Leptospira interrogans Lsa23 protein recruits plasminogen, factor H and C4BP from normal human serum and mediates C3b and C4b degradation.
Leptospira interrogans Lsa23 protein recruits plasminogen, factor H and C4BP from normal human serum and mediates C3b and C4b degradation.
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DOI：
10.1099/mic.0.000217
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发表时间：
2016-02
期刊：
影响因子：
1.5
通讯作者：
G. Siqueira;M. V. Atzingen;G. O. de Souza;S. Vasconcellos;A. L. Nascimento
中科院分区：
文献类型：
--
作者：
G. Siqueira;M. V. Atzingen;G. O. de Souza;S. Vasconcellos;A. L. Nascimento
据报道，致病性钩端螺旋体对正常人血清（NHS）具有抗性，这是由于它们能够通过与因子H（FH）和C4 b结合蛋白（C4 BP）调节剂相互作用来逃避补体免疫系统。此外，在钩端螺旋体表面上的纤溶酶产生减少C3 b和IgG沉积，减少免疫活性细胞的调理吞噬作用。我们以前曾报道，Lsa 23（LIC 11360）是一种多用途蛋白，能够结合纯化的细胞外基质分子，FH，C4 BP和纤溶酶原（PLG）/纤溶酶在PLG激活剂的存在下。在这项工作中，我们提供了进一步的证据表明，Lsa 23是位于细菌表面，通过使用免疫荧光显微镜。我们发现Lsa 23具有从NHS获得FH、C4 BP和PLG的能力，并利用这些相互作用来逃避先天免疫。与补体调节剂FH和C4 BP的结合保留了因子I（FI）活性，分别产生C3 b和C4 b降解产物。当Lsa 23与PLG结合产生纤溶酶时，也观察到C3 b和C4 b α链切割，该作用被蛋白酶抑制剂抑肽酶阻断。Lsa 23还抑制由经典和替代补体途径介导的NHS的裂解活性。因此，Lsa 23具有阻断补体系统的两种途径的能力，并且可以帮助致病性钩端螺旋体逃避人类宿主中补体介导的清除。事实上，用Lsa 23处理的NHS赋予双曲钩端螺旋体部分血清抗性表型，而用抗Lsa 23阻断该蛋白质使致病性L.更容易受到补体介导的杀伤。因此，Lsa 23是一种参与许多途径的多功能蛋白质，其特征在于通过纤溶酶切割C4 b，这一知识可能有助于开发预防性方法来干预这种多功能病原体引起的人类补体逃逸。
It has been reported that pathogenic Leptospira are resistant to normal human serum (NHS) due to their ability to evade the complement immune system by interacting with factor H (FH) and C4b-binding protein (C4BP) regulators. Moreover, plasmin generation on the leptospiral surface diminishes C3b and IgG deposition, decreasing opsonophagocytosis by immune competent cells. We have previously reported that Lsa23 (LIC11360) is a multipurpose protein capable of binding purified extracellular matrix molecules, FH, C4BP and plasminogen (PLG)/plasmin in the presence of PLG activators. In this work, we provide further evidence that Lsa23 is located at the bacterial surface by using immunofluorescence microscopy. We show that Lsa23 has the ability to acquire FH, C4BP and PLG from NHS, and use these interactions to evade innate immunity. The binding with the complement regulators FH and C4BP preserves factor I (FI) activity, leading to C3b and C4b degradation products, respectively. C3b and C4b alpha-chain cleavage was also observed when Lsa23 bound to PLG generating plasmin, an effect blocked by the protease inhibitor aprotinin. Lsa23 also inhibited lytic activity by NHS mediated by both classical and alternative complement pathways. Thus, Lsa23 has the ability to block both pathways of the complement system, and may help pathogenic Leptospira to escape complement-mediated clearance in human hosts. Indeed, NHS treated with Lsa23 confers a partial serum resistance phenotype to Leptospira biflexa, whereas blocking this protein with anti-Lsa23 renders pathogenic L. interrogans more susceptible to complement-mediated killing. Thus, Lsa23 is a multifunctional protein involved in many pathways, featuring C4b cleavage by plasmin, knowledge that may help in the development of preventive approaches to intervene with human complement escape by this versatile pathogen.