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Production of C5a by ASP, a Serine Protease Released from Aeromonas sobria¹

Hidetoshi Nitta^*,, Takahisa Imamura^2,*, Yoshihiro Wada, Atsushi Irie, Hidetomo Kobayashi^¶, Keinosuke Okamoto^|| and Hideo Baba

^* Department of Molecular Pathology, Department of Gastroenterological Surgery, Department of Immunogenetics, and Department of Urology; Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; ^¶ Laboratory of Molecular Microbiological Science, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Japan; and ^|| Department of Pharmacogenetics, Faculty of Pharmaceutical Sciences, Okayama University, Okayama, Japan

Aeromonas sobria causes pus and edema at sites of infection. However, the mechanisms underlying these effects have not been elucidated. C5a, the amino-terminal fragment of the complement 5th component (C5), mimics these events. To investigate the involvement of C5a in the pathophysiology of A. sobria infection, we examined release of C5a from human C5 by a serine protease (ASP), a putative virulence factor secreted by this bacterium. C5 incubated with enzymatically active ASP induced neutrophil migration in a dose-dependent manner from an ASP concentration of 3 nM and in an incubation time-dependent manner in as little as 7 min, with neutrophil accumulation in guinea pigs at intradermal injection sites and neutrophil superoxide release. These effects on neutrophils were inhibited by a C5a-receptor antagonist. The ASP incubation mixture with C5 but not C3 elicited vascular leakage in a dose- and incubation time-dependent manner, which was inhibited by a histamine H₁-receptor antagonist. Together with these C5a-like activities, ASP cleaved C5 to release only one C5a Ag, the m.w. of which was similar to that of C5a. Immunoblotting using an anti-C5a Ab revealed generation of a C5a-like fragment from human plasma incubated with ASP. These results suggest that ASP-elicited neutrophil migration and vascular leakage via C5a production from C5 could occur in vivo, which was supported by that ASP did not affect functions of C5a and neutrophil C5a receptor. Through C5a generation, ASP could be associated with the induction of pus and edema caused by infection with this bacterium.

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-in-Aid for Scientific Research (B) (Grant No. 18390125 to T.I.).

² Address correspondence and reprint requests to Dr. T. Imamura, Department of Molecular Pathology, Faculty of Medical and Pharmaceutical Sciences, 1-1-1 Honjo, Kumamoto, Japan. E-mail address: taka{at}gpo.kumamoto-u.ac.jp

³ Abbreviations used in this paper: ASP, A. sobria serine proteinase; VL, vascular leakage; C5, complement 5th component; HPF, high-power field; CVF, cobra venom factor; DFP, diisopropyl fluorophosphate.