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J. Biol. Chem., Vol. 283, Issue 10, 6253-6260, March 7, 2008

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Group A Streptococcal Cysteine Protease Degrades C3 (C3b) and Contributes to Evasion of Innate Immunity^*

Yutaka Terao, Yuka Mori, Masaya Yamaguchi, Yoshikata Shimizu, Kenji Ooe^¶, Shigeyuki Hamada^||, and Shigetada Kawabata¹

From the Department of Oral and Molecular Microbiology, Osaka University Graduate School of Dentistry, Suita, Osaka, 565-0871, Japan, the Department of Anaesthesia, Asahi General Hospital, Chiba, 289-2511, Japan, the ^¶Department of Pathology and Laboratory Medicine, Asahi General Hospital, Chiba, 289-2511, Japan, and the ^||Department of Life Science, Nihon University Advanced Research Institute for the Sciences and Humanities, Tokyo, 102-0073, Japan

A relative lack of neutrophils around Streptococcus pyogenes is observed in streptococcal toxic shock syndrome (STSS). Because the bacteria spread rapidly into various organs in STSS, we speculated that S. pyogenes is equipped with molecules to evade the host innate immune system. Complement C3b opsonizes the pathogen to facilitate phagocytosis, and a complex of C3b converts C5 into anaphylatoxin. Because we found that C3 (C3b) is degraded in sera from patients with STSS, we investigated the mechanism of C3 (C3b) degradation by S. pyogenes. We incubated human C3b or serum with recombinant SpeB (rSpeB), a wild-type S. pyogenes strain isolated from an STSS patient or its isogenic speB mutant and examined the supernatant by Western blotting with anti-human C3b. Western blot and Biacore analyses revealed that rSpeB and wild-type S. pyogenes rapidly degrade C3b. Additionally, C3 (C3b) was not detected in sera collected from infected areas of STSS patients. Furthermore, the survival rate in human blood and in mice was lower for the speB mutant than the wild-type strain. Histopathological observations demonstrated that neutrophils were recruited to and phagocytosed the speB mutant, whereas with the wild-type strain, few neutrophils migrated to the site of infection, and the bacteria spread along the fascia. We observed the degradation of C3 (C3b) in sera from STSS patients and the degradation of C3 (C3b) by rSpeB. This suggests that SpeB contributes to the escape of S. pyogenes from phagocytosis at the site of initial infection, allowing it to invade host tissues during severe infections.

Received for publication, June 12, 2007 , and in revised form, December 6, 2007.

^* This work was supported in part by a grant from the 21st century Center for Excellence program and Grants-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology, Grants-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of Science, and Research Grant for Longevity Sciences 17C-5 from the Ministry of Health, Labour and Welfare, and a grant from the Naito Foundation and the Research for Promoting Technological Seeds from the Japan Science and Technology Agency. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ To whom correspondence should be addressed: Dept. of Oral and Molecular Microbiology, Osaka University Graduate School of Dentistry, 1-8, Yamadaoka, Suita-Osaka, 565-0871, Japan. Tel.: 81-6-6879-2896; Fax: 81-6-6879-2180; E-mail: kawabata{at}dent.osaka-u.ac.jp.

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