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Endogenous production of antimicrobial peptides in innate immunity and human disease

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Abstract

Antimicrobial peptides are diverse and evolutionarily ancient molecules produced by all living organisms. Peptides belonging to the cathelicidin and defensin gene families exhibit an immune strategy as they defend against infection by inhibiting microbial survival, and modify hosts through triggering tissue-specific defense and repair events. A variety of processes have evolved in microbes to evade the action of antimicrobial peptides, including the ability to degrade or inactivate antimicrobial peptides, or suppress host production of the peptide in response to infection. Animal models and clinical investigations have shown that an absence of cathelicidin or defensin antimicrobials can lead to disease. In this article, we review important recent advances in understanding the biology of antimicrobial peptides and their role in normal immunity and human disease.

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References and Recommended Reading

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

    Article  PubMed  CAS  Google Scholar 

  2. Zanetti M, Litteri L, Griffiths G, et al.: Stimulus-induced maturation of probactenecins, precursors of neutrophil antimicrobial polypeptides. J Immunol 1991, 146:4295–4300.

    PubMed  CAS  Google Scholar 

  3. Agerberth B, Gunne H, Odeberg J, et al.: FALL-39, a putative human peptide antibiotic, is cysteine-free and expressed in bone marrow and testis. Proc Natl Acad Sci U S A 1995, 92:195–199.

    Article  PubMed  CAS  Google Scholar 

  4. Larrick JW, Lee J, Ma S, et al.: Structural, functional analysis and localization of the human CAP18 gene. FEBS Lett 1996, 398:74–80.

    Article  PubMed  CAS  Google Scholar 

  5. Gudmundsson GH, Agerberth B, Odeberg J, et al.: The human gene Fall39 and processing of the cathelin precursor to the antibacterial peptide LL-37 in granulocytes. Eur J Biochem 1996, 238:325–332.

    Article  PubMed  CAS  Google Scholar 

  6. Sorensen OE, Follin P, Johnsen AH, et al.: Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3. Blood 2001, 97:3951–3959.

    Article  PubMed  CAS  Google Scholar 

  7. Zarember KA, Katz SS, Tack BF, et al.: Host defense functions of proteolytically processed and parent (unprocessed) cathelicidins of rabbit granulocytes. Infect Immun 2002, 70:569–576.

    Article  PubMed  CAS  Google Scholar 

  8. Zaiou M, Nizet V, Gallo RL: Antimicrobial and protease inhibitory functions of the human cathelicidin (hCAP18/LL-37) prosequence. J Invest Dermatol 2003, 120:810–816.

    Article  PubMed  CAS  Google Scholar 

  9. De Y, Chen Q, Schmidt AP, et al.: LL-37, the neutrophil granule- and epithelial-cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J Exp Med 2000, 192:1069–1074. Antimicrobial peptides act on the host as a chemotactic factor and kill bacteria. This study identified a receptor on host cells for human cathelicidin that might enable its chemotactic activity.

    Article  Google Scholar 

  10. Niyonsaba F, Iwabuchi K, Someya A, et al.: A cathelicidin family of human antibacterial peptide LL-37 induces mast cell chemotaxis. Immunology 2002, 106:20–26.

    Article  PubMed  CAS  Google Scholar 

  11. Di Nardo A, Vitiello A, Gallo RL: Cutting edge: mast cell antimicrobial activity is mediated by expression of cathelicidin antimicrobial peptide. J Immunol 2003, 170:2274–2278.

    Google Scholar 

  12. Gallo RL, Kim KJ, Bernfield M, et al.: Identification of CRAMP, a cathelin-related antimicrobial peptide expressed in the embryonic and adult mouse. J Biol Chem 1997, 272:13088–13093.

    Article  PubMed  CAS  Google Scholar 

  13. Agerberth B, Lee J, Bergman T, et al.: 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 1991, 202:849–854.

    Article  PubMed  CAS  Google Scholar 

  14. Gallo RL, Ono M, Povsic T, et al.: Syndecans, cell surface heparin sulfate proteoglycans, are induced by a proline-rich antimicrobial peptide from wounds. Proc Natl Acad Sci U S A 1994, 91:11035–11039.

    Article  PubMed  CAS  Google Scholar 

  15. Jones DE, Bevins CL: Paneth cells of the human small intestine express an antimicrobial peptide gene. J Biol Chem 1992, 267:23216–23225.

    PubMed  CAS  Google Scholar 

  16. Ouellette AJ, Hsieh MW, Cano-Gauci DF, et al.: Mouse Paneth cell defensins: primary structures and antibacterial activities of cryptdin isoforms expressed in a single intestinal crypt. Infect Immun 1994, 62:5040–5047.

    PubMed  CAS  Google Scholar 

  17. Chaly YV, Paleolog EM, Kolesnikova TS, et al.: Neutrophil alphadefensin human neutrophil peptide modulates cytokine production in human monocytes and adhesion molecule expression in endothelial cells. Eur Cytokine Netw 2000, 11:257–266.

    PubMed  CAS  Google Scholar 

  18. Schutte BC, Mitros JP, Bartlett JA, et al.: Discovery of five conserved beta-defensin gene clusters using a computational search strategy. Proc Natl Acad Sci U S A 2002, 99:2129–2133.

    Article  PubMed  CAS  Google Scholar 

  19. Yang D, Chertov O, Bykovskaia SN, et al.: Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 1999, 286:525–528.

    Article  PubMed  CAS  Google Scholar 

  20. Befus A, Mowat C, Gilchrist M, et al.: Neutrophil defensins induce histamine secretion from mast cells: mechanisms of action. J Immunol 1999, 163:947–953.

    PubMed  CAS  Google Scholar 

  21. Guo L, Lim KB, Poduje CM, et al.: Lipid A acylation and bacterial resistance against vertebrate antimicrobial peptides. Cell 1998, 95:189–198.

    Article  PubMed  CAS  Google Scholar 

  22. Gunn JS, Ryan SS, Van Velkinburgh JC, et al.: Genetic and functional analysis of a PmrA-PmrB-regulated locus necessary for lipopolysaccharide modification, antimicrobial peptide resistance, and oral virulence of Salmonella enterica serovar typhimurium. Infect Immun 2000, 68:6139–6146.

    Article  PubMed  CAS  Google Scholar 

  23. Lysenko ES, Gould J, Bals R, et al.: Bacterial phosphorylcholine decreases susceptibility to the antimicrobial peptide LL-37/ hCAP18 expressed in the upper respiratory tract. Infect Immun 2000, 68:1664–1671.

    Article  PubMed  CAS  Google Scholar 

  24. Peschel A, Otto M, Jack RW, et al.: Inactivation of the Dlt operon in Staphylococcus aureus confers sensitivity to defensins, protegrins, and other antimicrobial peptides. J Biol Chem 1999, 274:8405–8410.

    Article  PubMed  CAS  Google Scholar 

  25. Peschel A, Jack R.W, Otto M, et al.: Staphylococcus aureus resistance to human defensins and evasion of neutrophil killing via the novel virulence factor MprF is based on modification of membrane lipids with l-lysine. J Exp Med 2001, 193:1067–1076. Bacteria have several strategies for altering their sensitivity to killing by antimicrobial peptides. This study shows that the bacterial surface charge alters the virulence of Staphylococcus aureus by altering binding defensins.

    Article  PubMed  CAS  Google Scholar 

  26. Parra-Lopez C, Lin R, Aspedon A, et al.: A salmonella protein that is required for resistance to antimicrobial peptides and transport of potassium. Embo J 1994, 13:3964–3972.

    PubMed  CAS  Google Scholar 

  27. Shafer WM, Qu X, Waring AJ, et al.: Modulation of Neisseria gonorrhoeae susceptibility to vertebrate antibacterial peptides due to a member of the resistance/nodulation/division efflux pump family. Proc Natl Acad Sci U S A 1998, 95:1829–1833.

    Article  PubMed  CAS  Google Scholar 

  28. Guina T, Yi EC, Wang H, et al.: A PhoP-regulated outer membrane protease of Salmonella enterica serovar typhimurium promotes resistance to alpha-helical antimicrobial peptides. J Bacteriol 2000, 182:4077–4086.

    Article  PubMed  CAS  Google Scholar 

  29. Park PW, Pier GB, Preston MJ, et al.: Syndecan-1 shedding is enhanced by LasA, a secreted virulence factor of Pseudomonas aeruginosa. J Biol Chem 2000, 275:3057–3064.

    Article  PubMed  CAS  Google Scholar 

  30. Schmidtchen A, Frick IM, Bjorck L: Dermatan sulphate is released by proteinases of common pathogenic bacteria and inactivates antibacterial alpha-defensin. Mol Microbiol 2001, 39:708–713.

    Article  PubMed  CAS  Google Scholar 

  31. Schmidtchen A, Frick IM, Andersson E, et al.: Proteinases of common pathogenic bacteria degrade and inactivate the antibacterial peptide LL-37. Mol Microbiol 2002, 46:157–168.

    Article  PubMed  CAS  Google Scholar 

  32. Islam D, Bandholtz L, Nilsson J, et al.: Downregulation of bactericidal peptides in enteric infections: a novel immune escape mechanism with bacterial DNA as a potential regulator. Nat Med 2001, 7:180–185. Indentification of another virulence strategy for bacteria. In this case, shigella express a factor that suppresses the production of antimicrobial peptides in the gut.

    Article  PubMed  CAS  Google Scholar 

  33. Nizet V, Ohtake T, Lauth X, et al.: Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 2001, 414:454–457. Demonstration that mammals depend on the expression of antimicrobial peptides for immune defense. Knock-out mice lacking cathelicidin become more susceptible to infection, and bacteria engineered to be more resistant become more virulent.

    Article  PubMed  CAS  Google Scholar 

  34. Bals R, Weiner D, Meegalla R, et al.: Transfer of a cathelicidin peptide antibiotic gene restores bacterial killing in a cystic fibrosis xenograft model. J Clin Invest 1999, 103:1113–1117.

    PubMed  CAS  Google Scholar 

  35. Brogden KA, Kalfa VC, Ackermann MR, et al.: The ovine cathelicidin SMAP29 kills ovine respiratory pathogens in vitro and in an ovine model of pulmonary infection. Antimicrob Agents Chemother 2001, 45:331–334.

    Article  PubMed  CAS  Google Scholar 

  36. Lushbaugh WB, Blossom AC, Shah PH, et al.: Use of intravaginal microbicides to prevent acquisition of Trichomonas vaginalis infection in Lactobacillus-pretreated, estrogenized young mice. Am J Trop Med Hyg 2000, 63:284–289.

    PubMed  CAS  Google Scholar 

  37. Chalekson CP, Neumeister MW, Jaynes J: Improvement in burn wound infection and survival with antimicrobial peptide D2A21 (Demegel). Plast Reconstr Surg 2002, 109:1338–1343.

    Article  PubMed  Google Scholar 

  38. Ceccarelli AV, Cole AM, Park AK, et al.: Therapeutic effect of a pig-derived peptide antibiotic on porcine wound infections. Comp Med 2001, 51:75–79.

    PubMed  CAS  Google Scholar 

  39. Dorschner RA, Pestonjamasp VK, Tamakuwala S, et al.: Cutaneous injury induces the release of cathelicidin antimicrobial peptides active against group A Streptococcus. J Invest Dermatol 2001, 117:91–97.

    Article  PubMed  CAS  Google Scholar 

  40. Moser C, Weiner DJ, Lysenko E, et al.: Beta-defensin 1 contributes to pulmonary innate immunity in mice. Infect Immun 2002, 70:3068–3072.

    Article  PubMed  CAS  Google Scholar 

  41. Morrison G, Kilanowski F, Davidson D, et al.: Characterization of the mouse beta defensin 1, Defb1, mutant mouse model. Infect Immun 2002, 70:3053–3060.

    Article  PubMed  CAS  Google Scholar 

  42. Cole AM, Shi J, Ceccarelli A, et al.: Inhibition of neutrophil elastase prevents cathelicidin activation and impairs clearance of bacteria from wounds. Blood 2001, 97:297–304. Further demonstration that the activity of antimicrobial peptides is important to mammalian defense. Inhibition of the processing and activation of antimicrobial peptides enables the prolonged survival of bacteria in pig wounds.

    Article  PubMed  CAS  Google Scholar 

  43. Park PW, Pier GB, Hinkes MT, et al.: Exploitation of syndecan-1 shedding by Pseudomonas aeruginosa enhances virulence. Nature 2001, 411:98–102.

    Article  PubMed  CAS  Google Scholar 

  44. Cole AM, Tahk S, Oren A, et al.: Determinants of Staphylococcus aureus nasal carriage. Clin Diagn Lab Immunol 2001, 8:1064–1069.

    Article  PubMed  CAS  Google Scholar 

  45. Carothers DG, Graham SM, Jia HP, et al.: Production of betadefensin antimicrobial peptides by maxillary sinus mucosa. Am J Rhinol 2001, 15:175–179.

    Article  PubMed  CAS  Google Scholar 

  46. Schaller-Bals S, Schulze A, Bals R: Increased levels of antimicrobial peptides in tracheal aspirates of newborn infants during infection. Am J Respir Crit Care Med 2002, 165:992–995.

    PubMed  Google Scholar 

  47. Ashitani J, Mukae H, Hiratsuka T, et al.: Plasma and BAL fluid concentrations of antimicrobial peptides in patients with Mycobacterium avium-intracellulare infection. Chest 2001, 119:1131–1137.

    Article  PubMed  CAS  Google Scholar 

  48. Aarbiou J, Ertmann M, van Wetering S, et al.: Human neutrophil defensins induce lung epithelial cell proliferation in vitro. J Leukoc Biol 2002, 72:167–174.

    PubMed  CAS  Google Scholar 

  49. Zhang H, Porro G, Orzech N, et al.: Neutrophil defensins mediate acute inflammatory response and lung dysfunction in dose-related fashion. Am J Physiol Lung Cell Mol Physiol 2001, 280:L947-L954.

    PubMed  CAS  Google Scholar 

  50. Smith JJ, Travis SM, Greenberg EP, et al.: Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid. Cell 1996, 85:229–236.

    Article  PubMed  CAS  Google Scholar 

  51. Goldman MJ, Anderson GM, Stolzenberg ED, et al.: Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell 1997, 88:553–560.

    Article  PubMed  CAS  Google Scholar 

  52. Bals R, Wang X, Wu Z, et al.: Human beta-defensin 2 is a saltsensitive peptide antibiotic expressed in human lung. J Clin Invest 1998, 102:874–880.

    Article  PubMed  CAS  Google Scholar 

  53. Bajaj-Elliott M, Fedeli P, Smith GV, et al.: Modulation of host antimicrobial peptide (beta-defensins 1 and 2) expression during gastritis. Gut 2002, 51:356–361.

    Article  PubMed  CAS  Google Scholar 

  54. Uehara N, Yagihashi A, Kondoh K, et al.: Human betadefensin-2 induction in Helicobacter pylori-infected gastric mucosal tissues: antimicrobial effect of overexpression. J Med Microbiol 2003, 52:41–45.

    Article  PubMed  CAS  Google Scholar 

  55. Cunliffe RN, Kamal M, Rose FR, et al.: Expression of antimicrobial neutrophil defensins in epithelial cells of active inflammatory bowel disease mucosa. J Clin Pathol 2002, 55:298–304.

    PubMed  CAS  Google Scholar 

  56. O’Neil DA, Porter EM, Elewaut D, et al.: Expression and regulation of the human beta-defensins hBD-1 and hBD-2 in intestinal epithelium. J Immunol 1999, 163:6718–6724.

    PubMed  CAS  Google Scholar 

  57. Lehmann J, Retz M, Harder J, et al.: Expression of human betadefensins 1 and 2 in kidneys with chronic bacterial infection. BMC Infect Dis 2002, 2:20.

    Article  PubMed  Google Scholar 

  58. Wiesenfeld HC, Heine RP, Krohn MA, et al.: Association between elevated neutrophil defensin levels and endometritis. J Infect Dis 2002, 186:792–797.

    Article  PubMed  CAS  Google Scholar 

  59. Marchini G, Lindow S, Brismar H, et al.: The newborn infant is protected by an innate antimicrobial barrier: peptide antibiotics are present in the skin and vernix caseosa. Br J Dermatol 2002, 147:1127–1134.

    Article  PubMed  CAS  Google Scholar 

  60. Conner K, Nern K, Rudisill J, et al.: The antimicrobial peptide LL-37 is expressed by keratinocytes in condyloma acuminatum and verruca vulgaris. J Am Acad Dermatol 2002, 47:347–350.

    Article  PubMed  Google Scholar 

  61. Ong PY, Ohtake T, Brandt C, et al.: Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 2002, 347:1151–1160. The susceptibility of patients with atopic dermatitis to bacterial infections might be explained by a lack of expression of antimicrobial peptides.

    Article  PubMed  CAS  Google Scholar 

  62. Ortega MR, Ganz T, Milner SM: Human beta defensin is absent in burn blister fluid. Burns 2000, 26:724–726.

    Article  PubMed  CAS  Google Scholar 

  63. Heilborn JD, Nilsson MF, Kratz G, et al.: The cathelicidin antimicrobial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium. J Invest Dermatol 2003, 120:379–389.

    Article  PubMed  CAS  Google Scholar 

  64. Putsep K, Carlsson G, Boman HG, et al.: Deficiency of antibacterial peptides in patients with morbus Kostmann: an observation study. Lancet 2002, 360:1144–1149. Patients with the inherited neutrophil abnormality of Kostmann syndrome show frequent oral infections. This susceptibility might be explained by the lack of cathelicidin antimicrobial peptides in their saliva.

    Article  PubMed  CAS  Google Scholar 

  65. Aprikyan AA, Carlsson G, Stein S, et al.: Neutrophil elastase mutations in severe congenital neutropenia patients of the original Kostmann family. Blood first edition paper, prepublished online January 16, 2003; DOI 10:1182/blood-2002-04-1255.

  66. Bastian A, Schafer H: Human alpha-defensin 1 (HNP-1) inhibits adenoviral infection in vitro. Regul Pept 2001, 101:157–161.

    Article  PubMed  CAS  Google Scholar 

  67. Cole AM, Hong T, Boo LM, et al.: Retrocyclin: a primate peptide that protects cells from infection by T- and M-tropic strains of HIV-1. Proc Natl Acad Sci U S A 2002, 99:1813–1818.

    Article  PubMed  CAS  Google Scholar 

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  1. Departments of Medicine and Pediatrics, Division of Dermatology, University of California San Diego, and VA San Diego Healthcare System, San Diego, CA, USA

    Richard L. Gallo MD, PhD & Victor Nizet MD

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  1. Richard L. Gallo MD, PhD
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Gallo, R.L., Nizet, V. Endogenous production of antimicrobial peptides in innate immunity and human disease. Curr Allergy Asthma Rep 3, 402–409 (2003). https://doi.org/10.1007/s11882-003-0074-x

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