Human Astrovirus Coat Protein: A Novel C1 Inhibitor

  • Neel K. Krishna
  • Kenji M. Cunnion
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 632)


C1 is a multimolecular complex that initiates the classical pathway of complement. It is composed of the pattern recognition component C1q and the serine proteases C1r and C1s. Activation of C1 elicits a series of potent effector mechanisms directed at limiting infection by invading pathogens as well as participating in other biological functions such as immune tolerance. While many molecules in addition to antibody have been demonstrated to activate C1, only a handful of C1 inhibitors have been described. Disregulated control of complement activation is associated with numerous autoimmune and inflammatory disease processes, thus tight regulation of C1 activation is highly desirable. We have recently discovered a novel inhibitor of C1, the coat protein of the human astroviruses, a family of enteric pathogens that infect young children. The astrovirus coat protein binds to the A-chain of C1q and inhibits spontaneous as well as antibody-mediated activation of the C1 complex resulting in suppression of classical pathway activation and complement-mediated terminal effector functions. This is the first description of a non-enveloped icosahedral virus inhibiting complement activation and the first description of a viral inhibitor of C1. The known inhibitors of C1 are reviewed and then discussed in the context of this novel viral C1 inhibitor. Additionally, the properties of this compound are elucidated highlighting its potential as an anti-complement therapeutic for the many diseases associated with inappropriate complement activation.


Classical Pathway Normal Human Serum Hereditary Angioedema Cobra Venom Factor Multimolecular Complex 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported in part by National Institute of Health grant R21 AI060874 to NKK and by a grant from The Children’s Hospital of The King’s Daughters Research Endowment to KMC.


  1. Bass DM, Qiu S (2000) Proteolytic processing of the astrovirus capsid. J Virol 74:1810–1814PubMedCrossRefGoogle Scholar
  2. Bernet J, Mullick J (2003) Viral mimicry of the complement system. J Biosci 28:249–264PubMedCrossRefGoogle Scholar
  3. Bonaparte RS, Hair PS et al. (2008) Human astrovirus coat protein inhibits serum complement activation via C1, the first component of the classical pathway. J Virol 82:817'827PubMedCrossRefGoogle Scholar
  4. Borrow P, Oldstone MBA (1992) Characterization of lymphocytic choriomeningitis virus-binding protein(s): a candidate cellular receptor for the virus. J Virol 66:7270–7281PubMedGoogle Scholar
  5. Botto M, Walport MJ (2002) C1q, autoimmunity and apoptosis. Immunobiology 205:395–406PubMedCrossRefGoogle Scholar
  6. Cooper NR (1983) Activation and regulation of the first complement component. Federation Proc 42:134–138Google Scholar
  7. Cooper NR (1985) The classical complement pathway: activation and regulation of the first complement component. Adv Immunol 37:151–216PubMedCrossRefGoogle Scholar
  8. Davis AE III (1998) C1-INH and hereditary angioedema. In: Volanakis JE, Frank MM (eds.). The Human Complement System in Health and Disease, 1st edn, Marcel Dekker Inc, New YorkGoogle Scholar
  9. Davis AE III (2005) The pathophysiology of hereditary angioedema. Clin Immunol 114:3–9PubMedCrossRefGoogle Scholar
  10. Dennehy PH, Nelson SM et al. (2001)A prospective case-control study of the role of astrovirus in acute diarrhea among hospitalized young children. J Infect Dis 184:10–15PubMedCrossRefGoogle Scholar
  11. Favoreel HW, wan de Walle GR et al. (2003)Virus complement evasion strategies. J Gen Virol 84:1–15PubMedCrossRefGoogle Scholar
  12. Gaboriaud C, Thielens NM et al. (2004)Structure and activation of the C1 complex of complement: unraveling the puzzle. Trends Immunol 25:368–373PubMedCrossRefGoogle Scholar
  13. Ghebrehiwet B, Lim BL et al. (1994)Isolation, cDNA cloning, and overexpression of a 33-kD cell surface glycoprotein that binds to the globular “heads” of C1q. J Exp Med 179:1809–1821PubMedCrossRefGoogle Scholar
  14. Ghebrehiwet B, Peerschke EIB (2004) cC1q-R (calreticulin) and gC1q-R/p33: ubiquitously expressed multi-ligand binding cellular proteins involved in inflammation and infection. Mol Immunol 41:173–183PubMedCrossRefGoogle Scholar
  15. Gigli I, Mason JW et al. (1970)Interaction of plasma kallikrein with the C1 inhibitor. J Immunol 104:574–581PubMedGoogle Scholar
  16. Groeneveld TWL, Oroszlan M et al. (2005)Interaction of the extracellular matrix proteoglycans decorin and biglycan with C1q and collectins. J Immunol 175:4715–4723PubMedGoogle Scholar
  17. Groeneveld TWL, Ramwadhdoebé TH et al. (2007)Human neturophil peptide-1 inhibits both the classical and the lectin pathway of complement activation. Mol Immunol 44:3608–3614PubMedCrossRefGoogle Scholar
  18. Jiang B, Monroe SS et al. (1993)RNA sequence of astrovirus: Distinctive genomic organization and a putative retrovirus-like ribosomal frameshifting signal that directs the viral replicase synthesis. Proc Natl Acad Sci U S A 90:10539–10543PubMedCrossRefGoogle Scholar
  19. Jiang J, Wagner E et al. (2001)Complement 1 inhibitor is a regulator of the alternative pathway. J Exp Med 194:1609–1616PubMedCrossRefGoogle Scholar
  20. Johnston RB (1986) The complement system: physiology, disorders and activity in the newborn infant. Mead Johnson Symp Perinat Dev Med 24:7–12PubMedGoogle Scholar
  21. Kapikian AZ, Hoshino Y et al. (2001)Rotaviruses. In: Knipe DM, Howley (eds) PM Fields Virology, 4th edn, Lippincott, Williams & WilkinsPhiladelphiaGoogle Scholar
  22. Kishore U, Ghai R et al. (2004)Structural and functional anatomy of the globular domain of complement protein C1q. Immunol Lett 85:113–128CrossRefGoogle Scholar
  23. Klein MA, Kaeser PS (2001) Complement facilitates early prion pathogenesis. Nat Med 7:410–411CrossRefGoogle Scholar
  24. Koci MD, Moser LA et al. (2003)Astrovirus induces diarrhea in the absence of inflammation and cell death. J Virol 77:11798–11808PubMedCrossRefGoogle Scholar
  25. Kovacs H, Campbell ID et al. (1998)Evidence that C1q binds specifically to CH. 2-like immunoglobulin gamma motifs present in the autoantigen calreticulin and interferes with complement activation Biochemistry 37:17865–17874PubMedCrossRefGoogle Scholar
  26. Krumdieck R, Hook M et al. (1992)The proteoglycan decorin binds C1q and inhibits the activity of the C1 complex. J Immunol 149:3695–3701PubMedGoogle Scholar
  27. Lauvrak V, Brekke OH et al. (1997)Identification and characterisation of C1q-binding phage displayed peptides. Biol Chem 378:1509–1519PubMedCrossRefGoogle Scholar
  28. Levy L, Lepow I (1959) Assay and properties of serum inhibitor of C’1 esterase. Proc Soc Exp Biol Med 101:608–611PubMedGoogle Scholar
  29. Lewis TL, Greenberg HB et al. (1994)Analysis of astrovirus serotype 1 RNA, identification of the viral RNA-dependent RNA polymerase motif, and expression of a viral structural protein. J Virol 68:77–83PubMedGoogle Scholar
  30. Mabbott NA, Bruce ME (2001) Temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays onset of scrapie. Nat Med 7:485–487PubMedCrossRefGoogle Scholar
  31. Matsui SM, Greenberg HB (2001) Astroviruses. In: Knipe DM, Howley (eds) PM Fields Virology, 4th edn, Lippincott, Williams & WilkinsPhiladelphiaGoogle Scholar
  32. Matsui SM, Kiang D et al. (2001)Molecular biology of astroviruses: selected highlights. Novartis Found Symp 238:219–236PubMedCrossRefGoogle Scholar
  33. Matsushita MS, Thiel S et al. (2000)Proteolytic activities of two types of mannose-binding lectin-associated serine protease. J Immunol 165:2637–2642PubMedGoogle Scholar
  34. Méndez E, Fernández-Luna T et al. (2002)Proteolytic processing of a serotype 8 human astrovirus ORF2 polyprotein. J Virol 76:7996–8002PubMedCrossRefGoogle Scholar
  35. Moser LA, Schultz-Cherry S (2005) Pathogenesis of astrovirus infection. Viral Immunol 18:4–10PubMedCrossRefGoogle Scholar
  36. Poon PH, Schumaker VN et al. (1983)Conformation and restricted segmental flexibility of C1, the first component of human complement. J Mol Biol 168:563–577PubMedCrossRefGoogle Scholar
  37. Reid KBM, Lowe DM et al. (1972)Isolation and characterization of C1q, a subcomponent of the first component of complement. Biochem J 130:749–763PubMedGoogle Scholar
  38. Ricklin D, Lambris JD (2007) Complement-targeted therapeutics. Nat Biotech 25:1265–1275CrossRefGoogle Scholar
  39. Risco C, Carrascosa JL et al. (1995)Ultrastructure of human astrovirus serotype 2. J Gen Virol 76:2075–2080PubMedCrossRefGoogle Scholar
  40. Rogers J, Cooper NR et al. (1992)Complement activation by beta-amyloid in Alzheimer disease. Proc Natl Acad Sci U S A 89:10016–10020PubMedCrossRefGoogle Scholar
  41. Rooijakkers SH, van Strijp JA (2007) Bacterial complement evasion. Mol Immunol 44:23–32PubMedCrossRefGoogle Scholar
  42. Roos A, Nauta AJ et al. (2001)Specific inhibition of the classical complement pathway by C1q-binding peptides. J Immunol 167:7052–7059PubMedGoogle Scholar
  43. Sebire NJ, Malone M et al. (2004)Pathology of astrovirus associated diarrhoea in a paediatric bone marrow transplant recipient. J Clin Pathol 57:1001–1003PubMedCrossRefGoogle Scholar
  44. Shastri S, Doane AM et al. (1998)Prevalence of astroviruses in a children’s hospital. J Clin Microbiol 36:2571–2574PubMedGoogle Scholar
  45. Sim RB, Arlaud G et al. (1979)C1-inhibitor-dependent dissociation of human complement component C1 bound to immune complexes. Biochem J 179:449–457PubMedGoogle Scholar
  46. Sjoberg A, Onnerfjord P et al. (2005)The extracellular matrix and inflammation: fibromodulin activates the classical pathway of complement by directly binding C1q. J Biol Chem 280:32301–32308PubMedCrossRefGoogle Scholar
  47. Tacnet-Delorme, Chevallier S et al. (2001)Beta-amyloid fibrils activate the C1 complex of complement under physiological conditions. Evidence for a binding site for Ab on the C1q globular regions. J Immunol 167:6374–6381PubMedGoogle Scholar
  48. Trinder PKE, Maeurer MJ et al. (1993)Functional domains of the human C1q A-chain. Behring Inst Mitt 93:180–188PubMedGoogle Scholar
  49. van den Berg RH, Faber-Krol MC et al. (1996)Inhibition of hemolytic activity of the first component of complement C1 by an Escherichia coli. C1q binding protein J Immunol 156:4466–4473PubMedGoogle Scholar
  50. van den Berg RH, Faber-Krol MC et al. (1998)Inhibition of activation of the classical pathway of complement by human neutrophil defensins. Blood 92:3898–3903PubMedGoogle Scholar
  51. Vogel CW, Smith CA et al. (1984)Cobra venom factor: structural homology with the third component of complement. J Immunol 133:3235–3241PubMedGoogle Scholar
  52. Volanakis JE (1998) Overview of the complement system. In: Volanakis JE, Frank MM (eds.). The Human Complement System in Health and Disease, 1st ed, Marcel Dekker Inc, New YorkGoogle Scholar
  53. Willcocks MM, Brown TDK et al. (1994) The complete sequence of a human astrovirus J Gen Virol 75:1785–1788PubMedCrossRefGoogle Scholar
  54. Willcocks MM, Carter MJ (1993) Identification and sequence determination of the capsid protein gene of human astrovirus serotype 1. FEMS Microbiol Lett 114:1–8PubMedCrossRefGoogle Scholar
  55. Ziccardi RJ, Cooper N (1979) Active disassembly of the first complement component C1 by C1 inactivator. J Immunol 123:788–792ssPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Department of Microbiology and Molecular Cell BiologyEastern Virginia Medical SchoolNorfolkUSA
  2. 2.Department of PediatricsEastern Virginia Medical School and Children’s Specialty GroupNorfolkUSA, 23507

Personalised recommendations