornfeld H: Hypercholesterolemia impairs immunity to tuberculosis. Infect Immun 2008;76:3464–3472.
  97. Van der Geize R, Yam K, Heuser T, Wilbrink MH, Hara H, Anderton MC, Sim E, Dijkhuizen L, Davies JE, Mohn WW, Eltis LD: A gene cluster encoding cholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages. Proc Natl Acad Sci USA 2007;104:1947–1952.
  98. Stokes RW, Norris-Jones R, Brooks DE, Beveridge TJ, Doxsee D, Thorson LM: The glycan-rich outer layer of the cell wall of Mycobacterium tuberculosis acts as an antiphagocytic capsule limiting the association of the bacterium with macrophages. Infect Immun 2004;72:5676–5686.
  99. Hall-Stoodley L, Watts G, Crowther JE, Balagopal A, Torrelles JB, Robison-Cox J, Bargatze RF, Harmsen AG, Crouch EC, Schlesinger LS: Mycobacterium tuberculosis binding to human surfactant proteins A and D, fibronectin, and small airway epithelial cells under shear conditions. Infect Immun 2006;74:3587–3596.
  100. North RJ: Mycobacterium tuberculosis is strikingly more virulent for mice when given via the respiratory than via the intravenous route. J Infect Dis 1995;172:1550–1553.