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Instituto Nacional de Salud Pública

2006, Número 1

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salud publica mex 2006; 48 (1)


Péptidos antimicrobianos en la inmunidad innata de enfermedades infecciosas

Rivas-Santiago B, Sada E, Hernández-Pando R, Tsutsumi V

Idioma: Español
Referencias bibliográficas: 101
Paginas: 62-71
Archivo PDF: 168.12 Kb.


RESUMEN

Los péptidos antimicrobianos son moléculas efectoras clave en la inmunidad innata. Generalmente contienen de 15 a 45 residuos de aminoácidos y en su gran mayoría poseen carga positiva, además de que tienen la propiedad de ser anfipáticos. Estos péptidos son secretados por células epiteliales y leucocitos, como es el caso de los macrófagos y neutrófilos. En la actualidad, con base en la traducción de secuencias en programas computacionales se han descrito más de 800 tipos de péptidos antimicrobianos distribuidos en los reinos animal y vegetal. Estos péptidos pueden ser clasificados de acuerdo con su conformación estructural y la ubicación de sus puentes disulfuro. Las defensinas constituyen uno de los tipos de péptidos antimicrobianos más estudiados, y se dividen en dos familias de acuerdo con la ubicación de sus puentes disulfuro: α-defensinas y β-defensinas. Algunas de estas defensinas pueden ser inducidas por citocinas proinflamatorias, así como por moléculas propias de patógenos, y se ha observado que están relacionadas con la inmunopatogenia de varias enfermedades. El papel principal de los péptidos antimicrobianos es la lisis directa de microorganismos; sin embargo, a la fecha también se han descrito propiedades quimiotácticas, que le permiten modular el sistema inmune y de esta forma constituir un puente entre la inmunidad innata y la inmunidad adaptativa. Actualmente se han iniciado estudios con la posibilidad de utilizar esta clase de moléculas como nuevos fármacos en diferentes tipos de enfermedades infecciosas.


REFERENCIAS (EN ESTE ARTÍCULO)

  1. Fleming A. Antibiotic therapy, an introductory article.

  2. Med. Illus1950;10:477-478.

  3. Zasloff M. Antimicrobial peptides of multicellular organism. Nature 2002;415:389-395.

  4. Lehrer R, Lichtenstein A, Ganz T. Defensins: Antimicrobial and cytotoxic peptides of mammalian cells. Annu Rev Immunol 1993;11:105-128.

  5. Boman HG. Peptide antibiotics and their role in innate immunity. Annu Rev Immunol 1995;13:61-92.

  6. Kaiser V. Diamond G. Expression of mammalian defensin genes. J Leukoc Biol 2000;68:779-784.

  7. Ganz T, Selsted ME, Szklarek D, Harwing SS, Daher K, Bainton DF et al. Defensins. Natural peptide antibiotics of human neutrophils. J Clin Invest 1985;76:1427-1435.

  8. Valore EV, Park CH, Quayle AJ, Wiles KR, MCCray PB Jr, Ganz T. Human b-defensin-1: an antimicrobial peptide of urogenital tissues. J Clin Invest 1998;101:1633-1642.

  9. Tang Y-Q, Vaun J, Osapay C, Tran D, Miller CA. Cyclic antimicrobial peptide produced in primate leukocytes by the ligation of two truncated a-defensins. Science 1999;286: 498-502.

  10. Ogata K, Linzer BA, Zuberi RI, Ganz T, Catanzaro S. Activity of defensins of human neutrophilic granulocytes against Mycobacterium avium and Mycobacterium intracellulare. Infect immune 1992;60:4720-4725.

  11. Ethan D, Stolzenberg G, Anderson M. Ephitelial antibiotic induced in states of disease. Proc Natl Acad Sci USA 1997; 16:8686-8690.

  12. Selsted ME, Ganz T, Leherer RI. Primary structures of three human neutrophil defensins. J Clin Invest 1985;76:1436-1439.

  13. Wilson CL, Oullette AJ, Satchel DP, Ayabe T, Lopez-Boado YS, Stratman JL. Regulation of intestinal a-defensins activation by the metalloproteinase matrylsin in innate host defense. Science 1999;286:113-117.

  14. Kisich K, Michael H, Diamond G, Heifets L. Tumor necrosis factor alpha stimulates killing of Mycobacterium tuberculosis by human neutrophils. Infect Immun 2002;70:4591-4599.

  15. Linzmeier R, Ho CH, Ganz T. A 450-kb contig of defensins genes on human chromosome 8p23. Gene 1999;233:205-211.

  16. Sharma S, Verma I, Khuller G. Therapeutic potential of human neutrophil peptide-1 against experimental tuberculosis. Antimicrob Agents Chemother 2001;45:639-640.

  17. Quayle AJ, Porter EM, Nussbaum AA, Wang YM, Brabec C. Gene expression, immunolocalization and secretion of human defensin-5 in human female reproductive tract. Am J Pathol 1998;152:1247-1258.

  18. Sharma S, Verma I, Khuller G. Antibacterial activity of human neutrophil peptide-1 against Mycobacterium tuberculosis H37Rv in vitro and ex vivo study. Eur Respir J 2000;16:112-117.

  19. Diamond G, Zasloff M, Eck H, Brasseur M, Maloy WL, Bevins CL. Tracheal antimicrobial peptide, a cysteine-rich peptide from mamalian tracheal mucosa: peptide isolation and cloning of a cDNA. Proc Natl Acad Sci USA 1991;88:3952-3956.

  20. Bensch K, Raida M, Magert H-J, Schulz-Knappe P, Forssmann WG. HBD-1: a novel b-defensin from human plasma. FEBS Lett 1995;368:331-335.

  21. Singh P, Jia H, Wiles K, Hesselberth J, Liu L, Conway B et al. Production of b-defensin, by human airway epithelia. Proc Natl Acad Sci USA 1998;95:14961-14966.

  22. Bals R, Wang X, Wu Z, Freeman, Banfa V, Zasloff M et al. HBD-2 is a salt sensitivity peptide antibiotic expressed in human lung. J Clin Invest 1998;102:874-880.

  23. Hiratsuka T, Nakazato M, Date Y, Ashitani J, Minematsu T, Chino N, Matsukara S. Identification of b-defensins –2 in respiratory tract and plasma and its increase in bacterial pneumonia. Commun. Biochem Biophys Res Commun 1998;249: 943-947.

  24. O’Neil DA, Porter EM, Elawaut D, Anderson GM, Eckman L, Ganz T. Expression and regulation of HBD-1 and HBD-2 in intestinal epithelium. J Immunol 1999;163:6718-6724.

  25. Harder J, Bartels J, Christophers E. Isolation and characterization of Human Beta Defensin-3, a novel human inducible peptide antibiotic. J Biol Chem 2001;276:5707-5713.

  26. Schutte B, McCray P. b-defensins in lung host defense. Annu Rev Physiol 2002;64:709-748.

  27. Birchsler T, Reinhart S, Büchner K, Loeliger S, Reinhard S, Hossle P, Aguzzi A, Launer R. Human Toll-like receptor mediates induction of the antimicrobial peptide human beta-defensin 2 in response to bacterial lipoprotein. Eur J Immunol 2001;31:3131-3137.

  28. Ashitani J, Mukae H, Hiratsuka T, Nakazato M, Kumamoto K,Matsukura S. Plasma and BAL fluid concentrations of antimicrobial peptides in patients with Mycobacterium avium-intracellulare infection. Chest 2001;4:1131-1137.

  29. Goldman MJ, Anderson GM, Stolzenberg ED, Kari UP, Zassloff M. Human b-defensin-1 is salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell 1997;4:553-560.

  30. Lehrer R, Ganz T. Defensins of vertebrate animals. Curr Opin Immun 2002;14:96-102.

  31. Harder J, Meyer-hoffert U, Teran LM. Mucoid Pseudomonas aeruginosa, TNFa, and IL1b, but not IL-6 induce HBD-2 in respiratory epithelia. Cell Mol Biol Res 2000;22:714-721.

  32. Hiratsuka T, Nakasato M, Date Y, Minematsu T, Matsukura S. Identification of HBD-2 in respiratory tract and plasma and its increase in bacterial pnumonia. Biochem Biophys Res Comm 1998;249:943-947.

  33. Bals R. Epithelial peptides in host defense against infection. Respir Res 2000;1:141-150.

  34. Kisich K, Heifets L, Higgins M,Diamond G. Antimicobacterial agent based on mRNA encoding human b-defensin-2 enables primary macrophages to restrict growth of Mycobacterium tuberculosis. Infect Immun 2002;69:2692-2699.

  35. Milner S, Poindexter B, Buja M, Smith E, Bick R. Localization of human Beta-Defensin in normal and burns skin by fluorescence deconvolution microscopy. Burns 2002;1:1-4.

  36. Miyakawa Y, Ratnakar P, Costello M, Catanzaro A. In vitro activity of the antimicrobial peptide human and rabbit defensins and porcine leukocyte protegrin against Mycobacterium tuberculosis. Infect Immun 1996;64:926-932.

  37. Starner TD,Agerberth B, Gudmundsson GH, McCray PB Jr. Expression and activity of beta-defensins and LL-37 in the developing human lung. J Immunol 2005;3:1608-1615.

  38. Durr M. and Peschel A. Chemokine Meet Defensin: the Merging Concepts of Chemoattractants and antimicrobial peptides in host defense. Infect Immun 2002;4:615-617.

  39. Tani K, Murphy WJ, Chertov O, Salcedo R, Koh CY, Utsonomiya I et al. Defensins act as potent adjuvants that promote cellular an humoral immune responses in mice to a lymphoma idiotype and carrier antigens. Int Immunol 2002;12:691-700.

  40. Yang D, Chertov O, Oppenheim JJ. Human neutrophil defensin selectevely chemoattract naive and immature dendritic cells. J Leukoc Biol 2002;68:9-14.

  41. Zanetti M, Gennaro R, Romeo D. Cathelicidins: a novel protein family with a common proregion and a variable C-terminal antimicrobial domain. FEBS Lett 1995;374:1-5.

  42. Gallo RL, Ono M, Povsic T, Page C, Eriksson E, Klagsbrun M. Syndecans, cell surface heparin sulfate proteoglycans, are induced by a prolin-rich antimicrobial peptide from wounds. Proc Natl Acad Sci U S A 1994;91:11035-11039.

  43. Shi JS, Zhang G, Minton JE, Ross CR, Blecha F. PR-39, aproline-rich antibacterial peptide that inhibits phagocyteNADPH oxidase activity by binding to src homology 3 domains of p47 (phox). Proc Natl Acad Sci 1996;93:6014-6018.

  44. Oppenheim J, Biragyn A, Kwak L,Yang D. Roles of antimicrobial peptides such as defensins in innate and adaptative immunity. Ann Rheum Dis 2003;62:17-21.

  45. Chun-Hua Hsu, Chinpan Chen, Maou-Lin Jou, Alan Yueh-Luen Lee, Yu-Ching Lin, Yi-Ping Yu et al. Structural and DNA-binding studies on the bovine antimicrobial peptide, indolicidin: evidence for multiple conformations involved in binding to membranes and DNA. Nucleic Acids Res 2005;33:4053-4064.

  46. Boman GH. Antimicrobial peptides: basic facts and emerging concepts. J Intern Med 2003;254: 197-215.

  47. Scott M, Davidson D, Gold M, Bowdish D, Hancock R. The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses. J Immunol 2002;169: 3883-3891.

  48. Nizet V, Ohtake T, Lauth T, Trowbridge J, Rudisill J, Dorschner R et al. Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 2003;414:5454-5457.

  49. Uehara N, Yagihashi K, Tsuji N, Watanabe N. Human b-defensin-2 induction in Helicobacter pylori –infected gastric mucosal tissues: antimicrobial effect of overexpression. J Med Microbiol 2003;52:41-45.

  50. Zhang L, Yu W, He T, Yu J, Caffrey RE, Dalmasso EA et al. Contribution of human alpha-defensin 1, 2, and 3 to the anti-HIV-1 activity of CD8+ antiviral factor. Science 2002;298:995-1000.

  51. Munk C, Wei G, Yang OO, Waring AJ, Wang W, Hong T et al. The theta-defensin retrocyclins inhibits HIV-1 entry. AIDS Res Hum Retroviruses 2003;19: 875-881.

  52. Fleming A. Antibiotic therapy, an introductory article. Med. Illus1950;10:477-478.

  53. Zasloff M. Antimicrobial peptides of multicellular organism. Nature 2002;415:389-395.

  54. Lehrer R, Lichtenstein A, Ganz T. Defensins: Antimicrobial and cytotoxic peptides of mammalian cells. Annu Rev Immunol 1993;11:105-128.

  55. Boman HG. Peptide antibiotics and their role in innate immunity. Annu Rev Immunol 1995;13:61-92.

  56. Kaiser V. Diamond G. Expression of mammalian defensin genes. J Leukoc Biol 2000;68:779-784.

  57. Ganz T, Selsted ME, Szklarek D, Harwing SS, Daher K, Bainton DF et al. Defensins. Natural peptide antibiotics of human neutrophils. J Clin Invest 1985;76:1427-1435.

  58. Valore EV, Park CH, Quayle AJ, Wiles KR, MCCray PB Jr, Ganz T. Human b-defensin-1: an antimicrobial peptide of urogenital tissues. J Clin Invest 1998;101:1633-1642.

  59. Tang Y-Q, Vaun J, Osapay C, Tran D, Miller CA. Cyclic antimicrobial peptide produced in primate leukocytes by the ligation of two truncated a-defensins. Science 1999;286: 498-502.

  60. Ogata K, Linzer BA, Zuberi RI, Ganz T, Catanzaro S. Activity of defensins of human neutrophilic granulocytes against Mycobacterium avium and Mycobacterium intracellulare. Infect immune 1992;60:4720-4725.

  61. Ethan D, Stolzenberg G, Anderson M. Ephitelial antibiotic induced in states of disease. Proc Natl Acad Sci USA 1997; 16:8686-8690.

  62. Selsted ME, Ganz T, Leherer RI. Primary structures of three human neutrophil defensins. J Clin Invest 1985;76:1436-1439.

  63. Wilson CL, Oullette AJ, Satchel DP, Ayabe T, Lopez-Boado YS, Stratman JL. Regulation of intestinal a-defensins activation by the metalloproteinase matrylsin in innate host defense. Science 1999;286:113-117.

  64. Kisich K, Michael H, Diamond G, Heifets L. Tumor necrosis factor alpha stimulates killing of Mycobacterium tuberculosis by human neutrophils. Infect Immun 2002;70:4591-4599.

  65. Linzmeier R, Ho CH, Ganz T. A 450-kb contig of defensins genes on human chromosome 8p23. Gene 1999;233:205-211.

  66. Sharma S, Verma I, Khuller G. Therapeutic potential of human neutrophil peptide-1 against experimental tuberculosis. Antimicrob Agents Chemother 2001;45:639-640.

  67. Quayle AJ, Porter EM, Nussbaum AA, Wang YM, Brabec C. Gene expression, immunolocalization and secretion of human defensin-5 in human female reproductive tract. Am J Pathol 1998;152:1247-1258.

  68. Sharma S, Verma I, Khuller G. Antibacterial activity of human neutrophil peptide-1 against Mycobacterium tuberculosis H37Rv in vitro and ex vivo study. Eur Respir J 2000;16:112-117.

  69. Diamond G, Zasloff M, Eck H, Brasseur M, Maloy WL, Bevins CL. Tracheal antimicrobial peptide, a cysteine-rich peptide from mamalian tracheal mucosa: peptide isolation and cloning of a cDNA. Proc Natl Acad Sci USA 1991;88:3952-3956.

  70. Bensch K, Raida M, Magert H-J, Schulz-Knappe P, Forssmann WG. HBD-1: a novel b-defensin from human plasma. FEBS Lett 1995;368:331-335.

  71. Singh P, Jia H, Wiles K, Hesselberth J, Liu L, Conway B et al. Production of b-defensin, by human airway epithelia. Proc Natl Acad Sci USA 1998;95:14961-14966.

  72. Bals R, Wang X, Wu Z, Freeman, Banfa V, Zasloff M et al. HBD-2 is a salt sensitivity peptide antibiotic expressed in human lung. J Clin Invest 1998;102:874-880.

  73. Hiratsuka T, Nakazato M, Date Y, Ashitani J, Minematsu T, Chino N, Matsukara S. Identification of b-defensins–2 in respiratory tract and plasma and its increase in bacterial pneumonia. Commun. Biochem Biophys Res Commun 1998;249: 943-947.

  74. O’Neil DA, Porter EM, Elawaut D, Anderson GM, Eckman L, Ganz T. Expression and regulation of HBD-1 and HBD-2 in intestinal epithelium. J Immunol 1999;163:6718-6724.

  75. Harder J, Bartels J, Christophers E. Isolation and characterization of Human Beta Defensin-3, a novel human inducible peptide antibiotic. J Biol Chem 2001;276:5707-5713.

  76. Schutte B, McCray P. b-defensins in lung host defense. Annu Rev Physiol 2002;64:709-748.

  77. Birchsler T, Reinhart S, Büchner K, Loeliger S, Reinhard S, Hossle P, Aguzzi A, Launer R. Human Toll-like receptor mediates induction of the antimicrobial peptide human beta-defensin 2 in response to bacterial lipoprotein. Eur J Immunol 2001;31:3131-3137.

  78. Ashitani J, Mukae H, Hiratsuka T, Nakazato M, Kumamoto K,Matsukura S. Plasma and BAL fluid concentrations of antimicrobial peptides in patients with Mycobacterium avium-intracellulare infection. Chest 2001;4:1131-1137.

  79. Goldman MJ, Anderson GM, Stolzenberg ED, Kari UP, Zassloff M. Human b-defensin-1 is salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell 1997;4:553-560.

  80. Lehrer R, Ganz T. Defensins of vertebrate animals. Curr Opin Immun 2002;14:96-102.

  81. Harder J, Meyer-hoffert U, Teran LM. Mucoid Pseudomonas aeruginosa, TNFa, and IL1b, but not IL-6 induce HBD-2 in respiratory epithelia. Cell Mol Biol Res 2000;22:714-721.

  82. Hiratsuka T, Nakasato M, Date Y, Minematsu T, Matsukura S. Identification of HBD-2 in respiratory tract and plasma and its increase in bacterial pnumonia. Biochem Biophys Res Comm 1998;249:943-947.

  83. Bals R. Epithelial peptides in host defense against infection. Respir Res 2000;1:141-150.

  84. Kisich K, Heifets L, Higgins M,Diamond G. Antimicobacterial agent based on mRNA encoding human b-defensin-2 enables primary macrophages to restrict growth of Mycobacterium tuberculosis. Infect Immun 2002;69:2692-2699.

  85. Milner S, Poindexter B, Buja M, Smith E, Bick R. Localization of human Beta-Defensin in normal and burns skin by fluorescence deconvolution microscopy. Burns 2002;1:1-4.

  86. Miyakawa Y, Ratnakar P, Costello M, Catanzaro A. In vitro activity of the antimicrobial peptide human and rabbit defensins and porcine leukocyte protegrin against Mycobacterium tuberculosis. Infect Immun 1996;64:926-932.

  87. Starner TD,Agerberth B, Gudmundsson GH, McCray PB Jr. Expression and activity of beta-defensins and LL-37 in the developing human lung. J Immunol 2005;3:1608-1615.

  88. Durr M. and Peschel A. Chemokine Meet Defensin: the Merging Concepts of Chemoattractants and antimicrobial peptides in host defense. Infect Immun 2002;4:615-617.

  89. Tani K, Murphy WJ, Chertov O, Salcedo R, Koh CY, Utsonomiya I et al. Defensins act as potent adjuvants that promote cellular an humoral immune responses in mice to a lymphoma idiotype and carrier antigens. Int Immunol 2002;12:691-700.

  90. Yang D, Chertov O, Oppenheim JJ. Human neutrophil defensin selectevely chemoattract naive and immature dendritic cells. J Leukoc Biol 2002;68:9-14.

  91. Zanetti M, Gennaro R, Romeo D. Cathelicidins: a novel protein family with a common proregion and a variable C-terminal antimicrobial domain. FEBS Lett 1995;374:1-5.

  92. Gallo RL, Ono M, Povsic T, Page C, Eriksson E, Klagsbrun M. Syndecans, cell surface heparin sulfate proteoglycans, are induced by a prolin-rich antimicrobial peptide from wounds. Proc Natl Acad Sci U S A 1994;91:11035-11039.

  93. Shi JS, Zhang G, Minton JE, Ross CR, Blecha F. PR-39, aproline-rich antibacterial peptide that inhibits phagocyteNADPH oxidase activity by binding to src homology 3 domains of p47 (phox). Proc Natl Acad Sci 1996;93:6014-6018.

  94. Oppenheim J, Biragyn A, Kwak L,Yang D. Roles of antimicrobial peptides such as defensins in innate and adaptative immunity. Ann Rheum Dis 2003;62:17-21.

  95. Chun-Hua Hsu, Chinpan Chen, Maou-Lin Jou, Alan Yueh-Luen Lee, Yu-Ching Lin, Yi-Ping Yu et al. Structural and DNA-binding studies on the bovine antimicrobial peptide, indolicidin: evidence for multiple conformations involved in binding to membranes and DNA. Nucleic Acids Res 2005;33:4053-4064.

  96. Boman GH. Antimicrobial peptides: basic facts and emerging concepts. J Intern Med 2003;254: 197-215.

  97. Scott M, Davidson D, Gold M, Bowdish D, Hancock R. The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses. J Immunol 2002;169: 3883-3891.

  98. Nizet V, Ohtake T, Lauth T, Trowbridge J, Rudisill J, Dorschner R et al. Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 2003;414:5454-5457.

  99. Uehara N, Yagihashi K, Tsuji N, Watanabe N. Human b-defensin-2 induction in Helicobacter pylori –infected gastric mucosal tissues: antimicrobial effect of overexpression. J Med Microbiol 2003;52:41-45.

  100. Zhang L, Yu W, He T, Yu J, Caffrey RE, Dalmasso EA et al. Contribution of human alpha-defensin 1, 2, and 3 to the anti-HIV-1 activity of CD8+ antiviral factor. Science 2002;298:995-1000.

  101. Munk C, Wei G, Yang OO, Waring AJ, Wang W, Hong T et al. The theta-defensin retrocyclins inhibits HIV-1 entry. AIDS Res Hum Retroviruses 2003;19: 875-881.




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