Research Division for Radiation Science, Korea Atomic Energy Research Institute, Jeongeup, Republic of Korea.
Department of Oral Microbiology and Immunology, DRI, and BK21 Plus Program, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
mBio. 2021 Jun 29;12(3):e0074621. doi: 10.1128/mBio.00746-21. Epub 2021 Jun 22.
Expression of bacteriophage lysin by Streptococcus oralis strain SF100 is thought to be important for the pathogenesis of infective endocarditis, due to its ability to mediate bacterial binding to fibrinogen. To better define the lysin binding site on fibrinogen Aα, and to investigate the impact of binding on fibrinolysis, we examined the interaction of lysin with a series of recombinant fibrinogen Aα variants. These studies revealed that lysin binds the C-terminal region of fibrinogen Aα spanned by amino acid residues 534 to 610, with an affinity of equilibrium dissociation constant () of 3.23 × 10 M. This binding site overlaps the known binding site for plasminogen, an inactive precursor of plasmin, which is a key protease responsible for degrading fibrin polymers. When tested , lysin competitively inhibited plasminogen binding to the αC region of fibrinogen Aα. It also inhibited plasminogen-mediated fibrinolysis, as measured by thromboelastography (TEG). These results indicate that lysin is a bi-functional virulence factor for streptococci, serving as both an adhesin and a plasminogen inhibitor. Thus, lysin may facilitate the attachment of bacteria to fibrinogen on the surface of damaged cardiac valves and may also inhibit plasminogen-mediated lysis of infected thrombi (vegetations) on valve surfaces. The interaction of streptococci with human fibrinogen and platelets on damaged endocardium is a central event in the pathogenesis of infective endocarditis. Streptococcus oralis can bind platelets via the interaction of bacteriophage lysin with fibrinogen on the platelet surface, and this process has been associated with increased virulence in an animal model of endocarditis. We now report that lysin binds to the αC region of the human fibrinogen Aα chain. This interaction blocks plasminogen binding to fibrinogen and inhibits fibrinolysis. , this inhibition could prevent the lysis of infected vegetations, thereby promoting bacterial persistence and virulence.
唾液链球菌 SF100 表达噬菌体溶素被认为对感染性心内膜炎的发病机制很重要，因为它能够介导细菌与纤维蛋白原结合。为了更好地确定纤维蛋白原 Aα 上溶素的结合位点，并研究结合对纤维蛋白溶解的影响，我们研究了溶素与一系列重组纤维蛋白原 Aα 变体的相互作用。这些研究表明，溶素结合纤维蛋白原 Aα 的 C 末端区域，氨基酸残基 534 至 610 ，其平衡解离常数（）为 3.23×10 M。该结合位点与纤溶酶原（纤溶酶的无活性前体）的已知结合位点重叠，纤溶酶原是负责降解纤维蛋白聚合物的关键蛋白酶。当测试时，溶素竞争性抑制纤溶酶原与纤维蛋白原 Aα 的αC 区域结合。它还抑制纤溶酶原介导的纤维蛋白溶解，如血栓弹性描记图（TEG）所示。这些结果表明，溶素是链球菌的一种双功能毒力因子，既是一种黏附素，也是一种纤溶酶原抑制剂。因此，溶素可能有助于细菌附着在受损心瓣膜表面的纤维蛋白原上，也可能抑制纤溶酶原介导的感染血栓（赘生物）在瓣膜表面的溶解。链球菌与受损心内膜上的人类纤维蛋白原和血小板的相互作用是感染性心内膜炎发病机制的核心事件。唾液链球菌可以通过噬菌体溶素与血小板表面纤维蛋白原的相互作用结合血小板，这一过程与动物模型中心内膜炎的毒力增加有关。我们现在报告溶素结合到人类纤维蛋白原 Aα 链的αC 区域。这种相互作用阻止纤溶酶原与纤维蛋白原结合并抑制纤维蛋白溶解。因此，这种抑制可能防止感染性赘生物的溶解，从而促进细菌的持续存在和毒力。
