Complement Activation Products C3a and C4a as Endogenous Antimicrobial Peptides

Article

Abstract

All vertebrate species are constantly challenged by infectious agents and pathogens. In order to fight these infectious agents the human host has developed a sophisticated and powerful immune defense. The complement system, which represents the first defense line of innate immunity is activated immediately, within seconds. The activated immune system recognizes and damages an invading microbe, coordinates the host immune response and further orchestrates the adaptive immune response. Activation of the complement system leads to a rapid and amplified response which includes the generation of small peptides like C3a and C4a that display antimicrobial, anti-fungal and anaphylactic activity. Here we report how these antimicrobial peptides are generated during the immune response and summarize the functional mechanisms of these intrinsically generated anti microbial peptides.

Keywords

Complement Host defense Antimicrobial peptides Bactericidal activity Anaphylatoxins C3a C4a 

References

  1. Behnsen J, Hartmann A et al (2008) The opportunistic human pathogenic fungus Aspergillus fumigatus evades the host complement system. Infect Immun 76(2):820–827PubMedCrossRefGoogle Scholar
  2. Bowdish DM, Davidson DJ et al (2005) A re-evaluation of the role of host defence peptides in mammalian immunity. Curr Protein Pept Sci 6(1):35–51PubMedCrossRefGoogle Scholar
  3. Brogden KA (2005) Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol 3(3):238–250PubMedCrossRefGoogle Scholar
  4. DiScipio RG, Schraufstatter IU (2007) The role of the complement anaphylatoxins in the recruitment of eosinophils. Int Immunopharmacol 7(14):1909–1923PubMedCrossRefGoogle Scholar
  5. Durr UH, Sudheendra US et al (2006) LL-37, the only human member of the cathelicidin family of antimicrobial peptides. Biochim Biophys Acta 1758(9):1408–1425PubMedCrossRefGoogle Scholar
  6. Ehrenstein G, Lecar H (1977) Electrically gated ionic channels in lipid bilayers. Q Rev Biophys 10(1):1–34PubMedCrossRefGoogle Scholar
  7. Ernst RK, Guina T et al (2001) Salmonella typhimurium outer membrane remodeling: role in resistance to host innate immunity. Microbes Infect 3(14–15):1327–1334PubMedCrossRefGoogle Scholar
  8. Fischetti VA (1989) Streptococcal M protein: molecular design and biological behavior. Clin Microbiol Rev 2(3):285–314PubMedGoogle Scholar
  9. Ganz T (2001) Antimicrobial proteins and peptides in host defense. Semin Respir Infect 16(1):4–10PubMedCrossRefGoogle Scholar
  10. Gorski JP, Hugli TE et al (1979) C4a: the third anaphylatoxin of the human complement system. Proc Natl Acad Sci USA 76(10):5299–5302PubMedCrossRefGoogle Scholar
  11. Hallstrom T, Jarva H et al (2007) Interaction with C4b-binding protein contributes to nontypeable Haemophilus influenzae serum resistance. J Immunol 178(10):6359–6366PubMedGoogle Scholar
  12. Hallstrom T, Zipfel PF et al (2008) Haemophilus influenzae interacts with the human complement inhibitor factor H. J Immunol 181(1):537–545PubMedGoogle Scholar
  13. Haupt K, Reuter M et al (2008) The Staphylococcus aureus protein Sbi acts as a complement inhibitor and forms a tripartite complex with host complement Factor H and C3b. PLoS Pathog 4(12):e1000250PubMedCrossRefGoogle Scholar
  14. Hsu JC, Yip CM (2007) Molecular dynamics simulations of indolicidin association with model lipid bilayers. Biophys J 92(12):L100–L102PubMedCrossRefGoogle Scholar
  15. Hugli TE (1990) Structure and function of C3a anaphylatoxin. Curr Top Microbiol Immunol 153:181–208PubMedGoogle Scholar
  16. Jarva H, Jokiranta TS et al (2003) Complement resistance mechanisms of streptococci. Mol Immunol 40(2–4):95–107PubMedCrossRefGoogle Scholar
  17. Jean-Francois F, Elezgaray J et al (2008) Pore formation induced by an antimicrobial peptide: electrostatic effects. Biophys J 95(12):5748–5756PubMedCrossRefGoogle Scholar
  18. Kirjavainen V, Jarva H et al (2008) Yersinia enterocolitica serum resistance proteins YadA and ail bind the complement regulator C4b-binding protein. PLoS Pathog 4(8):e1000140PubMedGoogle Scholar
  19. Kraiczy P, Wurzner R (2006) Complement escape of human pathogenic bacteria by acquisition of complement regulators. Mol Immunol 43(1–2):31–44PubMedCrossRefGoogle Scholar
  20. Kunert A, Losse J et al (2007) Immune evasion of the human pathogen Pseudomonas aeruginosa: elongation factor Tuf is a factor H and plasminogen binding protein. J Immunol 179(5):2979–2988PubMedGoogle Scholar
  21. Lambris JD, Ricklin D et al (2008) Complement evasion by human pathogens. Nat Rev Microbiol 6(2):132–142PubMedCrossRefGoogle Scholar
  22. Lapis K (2009) Characteristics of the main groups of human host-defensive peptides. Orv Hetil 150(3):109–119PubMedCrossRefGoogle Scholar
  23. Lewis LA, Choudhury B et al (2008) Phosphoethanolamine substitution of lipid A and resistance of Neisseria gonorrhoeae to cationic antimicrobial peptides and complement-mediated killing by normal human serum. Infect Immun 77:1112–1120PubMedCrossRefGoogle Scholar
  24. Matsuzaki K, Sugishita K et al (1998) Relationship of membrane curvature to the formation of pores by magainin 2. Biochemistry 37(34):11856–11863PubMedCrossRefGoogle Scholar
  25. McPhee JB, Lewenza S et al (2003) Cationic antimicrobial peptides activate a two-component regulatory system, PmrA–PmrB, that regulates resistance to polymyxin B and cationic antimicrobial peptides in Pseudomonas aeruginosa. Mol Microbiol 50(1):205–217PubMedCrossRefGoogle Scholar
  26. Menendez A, Brett Finlay B (2007) Defensins in the immunology of bacterial infections. Curr Opin Immunol 19(4):385–391PubMedCrossRefGoogle Scholar
  27. Meri T, Hartmann A et al (2002) The yeast Candida albicans binds complement regulators factor H and FHL-1. Infect Immun 70(9):5185–5192PubMedCrossRefGoogle Scholar
  28. Meri T, Blom AM et al (2004) The hyphal and yeast forms of Candida albicans bind the complement regulator C4b-binding protein. Infect Immun 72(11):6633–6641PubMedCrossRefGoogle Scholar
  29. Meuer S, Hugli TE et al (1981) Comparative study on biological activities of various anaphylatoxins (C4a, C3a, C5a). Investigations on their ability to induce platelet secretion. Inflammation 5(4):263–273PubMedCrossRefGoogle Scholar
  30. Mookherjee N, Hancock RE (2007) Cationic host defence peptides: innate immune regulatory peptides as a novel approach for treating infections. Cell Mol Life Sci 64(7–8):922–933PubMedCrossRefGoogle Scholar
  31. Muller-Eberhard HJ (1988) Molecular organization and function of the complement system. Annu Rev Biochem 57:321–347PubMedCrossRefGoogle Scholar
  32. Nordahl EA, Rydengard V et al (2004) Activation of the complement system generates antibacterial peptides. Proc Natl Acad Sci USA 101(48):16879–16884PubMedCrossRefGoogle Scholar
  33. Oppenheim JJ, Yang D (2005) Alarmins: chemotactic activators of immune responses. Curr Opin Immunol 17(4):359–365PubMedCrossRefGoogle Scholar
  34. Oppenheim JJ, Tewary P et al (2007) Alarmins initiate host defense. Adv Exp Med Biol 601:185–194PubMedGoogle Scholar
  35. Oren Z, Shai Y (1998) Mode of action of linear amphipathic alpha-helical antimicrobial peptides. Biopolymers 47(6):451–463PubMedCrossRefGoogle Scholar
  36. Pandiripally V, Wei L et al (2003) Recruitment of complement factor H-like protein 1 promotes intracellular invasion by group A streptococci. Infect Immun 71(12):7119–7128PubMedCrossRefGoogle Scholar
  37. Pasupuleti M, Walse B et al (2007) Preservation of antimicrobial properties of complement peptide C3a, from invertebrates to humans. J Biol Chem 282(4):2520–2528PubMedCrossRefGoogle Scholar
  38. Peschel A, Otto M et al (1999) Inactivation of the dlt operon in Staphylococcus aureus confers sensitivity to defensins, protegrins, and other antimicrobial peptides. J Biol Chem 274(13):8405–8410PubMedCrossRefGoogle Scholar
  39. Peschel A, Jack RW et al (2001) 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 193(9):1067–1076PubMedCrossRefGoogle Scholar
  40. Poltermann S, Kunert A et al (2007) Gpm1p is a factor H-, FHL-1-, and plasminogen-binding surface protein of Candida albicans. J Biol Chem 282(52):37537–37544PubMedCrossRefGoogle Scholar
  41. Poole K (2004) Efflux-mediated multiresistance in Gram-negative bacteria. Clin Microbiol Infect 10(1):12–26PubMedCrossRefGoogle Scholar
  42. Poole K (2005) Efflux-mediated antimicrobial resistance. J Antimicrob Chemother 56(1):20–51PubMedCrossRefGoogle Scholar
  43. Schmidtchen A, Frick IM et al (2002) Proteinases of common pathogenic bacteria degrade and inactivate the antibacterial peptide LL-37. Mol Microbiol 46(1):157–168PubMedCrossRefGoogle Scholar
  44. Shafer WM, Qu X et al (1998) 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 USA 95(4):1829–1833PubMedCrossRefGoogle Scholar
  45. Shai Y (1999) Mechanism of the binding, insertion and destabilization of phospholipid bilayer membranes by alpha-helical antimicrobial and cell non-selective membrane-lytic peptides. Biochim Biophys Acta 1462(1–2):55–70PubMedGoogle Scholar
  46. Sieprawska-Lupa M, Mydel P et al (2004) Degradation of human antimicrobial peptide LL-37 by Staphylococcus aureus-derived proteinases. Antimicrob Agents Chemother 48(12):4673–4679PubMedCrossRefGoogle Scholar
  47. Sonesson A, Ringstad L et al (2007) Antifungal activity of C3a and C3a-derived peptides against Candida. Biochim Biophys Acta 1768(2):346–353PubMedCrossRefGoogle Scholar
  48. Tamayo R, Choudhury B et al (2005) Identification of cptA, a PmrA-regulated locus required for phosphoethanolamine modification of the Salmonella enterica serovar typhimurium lipopolysaccharide core. J Bacteriol 187(10):3391–3399PubMedCrossRefGoogle Scholar
  49. Taylor P, Botto M et al (1998) The complement system. Curr Biol 8(8):R259–R261PubMedCrossRefGoogle Scholar
  50. Tremouilhac P, Strandberg E et al (2006) Synergistic transmembrane alignment of the antimicrobial heterodimer PGLa/magainin. J Biol Chem 281(43):32089–32094PubMedCrossRefGoogle Scholar
  51. Tzeng YL, Ambrose KD et al (2005) Cationic antimicrobial peptide resistance in Neisseria meningitidis. J Bacteriol 187(15):5387–5396PubMedCrossRefGoogle Scholar
  52. Visser LG, Hiemstra PS et al (1996) Role of YadA in resistance to killing of Yersinia enterocolitica by antimicrobial polypeptides of human granulocytes. Infect Immun 64(5):1653–1658PubMedGoogle Scholar
  53. Vogl G, Lesiak I et al (2008) Immune evasion by acquisition of complement inhibitors: the mould Aspergillus binds both factor H and C4b binding protein. Mol Immunol 45(5):1485–1493PubMedCrossRefGoogle Scholar
  54. Walport MJ (2001a) Complement. First of two parts. N Engl J Med 344(14):1058–1066PubMedCrossRefGoogle Scholar
  55. Walport MJ (2001b) Complement. Second of two parts. N Engl J Med 344(15):1140–1144PubMedCrossRefGoogle Scholar
  56. Wang Y, Agerberth B et al (1998) Apolipoprotein A-I binds and inhibits the human antibacterial/cytotoxic peptide LL-37. J Biol Chem 273(50):33115–33118PubMedCrossRefGoogle Scholar
  57. Wi S, Kim C (2008) Pore structure, thinning effect, and lateral diffusive dynamics of oriented lipid membranes interacting with antimicrobial peptide protegrin-1: 31P and 2H solid-state NMR study. J Phys Chem B 112(36):11402–11414PubMedCrossRefGoogle Scholar
  58. Yang L, Harroun TA et al (2001) Barrel-stave model or toroidal model? A case study on melittin pores. Biophys J 81(3):1475–1485PubMedCrossRefGoogle Scholar
  59. Zipfel PF, Wurzner R et al (2007) Complement evasion of pathogens: common strategies are shared by diverse organisms. Mol Immunol 44(16):3850–3857PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Infection BiologyLeibniz Institute for Natural Product Research and Infection Biology, Hans Knoell InstituteJenaGermany
  2. 2.Friedrich-Schiller-UniversityJenaGermany

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