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Infection and Immunity, February 2005, p. 883-893, Vol. 73, No. 2
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.2.883-893.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

A Functional Virulence Complex Composed of Gingipains, Adhesins, and Lipopolysaccharide Shows High Affinity to Host Cells and Matrix Proteins and Escapes Recognition by Host Immune Systems

Ryosuke Takii, Tomoko Kadowaki, Atsuyo Baba, Takayuki Tsukuba, and Kenji Yamamoto*

Department of Pharmacology, Graduate School of Dental Science, Kyushu University, Fukuoka, Japan

Received 18 August 2004/ Returned for modification 14 September 2004/ Accepted 5 October 2004

Arg-gingipain (Rgp) and Lys-gingipain (Kgp) are Porphyromonas gingivalis cysteine proteinases implicated as major virulence factors in pathologies of periodontitis. We purified a 660-kDa cell-associated gingipain complex existing as a homodimer of two catalytically active monomers which comprises their catalytic and adhesin domains. Electron microscopy revealed that the complex was composed of a globular particle with a 10-nm external diameter possessing one or two electron-dense hole-like structures. Two-dimensional gel electrophoresis and immunoblot analyses revealed the association of lipopolysaccharide (LPS) with the catalytic domains and a hemagglutinin domain, Hgp44, of Rgp and Kgp in the complex. The complex significantly degraded human type I collagen and elastin and strongly disrupted viability of human gingival fibroblasts and umbilical vein endotherial cells with an efficiency which was higher than that of the monomeric gingipains. The native complex produced only a small amount of nitrogen dioxide, tumor necrosis factor alpha, and interleukin-6 by macrophages, whereas the heat-denatured complex resulted in increased production. Inhibition of the proteolytic activities of the gingipain complex did not up-regulate the cytokine production, indicating that the functional domains in LPS are structurally masked by the complex proteins. These results indicate the importance of the complex in evasion of host defense mechanisms as well as in host tissue breakdown.

* Corresponding author. Mailing address: Department of Pharmacology, Graduate School of Dental Science, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan. Phone: 81-92-642-6337. Fax: 81-92-642-6342. E-mail: kyama{at}dent.kyushu-u.ac.jp.

Editor: A. D. O'Brien

Infection and Immunity, February 2005, p. 883-893, Vol. 73, No. 2
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.2.883-893.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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