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J Immunol. 2014 Dec 15;193(12):6161-71. doi: 10.4049/jimmunol.1401600. Epub 2014 Nov 7.

The extracellular adherence protein from Staphylococcus aureus inhibits the classical and lectin pathways of complement by blocking formation of the C3 proconvertase.

Author information

  • 1Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, KS 66506;
  • 2Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands;
  • 3School of Biological Sciences, University of Missouri-Kansas City, Kansas City, MO 64110; and.
  • 4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19105.
  • 5Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, KS 66506; School of Biological Sciences, University of Missouri-Kansas City, Kansas City, MO 64110; and GeisbrechtB@k-state.edu.

Abstract

The pathogenic bacterium Staphylococcus aureus actively evades many aspects of human innate immunity by expressing a series of small inhibitory proteins. A number of these proteins inhibit the complement system, which labels bacteria for phagocytosis and generates inflammatory chemoattractants. Although the majority of staphylococcal complement inhibitors act on the alternative pathway to block the amplification loop, only a few proteins act on the initial recognition cascades that constitute the classical pathway (CP) and lectin pathway (LP). We screened a collection of recombinant, secreted staphylococcal proteins to determine whether S. aureus produces other molecules that inhibit the CP and/or LP. Using this approach, we identified the extracellular adherence protein (Eap) as a potent, specific inhibitor of both the CP and LP. We found that Eap blocked CP/LP-dependent activation of C3, but not C4, and that Eap likewise inhibited deposition of C3b on the surface of S. aureus cells. In turn, this significantly diminished the extent of S. aureus opsonophagocytosis and killing by neutrophils. This combination of functional properties suggested that Eap acts specifically at the level of the CP/LP C3 convertase (C4b2a). Indeed, we demonstrated a direct, nanomolar-affinity interaction of Eap with C4b. Eap binding to C4b inhibited binding of both full-length C2 and its C2b fragment, which indicated that Eap disrupts formation of the CP/LP C3 proconvertase (C4b2). As a whole, our results demonstrate that S. aureus inhibits two initiation routes of complement by expression of the Eap protein, and thereby define a novel mechanism of immune evasion.

Copyright © 2014 by The American Association of Immunologists, Inc.

PMID:
25381436
[PubMed - indexed for MEDLINE]
PMCID:
PMC4258549
Free PMC Article

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