West Nile virus nonstructural protein NS1 inhibits complement activation by binding the regulatory protein factor H
- Kyung Min Chung*,
- M. Kathryn Liszewski*,
- Grant Nybakken†,
- Alan E. Davis*,‡,
- R. Reid Townsend*,‡,
- Daved H. Fremont†,§,
- John P. Atkinson*,†,¶, and
- Michael S. Diamond*,†,¶,‖
- Departments of *Medicine,
- †Pathology and Immunology,
- §Biochemistry and Molecular Biophysics,
- ‡Cell Biology and Physiology, and
- ¶Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110
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Edited by Charles M. Rice, The Rockefeller University, New York, NY, and approved October 14, 2006 (received for review July 6, 2006)
Abstract
The complement system, by virtue of its dual effector and priming functions, is a major host defense against pathogens. Flavivirus nonstructural protein (NS)-1 has been speculated to have immune evasion activity, because it is a secreted glycoprotein, binds back to cell surfaces, and accumulates to high levels in the serum of infected patients. Herein, we demonstrate an immunomodulatory function of West Nile virus NS1. Soluble and cell-surface-associated NS1 binds to and recruits the complement regulatory protein factor H, resulting in decreased complement activation in solution and attenuated deposition of C3 fragments and C5b–9 membrane attack complexes on cell surfaces. Accordingly, extracellular NS1 may function to minimize immune system targeting of West Nile virus by decreasing complement recognition of infected cells.
Footnotes
- ‖To whom correspondence should be addressed. E-mail: diamond{at}borcim.wustl.edu
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Author contributions: K.M.C., M.K.L., R.R.T., D.H.F., J.P.A., and M.S.D. designed research; K.M.C., M.K.L., and A.E.D. performed research; G.N. contributed new reagents/analytic tools; K.M.C., R.R.T., J.P.A., and M.S.D. analyzed data; and K.M.C., M.K.L., G.N., R.R.T., D.H.F., J.P.A., and M.S.D. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS direct submission.
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See Commentary on page 18879.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0605668103/DC1.
- Abbreviations:
- WNV,
- West Nile virus;
- DENV,
- dengue virus;
- fH,
- plasma glycoprotein factor H;
- fI,
- serine protease factor I;
- NHS,
- normal human serum;
- BHK,
- baby hamster kidney;
- C7d-HS,
- C7-deficient human serum.
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Freely available online through the PNAS open access option.
- © 2006 by The National Academy of Sciences of the USA
