轉糖鏈球菌利用血漿成分增加在血液中的存活及引起感染性心內膜炎的能力

Abstract

感染性心內膜炎(Infective endocarditis)是一種高致死率的心血管疾病。轉糖鏈球菌(Streptococcus mutans)是口腔中的正常菌株，也是在心臟瓣膜上引起感染性心內膜炎的伺機性病原菌，細菌能在血液循環中生存及在受傷辦膜上利用血小板形成贅生物，是感染性心內膜炎的主要致病機轉。本研究證明了轉糖鏈球菌可利用血漿成分，增加引發感染性心內膜炎的致病力。當細菌受低濃度血漿的刺激後，抵抗白血球毒殺及存活在血液循環中的能力有增加的現象；並與纖維結合素(Fibronectin)結合能力相關。一個新發現且普遍存在於草綠色鏈球菌中的纖維結合素結合蛋白質，AtlA，其成熟型較未成熟型對纖維結合素具有較高的結合能力，有趣的是血漿中的鈣離子，可促使AtlA由104 kDa的未成熟型變成90 kDa的成熟型，可增加細菌抵抗白血球吞噬的能力。不表現AtlA的變異株在感染性心內膜炎的動物實驗中，其血液中的存活率及致病力皆較低，回補AtlA後則可回復致病力。此外，除了纖維結合素外，轉糖鏈球菌也可借由具專一性的免疫球蛋白IgG及纖維素原(Fibrinogen)的結合來引發血小板的凝集，並且由轉糖鏈球菌的細胞壁中找到一個血小板凝集相關分子(platelet aggregation associated molecule; PAAM)，由轉糖鏈球菌或PAAM所引起的血小板凝集需要IgG，GPIb，纖維素原和thromboxane A2的參與，但不需要thrombin，vWF和ADP。這些結果支持原先的假設，轉糖鏈球菌可藉由與血漿中的成分或血小板的結合，來抵抗宿主血液循環中的免疫攻擊及增加引發感染性心內膜炎的致病力。

Infective endocarditis (IE) is an infectious disease of the cardiovascular system, and carries a high mortality rate. Streptococcus mutans, a commensal in the human oral cavity, is an opportunistic pathogen of IE. The pathogenesis of IE depends on the ability of bacteria to survive in the bloodstream and to form the vegetation through platelet aggregation. This report demonstrates that, through interaction with plasma components, S. mutans enhances its virulence for IE. Prior exposure to low plasma concentrations is sufficient to enhance bacterial resistance to phagocytosis and survival in the circulation. An autolysin, AtlA, located on the surface of viridans streptococci, is a newly identified Fibronectin (Fn)-binding protein and its mature form exhibits significantly higher binding activity to soluble Fn. Interestingly, plasma or calcium ions at physiological concentrations induces degradation of AtlA from 104 kDa to 90 kDa, resulting in increased Fn binding and resistance to phagocytosis. An isogenic mutant strain defective in the expression of AtlA exhibits reduced survival and virulence when tested in a rat model of IE, whereas complementation of AtlA restores survival and virulence to wild type level. In addition to Fn, S. mutans binds specific IgG and fibrinogen (Fg) to induce platelet aggregation. A soluble bacterial component, named platelet aggregation associated molecule (PAAM), is purified from the cell wall of S. mutans. S. mutans or the PAAM induce platelet aggregation in a IgG-, GPIb-, Fg-, or thromboxane A2-dependent but thrombin-, vWF- or ADP-independent manner. These results support the hypothesis that S. mutans hijacks the plasma components or platelet to escape immune surveillance in the bloodstream and to enhance the virulence for IE.