Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Complement evasion by human pathogens

Key Points

  • The human complement system has a pivotal role in the recognition, opsonization and elimination of microbial intruders. This functionality is maintained by a well-balanced interaction network of serum proteins and cell-surface receptors.

  • Over thousands of years of co-evolution, many microorganisms have developed specific complement-evasion strategies to escape the attack of the immune system. Although some of these strategies are highly specific for a single species, others are shared more broadly among bacteria, viruses, fungi and parasites.

  • The most prevalent complement-evasion mechanism seems to be the capture of soluble host complement regulators on the microbial surface or the expression of their structural mimics. However, the inactivation of complement components by proteolytic degradation or specific inhibition of essential functional sites is also frequently observed.

  • Staphylococcus aureus has a particularly wide and diverse arsenal of complement-evasion proteins, many of which have been discovered only recently. These numerous evasion strategies could contribute to the high virulence of this bacterium.

  • Structural biology is an indispensable tool for characterizing the structure and function of complement-evasion proteins. Recent publications of the co-crystal structures of evasion proteins with their human targets have allowed an even deeper insight into the molecular basis of these escape mechanisms.

  • The rapid increase in the structural and functional understanding of complement evasion could serve as an important starting point for the development of antimicrobial or complement-targeting therapeutics.

Abstract

The human immune system has developed an elaborate network of cascades for dealing with microbial intruders. Owing to its ability to rapidly recognize and eliminate microorganisms, the complement system is an essential and efficient component of this machinery. However, many pathogenic organisms have found ways to escape the attack of complement through a range of different mechanisms. Recent discoveries in this field have provided important insights into these processes on a molecular level. These vital developments could augment our knowledge of the pathology and treatment of infectious and inflammatory diseases.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Activation and evasion of complement.
Figure 2: Molecular mimicry of human complement regulators by viruses.
Figure 3: Complement-targeting proteins in Staphylococcus aureus.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

Protein Data Bank

References

  1. Lambris, J. D., Sahu, A. & Wetsel, R. A. in The Human Complement System in Health and Disease (eds Volanakis, J. E. & Frank, M. M.) 83–118 (Marcel Dekker, New York, 1998).

    Book  Google Scholar 

  2. Lambris, J. D. & Holers, V. M. (eds) Therapeutic Interventions in the Complement System (Humana, Totowa, 2000).

    Book  Google Scholar 

  3. Walport, M. J. Complement. First of two parts. N. Engl. J. Med. 344, 1058–1066 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Walport, M. J. Complement. Second of two parts. N. Engl. J. Med. 344, 1140–1144 (2001). References 3 and 4 provide a brief overview of the complement system and its ambiguous involvement in infections and other diseases.

    Article  CAS  PubMed  Google Scholar 

  5. Lambris, J. D. (ed.) Current Topics in Complement (Springer, New York, 2006).

    Book  Google Scholar 

  6. Atkinson, J. P. & Frank, M. M. Bypassing complement: evolutionary lessons and future implications. J. Clin. Invest. 116, 1215–1218 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Markiewski, M. M., Nilsson, B., Nilsson Ekdahl, K., Mollnes, T. E. & Lambris, J. D. Complement and coagulation: strangers or partners in crime? Trends Immunol. 28, 184–192 (2007). Presents the interesting connections between the complement and the coagulation systems, and discusses their impact on disease and the immune response.

    Article  CAS  PubMed  Google Scholar 

  8. Spitzer, D., Mitchell, L. M., Atkinson, J. P. & Hourcade, D. E. Properdin can initiate complement activation by binding specific target surfaces and providing a platform for de novo convertase assembly. J. Immunol. 179, 2600–2608 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Volanakis, J. E. & Frank, M. M. (eds) The Human Complement System in Health and Diseases (Marcel Dekker, New York, 1998).

    Book  Google Scholar 

  10. Ricklin, D. & Lambris, J. D. Complement-targeted therapeutics. Nature Biotechnol. 25, 1265–1275 (2007). A current overview of the complement-specific drugs that are on the market and in clinical trials, and a discussion of how endogenous, pathogen-derived or synthetic drugs can be used to develop such therapeutics.

    Article  CAS  Google Scholar 

  11. Morgan, B. P., Marchbank, K. J., Longhi, M. P., Harris, C. L. & Gallimore, A. M. Complement: central to innate immunity and bridging to adaptive responses. Immunol. Lett. 97, 171–179 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Hawlisch, H. et al. C5a negatively regulates toll-like receptor 4-induced immune responses. Immunity 22, 415–426 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Zhang, X. et al. Regulation of Toll-like receptor-mediated inflammatory response by complement in vivo. Blood 110, 228–236 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Joiner, K., Brown, E., Hammer, C., Warren, K. & Frank, M. Studies on the mechanism of bacterial resistance to complement-mediated killing. III. C5b-9 deposits stably on rough and type 7 S. pneumoniae without causing bacterial killing. J. Immunol. 130, 845–849 (1983).

    CAS  PubMed  Google Scholar 

  15. Zipfel, P. F., Wurzner, R. & Skerka, C. Complement evasion of pathogens: common strategies are shared by diverse organisms. Mol. Immunol. 44, 3850–3857 (2007). A supplementary description of the current topics in the field of complement evasion, with the focus on redundancy and multiplicity, the acquisition of host regulators and simultaneous binding to other host proteins.

    Article  CAS  PubMed  Google Scholar 

  16. Kraiczy, P. & Würzner, R. Complement escape of human pathogenic bacteria by acquisition of complement regulators. Mol. Immunol. 43, 31–44 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Bernet, J., Mullick, J., Singh, A. K. & Sahu, A. Viral mimicry of the complement system. J. Biosci. 28, 249–264 (2003). A broad overview of the use of complement proteins by viruses that discusses immune evasion and cell attachment and entry.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Meri, T. et al. The hyphal and yeast forms of Candida albicans bind the complement regulator C4b-binding protein. Infect. Immun. 72, 6633–6641 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Meri, T. et al. The yeast Candida albicans binds complement regulators factor H and FHL-1. Infect. Immun. 70, 5185–5192 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Inal, J. M. Parasite interaction with host complement: beyond attack regulation. Trends Parasitol. 20, 407–412 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Kooyman, D. L. et al. In vivo transfer of GPI-linked complement restriction factors from erythrocytes to the endothelium. Science 269, 89–92 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Rautemaa, R., Jarvis, G. A., Marnila, P. & Meri, S. Acquired resistance of Escherichia coli to complement lysis by binding of glycophosphoinositol-anchored protectin (CD59). Infect. Immun. 66, 1928–1933 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Rautemaa, R. et al. Survival of Helicobacter pylori from complement lysis by binding of GPI-anchored protectin (CD59). Gastroenterology 120, 470–479 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Tortorella, D., Gewurz, B. E., Furman, M. H., Schust, D. J. & Ploegh, H. L. Viral subversion of the immune system. Annu. Rev. Immunol. 18, 861–926 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. McKenzie, R., Kotwal, G. J., Moss, B., Hammer, C. H. & Frank, M. M. Regulation of complement activity by vaccinia virus complement-control protein. J. Infect. Dis. 166, 1245–1250 (1992).

    Article  CAS  PubMed  Google Scholar 

  26. Rosengard, A. M., Liu, Y., Nie, Z. & Jimenez, R. Variola virus immune evasion design: expression of a highly efficient inhibitor of human complement. Proc. Natl Acad. Sci. USA 99, 8808–8813 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Murthy, K. H. et al. Crystal structure of a complement control protein that regulates both pathways of complement activation and binds heparan sulfate proteoglycans. Cell 104, 301–311 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Sfyroera, G., Katragadda, M., Morikis, D., Isaacs, S. N. & Lambris, J. D. Electrostatic modeling predicts the activities of orthopoxvirus complement control proteins. J. Immunol. 174, 2143–2151 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Liszewski, M. K. et al. Structure and regulatory profile of the monkeypox inhibitor of complement: comparison to homologs in vaccinia and variola and evidence for dimer formation. J. Immunol. 176, 3725–3734 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Miller, C. G., Shchelkunov, S. N. & Kotwal, G. J. The cowpox virus-encoded homolog of the vaccinia virus complement control protein is an inflammation modulatory protein. Virology 229, 126–133 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Engelstad, M., Howard, S. T. & Smith, G. L. A constitutively expressed vaccinia gene encodes a 42-kDa glycoprotein related to complement control factors that forms part of the extracellular virus envelope. Virology 188, 801–810 (1992).

    Article  CAS  PubMed  Google Scholar 

  32. Mullick, J., Bernet, J., Singh, A. K., Lambris, J. D. & Sahu, A. Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) open reading frame 4 protein (kaposica) is a functional homolog of complement control proteins. J. Virol. 77, 3878–3881 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Daix, V. et al. Ixodes ticks belonging to the Ixodes ricinus complex encode a family of anticomplement proteins. Insect Mol. Biol. 16, 155–166 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Valenzuela, J. G., Charlab, R., Mather, T. N. & Ribeiro, J. M. Purification, cloning, and expression of a novel salivary anticomplement protein from the tick, Ixodes scapularis. J. Biol. Chem. 275, 18717–18723 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Rooijakkers, S. H. & van Strijp, J. A. Bacterial complement evasion. Mol. Immunol. 44, 23–32 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Oda, T. et al. Inactivation of chemotactic activity of C5a by the serratial 56-kilodalton protease. Infect. Immun. 58, 1269–1272 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Chmouryguina, I., Suvorov, A., Ferrieri, P. & Cleary, P. P. Conservation of the C5a peptidase genes in group A and B streptococci. Infect. Immun. 64, 2387–2390 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Tsao, N. et al. Streptococcal pyrogenic exotoxin B cleaves properdin and inhibits complement-mediated opsonophagocytosis. Biochem. Biophys. Res. Commun. 339, 779–784 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Ghendler, Y., Parizade, M., Arnon, R., McKerrow, J. H. & Fishelson, Z. Schistosoma mansoni: evidence for a 28-kDa membrane-anchored protease on schistosomula. Exp. Parasitol. 83, 73–82 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Lahteenmaki, K., Kuusela, P. & Korhonen, T. K. Bacterial plasminogen activators and receptors. FEMS Microbiol. Rev. 25, 531–552 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Rooijakkers, S. H., van Wamel, W. J., Ruyken, M., van Kessel, K. P. & van Strijp, J. A. Anti-opsonic properties of staphylokinase. Microbes Infect. 7, 476–484 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Frank, M. M. Annihilating host defense. Nature Med. 7, 1285–1286 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Lubinski, J., Nagashunmugam, T. & Friedman, H. M. Viral interference with antibody and complement. Semin. Cell Dev. Biol. 9, 329–337 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rux, A. H. et al. Kinetic analysis of glycoprotein C of herpes simplex virus types 1 and 2 binding to heparin, heparan sulfate, and complement component C3b. Virology 294, 324–332 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Kostavasili, I. et al. Mechanism of complement inactivation by glycoprotein C of herpes simplex virus. J. Immunol. 158, 1763–1771 (1997).

    CAS  PubMed  Google Scholar 

  46. Favoreel, H. W., Van de Walle, G. R., Nauwynck, H. J. & Pensaert, M. B. Virus complement evasion strategies. J. Gen. Virol. 84, 1–15 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Inal, J. M. & Sim, R. B. A Schistosoma protein, Sh-TOR, is a novel inhibitor of complement which binds human C2. FEBS Lett. 470, 131–134 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Deng, J., Gold, D., LoVerde, P. T. & Fishelson, Z. Inhibition of the complement membrane attack complex by Schistosoma mansoni paramyosin. Infect. Immun. 71, 6402–6410 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gobert, G. N. & McManus, D. P. Update on paramyosin in parasitic worms. Parasitol. Int. 54, 101–107 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Nunn, M. A. et al. Complement inhibitor of C5 activation from the soft tick Ornithodoros moubata. J. Immunol. 174, 2084–2091 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Roversi, P. et al. The structure of OMCI, a novel lipocalin inhibitor of the complement system. J. Mol. Biol. 369, 784–793 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lowy, F. D. Staphylococcus aureus infections. N. Engl. J. Med. 339, 520–532 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Patti, J. M., Allen, B. L., McGavin, M. J. & Hook, M. MSCRAMM-mediated adherence of microorganisms to host tissues. Annu. Rev. Microbiol. 48, 585–617 (1994).

    Article  CAS  PubMed  Google Scholar 

  54. Foster, T. J. & Hook, M. Surface protein adhesins of Staphylococcus aureus. Trends Microbiol. 6, 484–488 (1998).

    Article  CAS  PubMed  Google Scholar 

  55. Chavakis, T., Preissner, K. T. & Herrmann, M. The anti-inflammatory activities of Staphylococcus aureus. Trends Immunol. 28, 408–418 (2007). This comprehensive review discusses how S. aureus uses various target points (including complement) to escape the attack of the immune system.

    Article  CAS  PubMed  Google Scholar 

  56. Foster, T. J. Immune evasion by staphylococci. Nature Rev. Microbiol. 3, 948–958 (2005).

    Article  CAS  Google Scholar 

  57. Rooijakkers, S. H., van Kessel, K. P. & van Strijp, J. A. Staphylococcal innate immune evasion. Trends Microbiol. 13, 596–601 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. O'Riordan, K. & Lee, J. C. Staphylococcus aureus capsular polysaccharides. Clin. Microbiol. Rev. 17, 218–234 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Peterson, P. K. et al. Dichotomy between opsonization and serum complement activation by encapsulated staphylococci. Infect. Immun. 20, 770–775 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Cunnion, K. M., Lee, J. C. & Frank, M. M. Capsule production and growth phase influence binding of complement to Staphylococcus aureus. Infect. Immun. 69, 6796–6803 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Verbrugh, H. A., Peterson, P. K., Nguyen, B. Y., Sisson, S. P. & Kim, Y. Opsonization of encapsulated Staphylococcus aureus: the role of specific antibody and complement. J. Immunol. 129, 1681–1687 (1982).

    CAS  PubMed  Google Scholar 

  62. Cedergren, L., Andersson, R., Jansson, B., Uhlen, M. & Nilsson, B. Mutational analysis of the interaction between staphylococcal protein A and human IgG1. Protein Eng. 6, 441–448 (1993).

    Article  CAS  PubMed  Google Scholar 

  63. Gouda, H. et al. Three-dimensional solution structure of the B domain of staphylococcal protein A: comparisons of the solution and crystal structures. Biochemistry 31, 9665–9672 (1992).

    Article  CAS  PubMed  Google Scholar 

  64. Nguyen, T., Ghebrehiwet, B. & Peerschke, E. I. Staphylococcus aureus protein A recognizes platelet gC1qR/p33: a novel mechanism for staphylococcal interactions with platelets. Infect. Immun. 68, 2061–2068 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Peerschke, E. I., Bayer, A. S., Ghebrehiwet, B. & Xiong, Y. Q. gC1qR/p33 blockade reduces Staphylococcus aureus colonization of target tissues in an animal model of infective endocarditis. Infect. Immun. 74, 4418–4423 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hartleib, J. et al. Protein A is the von Willebrand factor binding protein on Staphylococcus aureus. Blood 96, 2149–2156 (2000).

    CAS  PubMed  Google Scholar 

  67. Gómez, M. I. et al. Staphylococcus aureus protein A induces airway epithelial inflammatory responses by activating TNFR1. Nature Med. 10, 842–848 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Zhang, L., Jacobsson, K., Vasi, J., Lindberg, M. & Frykberg, L. A second IgG-binding protein in Staphylococcus aureus. Microbiology 144, 985–991 (1998).

    Article  CAS  PubMed  Google Scholar 

  69. Jin, T. et al. Staphylococcus aureus resists human defensins by production of staphylokinase, a novel bacterial evasion mechanism. J. Immunol. 172, 1169–1176 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Cunnion, K. M., Hair, P. S. & Buescher, E. S. Cleavage of complement C3b to iC3b on the surface of Staphylococcus aureus is mediated by serum complement factor I. Infect. Immun. 72, 2858–2863 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Cunnion, K. M., Buescher, E. S. & Hair, P. S. Serum complement factor I decreases Staphylococcus aureus phagocytosis. J. Lab. Clin. Med. 146, 279–286 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Lee, L. Y. et al. Inhibition of complement activation by a secreted Staphylococcus aureus protein. J. Infect. Dis. 190, 571–579 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Lee, L. Y., Liang, X., Hook, M. & Brown, E. L. Identification and characterization of the C3 binding domain of the Staphylococcus aureus extracellular fibrinogen-binding protein (Efb). J. Biol. Chem. 279, 50710–50716 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Hammel, M. et al. A structural basis for complement inhibition by Staphylococcus aureus. Nature Immunol. 8, 430–437 (2007). Describes the first co-crystal structure between a microbial complement-evasion protein and its host target domain; also elucidates the inhibition mechanism on a molecular level by combining biochemical and biophysical approaches.

    Article  CAS  Google Scholar 

  75. Hammel, M. et al. Characterization of Ehp, a secreted complement inhibitory protein from Staphylococcus aureus. J. Biol. Chem. 282, 30051–30061 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Jongerius, I. et al. Staphylococcal complement evasion by various convertase-blocking molecules. J. Exp. Med. 204, 2461–2471 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Rooijakkers, S. H.M. et al. Immune evasion by a staphylococcal complement inhibitor that acts on C3 convertases. Nature Immunol. 6, 920–927 (2005).

    Article  CAS  Google Scholar 

  78. Rooijakkers, S. H. M. et al. Staphylococcal complement inhibitor: structure and active sites. J. Immunol. 179, 2989–2998 (2007). The authors describe the crystal structure of a SCIN protein and identify its functional sites by analysing protein chimeras of SCIN and an inactive homologue.

    Article  CAS  PubMed  Google Scholar 

  79. Langley, R. et al. The staphylococcal superantigen-like protein 7 binds IgA and complement C5 and inhibits IgA-FcaRI binding and serum killing of bacteria. J. Immunol. 174, 2926–2933 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. de Haas, C. J. et al. Chemotaxis inhibitory protein of Staphylococcus aureus, a bacterial antiinflammatory agent. J. Exp. Med. 199, 687–695 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Postma, B. et al. Chemotaxis inhibitory protein of Staphylococcus aureus binds specifically to the C5a and formylated peptide receptor. J. Immunol. 172, 6994–7001 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Wright, A. J. et al. Characterisation of receptor binding by the chemotaxis inhibitory protein of Staphylococcus aureus and the effects of the host immune response. Mol. Immunol. 44, 2507–2517 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Geisbrecht, B. V., Hamaoka, B. Y., Perman, B., Zemla, A. & Leahy, D. J. The crystal structures of EAP domains from Staphylococcus aureus reveal an unexpected homology to bacterial superantigens. J. Biol. Chem. 280, 17243–17250 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Payne, D. J., Gwynn, M. N., Holmes, D. J. & Pompliano, D. L. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nature Rev. Drug Discov. 6, 29–40 (2007). Although not directly related to complement evasion, this insider view on new screening initiatives for antibiotic drugs by pharmaceutical companies provides noteworthy information on targets and challenges for this endeavour.

    Article  CAS  Google Scholar 

  85. Woodman, M. E. et al. Borrelia burgdorferi binding of host complement regulator factor H is not required for efficient mammalian infection. Infect. Immun. 75, 3131–3139 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. A step in the right direction. Nature Rev. Drug Discov. 6, 419 (2007).

  87. Daly, J. & Kotwal, G. J. Pro-inflammatory complement activation by the Aβ peptide of Alzheimer's disease is biologically significant and can be blocked by vaccinia virus complement control protein. Neurobiol. Aging 19, 619–627 (1998).

    Article  CAS  PubMed  Google Scholar 

  88. Pillay, N. S., Kellaway, L. A. & Kotwal, G. J. Vaccinia virus complement control protein significantly improves sensorimotor function recovery after severe head trauma. Brain Res. 1153, 158–165 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Marsh, M. & Helenius, A. Virus entry: open sesame. Cell 124, 729–740 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Nemerow, G. R., Mold, C., Schwend, V. K., Tollefson, V. & Cooper, N. R. Identification of gp350 as the viral glycoprotein mediating attachment of Epstein–Barr virus (EBV) to the EBV/C3d receptor of B cells: sequence homology of gp350 and C3 complement fragment C3d. J. Virol. 61, 1416–1420 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Tsoukas, C. D. & Lambris, J. D. Expression of EBV/C3d receptors on T cells: biological significance. Immunol. Today 14, 56–59 (1993).

    Article  CAS  PubMed  Google Scholar 

  92. Naniche, D. et al. Human membrane cofactor protein (CD46) acts as a cellular receptor for measles virus. J. Virol. 67, 6025–6032 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Santoro, F. et al. Interaction of glycoprotein H of human herpesvirus 6 with the cellular receptor CD46. J. Biol. Chem. 278, 25964–25969 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Nowicki, B., Hart, A., Coyne, K. E., Lublin, D. M. & Nowicki, S. Short consensus repeat-3 domain of recombinant decay-accelerating factor is recognized by Escherichia coli recombinant Dr adhesin in a model of a cell–cell interaction. J. Exp. Med. 178, 2115–2121 (1993).

    Article  CAS  PubMed  Google Scholar 

  95. Datta, P. K. & Rappaport, J. HIV and complement: hijacking an immune defense. Biomed. Pharmacother. 60, 561–568 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Schorey, J. S., Carroll, M. C. & Brown, E. J. A macrophage invasion mechanism of pathogenic mycobacteria. Science 277, 1091–1093 (1997).

    Article  CAS  PubMed  Google Scholar 

  97. Janssen, B. J. & Gros, P. Structural insights into the central complement component C3. Mol. Immunol. 44, 3–10 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Lambris, J. D. & Morikis, D. (eds) Structural Biology of the Complement System (CRC, Boca Raton, 2005).

    Google Scholar 

  99. Deisenhofer, J., Jones, T. A., Huber, R., Sjodahl, J. & Sjoquist, J. Crystallization, crystal structure analysis and atomic model of the complex formed by a human Fc fragment and fragment B of protein A from Staphylococcus aureus. Hoppe-Seyler's Z. Physiol. Chem. 359, 975–985 (1978).

    Article  CAS  Google Scholar 

  100. Sauer-Eriksson, A. E., Kleywegt, G. J., Uhlen, M. & Jones, T. A. Crystal structure of the C2 fragment of streptococcal protein G in complex with the Fc domain of human IgG. Structure 3, 265–278 (1995).

    Article  CAS  PubMed  Google Scholar 

  101. Ricklin, D. & Lambris, J. D. Exploring the complement interaction network using surface plasmon resonance. Adv. Exp. Med. Biol. 598, 260–278 (2007).

    Article  PubMed  Google Scholar 

  102. Lukacik, P. et al. Complement regulation at the molecular level: the structure of decay-accelerating factor. Proc. Natl Acad. Sci. USA 101, 1279–1284 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Al-Shangiti, A. M. et al. Structural relationships and cellular tropism of staphylococcal superantigen-like proteins. Infect. Immun. 72, 4261–4270 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Haas, P. J. et al. The structure of the C5a receptor-blocking domain of chemotaxis inhibitory protein of Staphylococcus aureus is related to a group of immune evasive molecules. J. Mol. Biol. 353, 859–872 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Zhang, X., Boyar, W., Toth, M. J., Wennogle, L. & Gonnella, N. C. Structural definition of the C5a C terminus by two-dimensional nuclear magnetic resonance spectroscopy. Proteins 28, 261–267 (1997).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by National Institutes of Health grants GM-069736, GM-62134, AI-30040, AI-072106 and AI-068730, and by the research incentive funds of the School of Biological Sciences at the University of Missouri-Kansas City.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to John D. Lambris.

Ethics declarations

Competing interests

John D. Lambris and Brian V. Geisbrecht are the inventors of a patent application that is related to the use of Efb-C as a therapeutic complement inhibitor.

Supplementary information

Supplementary information S1 (table)

Microbial complement-targeting proteins (PDF 335 kb)

Related links

Related links

DATABASES

Entrez Genome

cowpox

HHV-8

HIV-1

monkeypox

vaccinia

variola

Entrez Genome Project

Borrelia burgdorferi

Candida albicans

Escherichia coli

Helicobacter pylori

Schistosoma mansoni

Serratia marcescens

Staphylococcus aureus

Protein Data Bank

human C5a

CHIPS

DAF

Efb

SCIN

SpA

SSL-7

VCP

FURTHER INFORMATION

John D. Lambris's homepage

Glossary

Pattern-recognition receptor

A highly diverse group of soluble and surface-bound proteins that can detect specific molecular surface structures. These receptors are important for discriminating between self and non-self cells (for example, microorganisms) and are, therefore, found in various pathways of the immune system. Prominent examples in the complement system are C1q and mannose-binding lectin.

Anaphylatoxin

A small protein fragment (approximately 10 kDa) that is generated during the activation of complement components. C3a and C5a trigger a range of inflammatory and immune-stimulating responses by binding to their receptors (C3aR and C5aR) on various effector cells. The chemotactic activity of C5a is 100-fold higher than that of C3a; no such activities or receptors have so far been described for C4a.

Toll-like receptor

A pattern-recognition receptor that recognizes a range of surface structures on pathogens (for example, proteoglycans and lipopolysaccharides). Toll-like receptors are expressed on most immune cells and their activation and signalling induces numerous inflammatory, innate and adaptive immune responses.

Short consensus repeat

The structural building block of many complement regulators and receptors (for example, factor H and CR1). These β-sheet-rich domains, which are composed of approximately 60 residues, are also found in viral complement-evasion factors and other proteins (for example, selectins, clotting factor XIII B and GABA receptors).

α-defensin

A cationic, cyclic, cysteine-rich peptide of 15–20 amino acids that belongs to a family of antimicrobial peptides. Whereas α-defensins are mainly expressed in mammalian neutrophils, other members of this family have been described in various species within mammals, insects and plants. Although these peptides are thought to primarily disrupt microbial cell walls, they might also act as immunomodulators.

β-grasp domain

A structural fold that consists of anti-parallel β-strands that 'grasp' a single α-helix. Initially described as the central structural element of ubiquitin, this fold was later identified in several other proteins. Despite its small size, it has a wide range of functions and is present in enzymatic, binding and signalling proteins. β-grasp domains are central elements in the structures of a number of bacterial immune-evasion proteins.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lambris, J., Ricklin, D. & Geisbrecht, B. Complement evasion by human pathogens. Nat Rev Microbiol 6, 132–142 (2008). https://doi.org/10.1038/nrmicro1824

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro1824

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing