| Summary: | 碩士 === 國立成功大學 === 微生物及免疫學研究所 === 92 === Clearance of apoptotic cells rapidly by phagocytes is important in innate immunity to maintain cell homeostasis. Serum-derived protein S-mediated apoptotic cell clearance by macrophages was recently demonstrated. In this study, we show that streptococcal pyrogenic exotoxin B (SPE B), a cysteine protease produced by Streptococcus pyogenes, causes an inhibitory effect on protein S-mediated phagocytosis. Streptococcus pyogenes is a Gram-positive bacterium that can cause a wide range of diseases, including uncomplicated pharygitis, bacteremia, necrotizing fasciitis, and streptococcal toxin shock syndrome (STSS). This bacterium is also responsible for nonsuppurative sequelae, such as acute rheumatic fever and acute glomerulonephritis. There is vast repertoire of virulence factors that may participate in group A streptococcal (GAS) infections. SPE B, a streptococcal cysteine protease, may play an important role in severe GAS pathogenesis. We found that the ability of murine peritoneal macrophage phagocytosis of apoptotic cells promoted by serum was inhibited in the presence of SPE B. Interestingly, SPE B cleaved protein S directly via dose- and time-dependent manner and reduced protein S-mediated macrophage phagocytosis of apoptotic cells. These effects caused by SPE B were dependent on its protease activity as compared with SPE B mutant C192S, SPE A, or SPE B inactivation by cysteine protease inhibitor E64 pretreatment. Analysis of SPE B-specific cutting site and the cleaved protein S sequencing suggest that the C-terminal site of protein S, SK (a.a. 615 and 616), acts as the initial site of SPE B cleavage function. The loss of support on macrophage phagocytosis by protein S actually occurred while C-terminal site was disrupted by SPE B. Further studies demonstrated that cleaved protein S lost the binding ability to the surface of apoptotic cells. Therefore, a novel pathogenic role of SPE B is proposed that SPE B causes protein S destruction, followed by the inhibition of apoptotic cell clearance by macrophages.
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