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Immune Evasion of Enterococcus faecalis by an Extracellular Gelatinase That Cleaves C3 and iC3b¹

Shin Yong Park^*, Yong Pyo Shin^*, Chong Han Kim^*, Ho Jin Park^*, Yeon Sun Seong, Byung Sam Kim, Sook Jae Seo and In Hee Lee^2,*

^* Department of Biotechnology, Hoseo University, Asan City, Chungnam, South Korea; Department of Biochemistry, College of Medicine, Dankook University, Cheonan, South Korea; Immunomodulation Research Center, University of Ulsan, Ulsan, South Korea; and Division of Life Science, College of Natural Sciences, Gyeongsang National University, Chinju, South Korea

Enterococcus faecalis (Ef) accounts for most cases of enterococcal bacteremia, which is one of the principal causes of nosocomial bloodstream infections (BSI). Among several virulence factors associated with the pathogenesis of Ef, an extracellular gelatinase (GelE) has been known to be the most common factor, although its virulence mechanisms, especially in association with human BSI, have yet to be demonstrated. In this study, we describe the complement resistance mechanism of Ef mediated by GelE. Using purified GelE, we determined that it cleaved the C3 occurring in human serum into a C3b-like molecule, which was inactivated rapidly via reaction with water. This C3 convertase-like activity of GelE was shown to result in a consumption of C3 and thus inhibited the activation of the complement system. Also, GelE was confirmed to degrade an iC3b that was deposited on the Ag surfaces without affecting the bound C3b. This proteolytic effect of GelE against the major complement opsonin resulted in a substantial reduction in Ef phagocytosis by human polymorphonuclear leukocytes. In addition, we verified that the action of GelE against C3, which is a central component of the complement cascade, was human specific. Taken together, it was suggested that GelE may represent a promising molecule for targeting human BSI associated with Ef.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant (2005-015-C00447) from Korea Research Foundation (KRF). S.Y.P. and C.H.K. received a scholarship from the World-Class 2030 Project of Hoseo University. S.J.S. and B.S.K. were supported by a scholarship (or grant) from the BK21 Program, the Ministry of Education and Human Resources Development, Korea.

² Address correspondence and reprint requests to Dr. In Hee Lee, Department of Biotechnology, Hoseo University, 165 Sechuli, Baebangmyun, Asan City, Chungnam, South Korea. E-mail address: leeih{at}hoseo.edu

³ Abbreviations used in this paper: MAC, membrane attack complex; PMN, polymorphonuclear leukocyte; f, factor; CR, complement receptor; BSI, bloodstream infection; Ef, Enterococcus faecalis; GelE, gelatinase; NHS, normal human serum; C3-def HS, C3-deficient human serum; O-Ef, pre-opsonized Ef; CVF, cobra venom factor.