Defensins and Cathelicidins: Antimicrobial Peptide Effectors of Mammalian Innate Immunity

Tomas Ganz; Robert I. Lehrer

doi:10.1128/9781555817978.ch8

Chapter 8 : Defensins and Cathelicidins: Antimicrobial Peptide Effectors of Mammalian Innate Immunity

VIEW AFFILIATIONS HIDE AFFILIATIONS

Affiliations: 1: Departments of Medicine and Pathology, UCLA School of Medicine, Los Angeles, CA 90095-1690; 2: Department of Medicine, UCLA School of Medicine, Los Angeles, CA 90095-1690

Content Type: Monograph

Publication Year: 2002

Category: Immunology

Book DOI: 10.1128/9781555817978

Chapter DOI: 10.1128/9781555817978.ch8

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:

Defensins and Cathelicidins: Antimicrobial Peptide Effectors of Mammalian Innate Immunity, Page 1 of 2

< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555817978/9781555812140_Chap08-1.gif /docserver/preview/fulltext/10.1128/9781555817978/9781555812140_Chap08-2.gif

Abstract:

This chapter centers on antimicrobial peptides, effector molecules that generally act by disrupting microbial membranes. When human neutrophils ingest Salmonella enterica serovar Typhimurium in the presence of radioactive iodide, defensins are the most abundant radioiodinated polypeptides in phagocytic vacuoles. Since iodination is produced by the neutrophil’s myeloperoxidase-hydrogen peroxide system, iodinated defensins provide evidence that the neutrophil’s oxidative and nonoxidative systems operate concurrently within the phagosome. Presumably, adverse consequences from the lack of neutrophil defensins in these species are mitigated by the presence of other antimicrobial effector mechanisms, such as NADPH oxidase, inducible nitric oxide synthase, cathelicidins, serprocidins, and other antimicrobial polypeptides. The only known human cathelicidin has been designated hCAP18 or FALL39/LL-37 by the three groups that described its cDNA, gene and peptide forms. Unlike defensins, which are stored in their mature form in the granules of neutrophils, hCAP18/LL-37 is stored as a 16-kDa (140-aminoacid) proform. Individual peptides differ in their antimicrobial spectrum, and early evidence suggests that they sometimes act synergistically with each other or with larger antimicrobial polypeptides. At sites that are more distant from the infected or inflamed locus, lower concentrations of defensins may act as signaling molecules, similarly to chemokines.

Citation: Ganz T, Lehrer R. 2002. Defensins and Cathelicidins: Antimicrobial Peptide Effectors of Mammalian Innate Immunity, p 105-110. In Kaufmann S, Sher A, Ahmed R (ed), Immunology of Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817978.ch8

Highlighted Text: Show | Hide

Full text loading...

References

/content/book/10.1128/9781555817978.chap8

1. Agerberth, B.,, H. Gunne,, J. Odeberg,, P. Kogner,, H. G. Boman,, and G. H. Gudmundsson. 1995. FALL-39, a putative human peptide antibiotic, is cysteine-free and expressed in bone marrow and testis. Proc. Natl. Acad. Sci. USA 92: 195– 199.

2. Agerberth, B.,, J. Y. Lee,, T. Bergman,, M. Carlquist,, H. G. Boman,, V. Mutt,, and H. Jornvall. 1991. Amino acid sequence of PR- 39. Isolation from pig intestine of a new member of the family of proline-arginine-rich antibacterial peptides. Eur. J. Biochem. 202: 849– 854.

3. Aumelas, A.,, M. Mangoni,, C. Roumestand,, L. Chiche,, E. Despaux,, G. Grassy,, B. Calas,, and A. Chavanieu. 1996. Synthesis and solution structure of the antimicrobial peptide protegrin-1. Eur. J. Biochem. 237: 575– 583.

4. Ayabe, T.,, D. P. Satchell,, C. L. Wilson,, W. C. Parks,, M. E. Selsted,, and A. J. Ouellette. 2000. Secretion of microbicidal a-defensins by intestinal Paneth cells in response to bacteria. Nat. Immunol. 1: 113– 118.

5. Bals, R.,, X. Wang,, M. Zasloff,, and J. M. Wilson. 1998. The peptide antibiotic LL-37/hCAP-18 is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface. Proc. Natl. Acad. Sci. USA 95: 9541– 9546.

6. Bensch, K. W.,, M. Raida,, H. J. Magert,, P. Schulz-Knappe,, and W. G. Forssmann. 1995. hBD-1: a novel beta-defensin from human plasma. FEBS Lett. 368: 331– 335.

7. Borregaard, N.,, M. Sehested,, B. S. Nielsen,, H. Sengelov,, and L. Kjeldsen. 1995. Biosynthesis of granule proteins in normal human bone marrow cells. Gelatinase is a marker of terminal neutrophil differentiation. Blood 85: 812– 817.

8. Cowland, J. B.,, A. H. Johnsen,, and N. Borregaard. 1995. hCAP- 18, a cathelin / pro-bactenecin-like protein of human neutrophil specific granules. FEBS Lett. 368: 173– 176.

9. Daher, K. A.,, M. E. Selsted,, and R. I. Lehrer. 1986. Direct inactivation of viruses by human granulocyte defensins. J.Virol. 60: 1068– 1074.

10. Del Sal, G.,, P. Storici,, C. Schneider,, D. Romeo,, and M. Zanetti. 1992. cDNA cloning of the neutrophil bactericidal peptide indolicidin. Biochem. Biophys. Res. Commun. 187: 467– 472.

11. Diamond, G.,, J. P. Russell,, and C. L. Bevins. 1996. Inducible expression of an antibiotic peptide gene in lipopolysaccharidechallenged tracheal epithelial cells. Proc. Natl. Acad. Sci. USA 93: 5156– 5160.

12. Diamond, G.,, M. Zasloff,, H. Eck,, M. Brasseur,, W. L. Maloy,, and C. L. Bevins. 1991. Tracheal antimicrobial peptide, a cysteinerich peptide from mammalian tracheal mucosa: peptide isolation and cloning of a cDNA. Proc. Natl. Acad. Sci. USA 88: 3952– 3956.

13. Fahrner, R. l.,, T. Dieckmann,, S. S. Harwig,, R. I. Lehrer,, D. Eisenberg,, and J. Feigon. 1996. Solution structure of protegrin-1, a broad-spectrum antimicrobial peptide from porcine leukocytes. Chem. Biol. 3: 543– 550.

14. Frank, R. W.,, R. Gennaro,, K. Schneider,, M. Przybylski,, and D. Romeo. 1990. Amino acid sequences of two proline-rich bactenecins. Antimicrobial peptides of bovine neutrophils. J. Biol. Chem. 265: 18871– 18874.

15. Frohm, M.,, B. Agerberth,, G. Ahangari,, M. Stahle-Backdahl,, S. Liden,, H. Wigzell,, and G. H. Gudmundsson. 1997. The expression of the gene coding for the antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders. J. Biol. Chem. 272: 15258– 15263.

16. Fujii, G.,, M. E. Selsted,, and D. Eisenberg. 1993. Defensins promote fusion and lysis of negatively charged membranes. Protein Sci. 2: 1301– 1312.

17. Ganz, T.,, and R. I. Lehrer. 1995. Defensins. Pharmacol.Ther. 66: 191– 205.

18. Ganz, T.,, L. Liu,, E. V. Valore,, and A. Oren. 1993. Posttranslational processing and targeting of transgenic human defensin in murine granulocyte, macrophage, fibroblast, and pituitary adenoma cell lines. Blood 82: 641– 650.

19. Ganz, T.,, J. R. Rayner,, E. V. Valore,, A. Tumolo,, K. Talmadge,, and F. Fuller. 1989. The structure of the rabbit macrophage defensin genes and their organ-specific expression. J. Immunol. 143: 1358– 1365.

20. Ganz, T.,, M. E. Selsted,, D. Szklarek,, S. S. Harwig,, K. Daher,, D. F. Bainton,, and R. I. Lehrer. 1985. Defensins. Natural peptide antibiotics of human neutrophils. J. Clin. Investig. 76: 1427– 1435.

21. Gennaro, R.,, B. Skerlavaj,, and D. Romeo. 1989. Purification, composition, and activity of two bactenecins, antibacterial peptides of bovine neutrophils. Infect. Immun. 57: 3142– 3146.

22. Gudmundsson, G. H.,, B. Agerberth,, J. Odeberg,, T. Bergman,, B. Olsson,, and R. Salcedo. 1996. The human gene FALL39 and processing of the cathelin precursor to the antibacterial peptide LL-37 in granulocytes. Eur. J. Biochem. 238: 325– 332.

23. Harder, J.,, J. Bartels,, E. Christophers,, and J.-M. Schroeder. 1997. A peptide antibiotic from human skin. Nature 387: 861– 862.

24. Harwig, S. S.,, V. N. Kokryakov,, K. M. Swiderek,, G. M. Aleshina,, C. Zhao,, and R. I. Lehrer. 1995. Prophenin-1, an exceptionally proline-rich antimicrobial peptide from porcine leukocytes. FEBS Lett. 362: 65– 69.

25. Higazi, A. A.,, I. I. Barghouti,, and R. Abu-Much. 1995. Identification of an inhibitor of tissue-type plasminogen activatormediated fibrinolysis in human neutrophils. A role for defensin. J. Biol. Chem. 270: 9472– 9477.

26. Hirata, M.,, J. Zhong,, S. C. Wright,, and J. W. Larrick. 1995. Structure and functions of endotoxin-binding peptides derived from CAP18. Prog. Clin. Biol. Res. 392: 317– 326.

27. Hoover, D. M.,, K. R. Rajashankar,, R. Blumenthal,, A. Puri,, J. J. Oppenheim,, O. Chertov,, and J. Lubkowski. 2000. The structure of human beta-defensin-2 shows evidence of higher-order oligomerization. J. Biol. Chem. 275: 32911– 32918.

28. Joiner, K. A.,, T. Ganz,, J. Albert,, and D. Rotrosen. 1989. The opsonizing ligand on Salmonella typhimurium influences incorporation of specific, but not azurophil, granule constituents into neutrophil phagosomes. J. Cell Biol. 109: 2771– 2782.

29. Jones, D. E.,, and C. L. Bevins. 1992. Paneth cells of the human small intestine express an antimicrobial peptide gene. J. Biol. Chem. 267: 23216– 23225.

30. Jones, D. E.,, and C. L. Bevins. 1993. Defensin-6 mRNA in human Paneth cells: implications for antimicrobial peptides in host defense of the human bowel. FEBS Lett. 315: 187– 192.

31. Kagan, B. L.,, M. E. Selsted,, T. Ganz,, and R. I. Lehrer. 1990. Antimicrobial defensin peptides form voltage-dependent ionpermeable channels in planar lipid bilayer membranes. Proc. Natl. Acad. Sci. USA 87: 210– 214.

32. Kokryakov, V. N.,, S. S. Harwig,, E. A. Panyutich,, A. A. Shevchenko,, G. M. Aleshina,, O. V. Shamova,, H. A. Korneva,, and R. I. Lehrer. 1993. Protegrins: leukocyte antimicrobial peptides that combine features of corticostatic defensins and tachyplesins. FEBS Lett. 327: 231– 236.

33. Larrick, J. W.,, M. Hirata,, R. F. Balint,, J. Lee,, J. Zhong,, and S. C. Wright. 1995. Human CAP18: a novel antimicrobial lipopolysaccharide-binding protein. Infect. Immun. 63: 1291– 1297.

34. Larrick, J. W.,, M. Hirata,, H. Zheng,, J. Zhong,, D. Bolin,, J. M. Cavaillon,, H. S. Warren,, and S. C. Wright. 1994. A novel granulocyte-derived peptide with lipopolysaccharideneutralizing activity. J. Immunol. 152: 231– 240.

35. Lehrer, R. I.,, A. Barton,, K. A. Daher,, S. S. Harwig,, T. Ganz,, and M. E. Selsted. 1989. Interaction of human defensins with Escherichia coli. Mechanism of bactericidal activity. J. Clin. Investig. 84: 553– 561.

36. Lehrer, R. I.,, A. Barton,, and T. Ganz. 1988a. Concurrent assessment of inner and outer membrane permeabilization and bacteriolysis in E. coli by multiple-wavelength spectrophotometry. J. Immunol. Methods 108: 153– 158.

37. Lehrer, R. I.,, T. Ganz,, D. Szklarek,, and M. E. Selsted. 1988b. Modulation of the in vitro candidacidal activity of human neutrophil defensins by target cell metabolism and divalent cations. J. Clin. Investig. 81: 1829– 1835.

38. Lehrer, R. I.,, A. K. Lichtenstein,, and T. Ganz. 1993. Defensins: antimicrobial and cytotoxic peptides of mammalian cells. Annu. Rev. Immunol. 11: 105– 128.

39. Lehrer, R. I.,, D. Szklarek,, T. Ganz,, and M. E. Selsted. 1985. Correlation of binding of rabbit granulocyte peptides to Candida albicans with candidacidal activity. Infect. Immun. 49: 207– 211.

40. Levy, O.,, C. E. Ooi,, P. Elsbach,, M. E. Doerfler,, R. I. Lehrer,, and J. Weiss. 1995. Antibacterial proteins of granulocytes differ in interaction with endotoxin. Comparison of bactericidal / permeability-increasing protein, p15s, and defensins. J. Immunol. 154: 5403– 5410.

41. Levy, O.,, J. Weiss,, K. Zarember,, C. E. Ooi,, and P. Elsbach. 1993. Antibacterial 15-kDa protein isoforms (p15s) are members of a novel family of leukocyte proteins. J. Biol. Chem. 268: 6058– 6063.

42. Lichtenstein, A.,, T. Ganz,, M. E. Selsted,, and R. I. Lehrer. 1986. In vitro tumor cell cytolysis mediated by peptide defensins of human and rabbit granulocytes. Blood 68: 1407– 1410.

43. Lichtenstein, A. K.,, T. Ganz,, T. M. Nguyen,, M. E. Selsted,, and R. I. Lehrer. 1988. Mechanism of target cytolysis by peptide defensins. Target cell metabolic activities, possibly involving endocytosis, are crucial for expression of cytotoxicity. J. Immunol. 140: 2686– 2694.

44. Linzmeier, R.,, D. Michaelson,, L. Liu,, and T. Ganz. 1993. The structure of neutrophil defensin genes. FEBS Lett. 321: 267– 273.

45. Liu, L.,, L. Wang,, H. P. Jia,, C. Zhao,, H. H. Q. Heng,, B. C. Schutte,, P. B. J. McCray,, and T. Ganz. 1998. Structure and mapping of the human β-defensin HBD-2 gene and its expression at sites of inflammation. Gene 222: 237– 244.

46. Liu, L.,, C. Zhao,, H. H. Q. Heng,, and T. Ganz. 1997. The human β-defensin-1 and α-defensins are encoded by adjacent genes: two peptide families with differing disulfide topology share a common ancestry. Genomics 43: 316– 320.

47. Malm, J.,, O. Sorensen,, T. Persson,, M. Frohm-Nilsson,, B. Johansson,, A. Bjartell,, H. Lilja,, M. Stahle-Backdahl,, N. Borregaard,, and A. Egesten. 2000. The human cationic antimicrobial protein (hCAP-18) is expressed in the epithelium of human epididymis, is present in seminal plasma at high concentrations, and is attached to spermatozoa. Infect. Immun. 68: 4297– 4302.

48. Marzari, R.,, B. Scaggiante,, B. Skerlavaj,, M. Bittolo,, R. Gennaro,, and D. Romeo. 1988. Small, antibacterial and large, inactive peptides of neutrophil granules share immunoreactivity to a monoclonal antibody. Infect. Immun. 56: 2193– 2197.

49. Mirgorodskaya, O. A.,, A. A. Shevchenko,, K. O. Abdalla,, I. V. Chernushevich,, T. A. Egorov,, A. X. Musoliamov,, V. N. Kokryakov,, and O. V. Shamova. 1993. Primary structure of three cationic peptides from porcine neutrophils. Sequence determination by the combined usage of electrospray ionization mass spectrometry and Edman degradation. FEBS Lett. 330: 339– 342.

50. Miyasaki, K. T.,, and A. L. Bodeau. 1992. Human neutrophil azurocidin synergizes with leukocyte elastase and cathepsin G in the killing of Capnocytophaga sputigena. Infect. Immun. 60: 4973– 4975.

51. Miyasaki, K. T.,, A. L. Bodeau,, T. Ganz,, M. E. Selsted,, and R. I. Lehrer. 1990. In vitro sensitivity of oral, gram-negative, facultative bacteria to the bactericidal activity of human neutrophil defensins. Infect. Immun. 58: 3934– 3940.

52. Moscinski, L. C.,, and B. Hill. 1995. Molecular cloning of a novel myeloid granule protein. J. Cell. Biochem. 59: 431– 442.

53. Murphy, C. J.,, B. A. Foster,, M. J. Mannis,, M. E. Selsted,, and T. W. Reid. 1993. Defensins are mitogenic for epithelial cells and fibroblasts. J. Cell. Physiol. 155: 408– 413.

54. Nakamura, T.,, H. Furunaka,, T. Miyata,, F. Tokunaga,, T. Muta,, S. Iwanaga,, M. Niwa,, T. Takao,, and Y. Shimonishi. 1988. Tachyplesin, a class of antimicrobial peptide from the hemocytes of the horseshoe crab ( Tachypleus tridentatus). Isolation and chemical structure. J. Biol. Chem. 263: 16709– 16713.

55. Odeberg, H.,, and I. Olsson. 1976. Microbicidal mechanisms of human granulocytes: synergistic effects of granulocyte elastase and myeloperoxidase or chymotrypsin-like cationic protein. Infect. Immun. 14: 1276– 1283.

56. Ogata, K.,, B. A. Linzer,, R. I. Zuberi,, T. Ganz,, R. I. Lehrer,, and A. Catanzaro. 1992. Activity of defensins from human neutrophilic granulocytes against Mycobacterium avium- Mycobacterium intracellulare. Infect. Immun. 60: 4720– 4725.

57. Panyutich, A.,, J. Shi,, P. L. Boutz,, C. Zhao,, and T. Ganz. 1997. Porcine polymorphonuclear leukocytes generate extracellular microbicidal activity by elastase-mediated activation of secreted proprotegrins. Infect. Immun. 65: 978– 985.

58. Porter, E. M.,, L. Liu,, A. Oren,, P. A. Anton,, and T. Ganz . 1997a. Localization of human intestinal defensin 5 in Paneth cell granules. Infect. Immun. 65: 2389– 2395.

59. Porter, E. M.,, E. van Dam,, E. V. Valore,, and T. Ganz. 1997b. Broad-spectrum antimicrobial activity of human intestinal defensin 5. Infect. Immun. 65: 2396– 2401.

60. Romeo, D.,, B. Skerlavaj,, M. Bolognesi,, and R. Gennaro. 1988. Structure and bactericidal activity of an antibiotic dodecapeptide purified from bovine neutrophils. J. Biol. Chem. 263: 9573– 9575.

61. Ryan, L. K.,, J. Rhodes,, M. Bhat,, and G. Diamond. 1998. Expression of beta-defensin genes in bovine alveolar macrophages. Infect. Immun. 66: 878– 881.

62. Schonwetter, B. S.,, E. D. Stolzenberg,, and M. A. Zasloff. 1995. Epithelial antibiotics induced at sites of inflammation. Science 267: 1645– 1648.

63. Scocchi, M.,, B. Skerlavaj,, D. Romeo,, and R. Gennaro. 1992. Proteolytic cleavage by neutrophil elastase converts inactive storage proforms to antibacterial bactenecins. Eur. J. Biochem. 209: 589– 595.

64. Selsted, M. E.,, M. J. Novotny,, W. L. Morris,, Y. Q. Tang,, W. Smith,, and J. S. Cullor. 1992. Indolicidin, a novel bactericidal tridecapeptide amide from neutrophils. J. Biol. Chem. 267: 4292– 4295.

65. Singh, A.,, A. Bateman,, Q. Z. Zhu,, S. Shimasaki,, F. Esch,, and S. Solomon. 1988. Structure of a novel human granulocyte peptide with anti-ACTH activity. Biochem. Biophys. Res. Commun. 155: 524– 529.

66. Sparkes, R. S.,, M. Kronenberg,, C. Heinzmann,, K. A. Daher,, I. Klisak,, T. Ganz,, and T. Mohandas. 1989. Assignment of defensin gene(s) to human chromosome 8p23. Genomics 5: 240– 244.

67. Tang, Y. Q.,, J. Yuan,, G. Osapay,, K. Osapay,, D. Tran,, C. J. Miller,, A. J. Ouellette,, and M. E. Selsted. 1999. A cyclic antimicrobial peptide produced in primate leukocytes by the ligation of two truncated alpha-defensins. Science 286: 498– 502.

68. Weinrauch, Y.,, A. Foreman,, C. Shu,, K. Zarember,, O. Levy,, P. Elsbach,, and J. Weiss. 1995. Extracellular accumulation of potently microbicidal bactericidal / permeability-increasing protein and p15s in an evolving sterile rabbit peritoneal inflammatory exudate. J. Clin. Investig. 95: 1916– 1924.

69. White, S. H.,, W. C. Wimley,, and M. E. Selsted. 1995. Structure, function, and membrane integration of defensins. Curr. Opin. Struct. Biol. 5: 521– 527.

70. Wilson, C. L.,, A. J. Ouellette,, D. P. Satchell,, T. Ayabe,, Y. S. Lopez-Boado,, J. L. Stratman,, S. J. Hultgren,, L. M. Matrisian,, and W. C. Parks. 1999. Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 286: 113– 117.

71. Wimley, W. C.,, M. E. Selsted,, and S. H. White. 1994. Interactions between human defensins and lipid bilayers: evidence for formation of multimeric pores. Protein Sci. 3: 1362– 1373.

72. Yang, D.,, O. Chertov,, S. N. Bykovskaia,, Q. Chen,, M. J. Buffo,, J. Shogan,, M. Anderson,, J. M. Schroder,, J. M. Wang,, O. M. Howard,, and J. J. Oppenheim. 1999. Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 286: 525– 528.

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

74. Zanetti, M.,, L. Litteri,, G. Griffiths,, R. Gennaro,, and D. Romeo. 1991. Stimulus-induced maturation of probactenecins, precursors of neutrophil antimicrobial polypeptides. J. Immunol. 146: 4295– 4300.

75. Zarember, K.,, P. Elsbach,, K. Shin-Kim,, and J. Weiss. 1997. p15s (15-kD antimicrobial proteins) are stored in the secondary granules of rabbit granulocytes: implications for antibacterial synergy with the bactericidal / permeability-increasing protein in inflammatory fluids. Blood 89: 672– 679.

76. Zhao, C. Q.,, I. Wang,, and R. I. Lehrer. 1996. Widespread expression of beta-defensin HBD-1 in human secretory glands and epithelial cells. FEBS Lett. 396: 319– 322.

77. Zhu, Q. Z.,, A. V. Singh,, A. Bateman,, F. Esch,, and S. Solomon. 1987. The corticostatic (anti-ACTH) and cytotoxic activity of peptides isolated from fetal, adult and tumor-bearing lung. J. Steroid. Biochem. 27: 1017– 1022.

78. Zimmermann, G. R.,, P. Legault,, M. E. Selsted,, and A. Pardi. 1995. Solution structure of bovine neutrophil beta-defensin-12: the peptide fold of the beta-defensins is identical to that of the classical defensins. Biochemistry 34: 13663– 13671.