Hammerschmidt Claudia, Klevenhaus Yvonne, Koenigs Arno, Hallström Teresia, Fingerle Volker, Skerka Christine, Pos Klaas Martinus, Zipfel Peter F, Wallich Reinhard, Kraiczy Peter
Institute of Medical Microbiology and Infection Control, University Hospital of Frankfurt, Frankfurt, Germany.
Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany.
Mol Microbiol. 2016 Jan;99(2):407-24. doi: 10.1111/mmi.13239. Epub 2015 Oct 27.
Borrelia (B.) bavariensis exhibits a marked tropism for nervous tissues and frequently causes neurological manifestations in humans. The molecular mechanism by which B. bavariensis overcomes innate immunity, in particular, complement remains elusive. In contrast to other serum-resistant spirochetes, none of the B. bavariensis isolates investigated bound complement regulators of the alternative (AP) and classical pathway (CP) or proteolytically inactivated complement components. Focusing on outer surface proteins BGA66 and BGA71, we demonstrated that both molecules either inhibit AP, CP and terminal pathway (TP) activation, or block activation of the CP and TP respectively. Both molecules bind complement components C7, C8 and C9, and thereby prevent assembly of the terminal complement complex. This inhibitory activity was confirmed by the introduction of the BGA66 and BGA71 encoding genes into a serum-sensitive B. garinii strain. Transformed spirochetes producing either BGA66 or BGA71 overcome complement-mediated killing, thus indicating that both proteins independently facilitate serum resistance of B. bavariensis. The generation of C-terminally truncated proteins as well as a chimeric BGA71 protein lead to the localization of the complement-interacting binding site within the N-terminus. Collectively, our data reveal a novel immune evasion strategy of B. bavariensis that is directed against the activation of the TP.
巴伐利亚疏螺旋体对神经组织表现出明显的嗜性，并经常在人类中引起神经学表现。巴伐利亚疏螺旋体克服先天免疫，特别是补体的分子机制仍然难以捉摸。与其他血清抗性螺旋体不同，所研究的巴伐利亚疏螺旋体分离株均未结合替代途径（AP）和经典途径（CP）的补体调节因子，也未对补体成分进行蛋白水解失活。聚焦于外表面蛋白BGA66和BGA71，我们证明这两种分子要么抑制AP、CP和终末途径（TP）的激活，要么分别阻断CP和TP的激活。这两种分子都结合补体成分C7、C8和C9，从而阻止终末补体复合物的组装。通过将编码BGA66和BGA71的基因导入血清敏感的伽氏疏螺旋体菌株，证实了这种抑制活性。产生BGA66或BGA71的转化螺旋体克服了补体介导的杀伤作用，因此表明这两种蛋白质独立促进了巴伐利亚疏螺旋体的血清抗性。C末端截短蛋白以及嵌合BGA71蛋白的产生导致补体相互作用结合位点定位于N末端。总的来说，我们的数据揭示了巴伐利亚疏螺旋体针对TP激活的一种新的免疫逃避策略。
