Versatile Roles of CspA Orthologs in Complement Inactivation of Serum-Resistant Lyme Disease Spirochetes
Versatile Roles of CspA Orthologs in Complement Inactivation of Serum-Resistant Lyme Disease Spirochetes
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DOI：
10.1128/iai.01094-13
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发表时间：
2014-01-01
影响因子：
3.1
通讯作者：
Kraiczy, Peter
中科院分区：
文献类型：
--
作者：
Hammerschmidt, Claudia;Koenigs, Arno;Kraiczy, Peter
莱姆病螺旋体伯氏疏螺旋体的CspA代表免疫逃避中的关键分子，保护疏螺旋体细胞免受补体介导的杀伤。由于以前的研究几乎完全集中在B的CspA上。为了研究伯氏疏螺旋体的CspA直系同源物的不同结合能力，在此我们研究伯氏疏螺旋体的CspA直系同源物，B。afzelii和B. spielmanii对补体调节因子H和纤溶酶原的作用，以及它们通过结合这些宿主来源的血浆蛋白或独立地通过与参与形成致死性孔样末端补体复合物的组分直接相互作用来抑制补体活化的能力。为了进一步研究它们在体内血清抵抗中的功能，使用血清敏感的B。garinii菌株用于产生螺旋体，异位产生功能性CspA直向同源物。无论其物种来源如何，当在血清敏感性B中产生时，所有三种CspA直系同源物均赋予对补体介导的杀伤的抗性。garinii替代菌株。为了分析对补体激活的抑制作用并评估通过H因子和纤溶酶原结合来灭活C3 b的潜力，还研究了重组CspA直系同源物。所有三种CspA直向同源物同时结合因子H和纤溶酶原，但在它们通过结合纤溶酶（原）抑制C3b和抑制末端补体复合物形成的能力方面不同。B的CspA。Afzelii结合纤溶酶（原）并比B的CspA更有效地抑制末端补体复合物。burgdorferi和B. spielmanii。总之，血清抗性莱姆病螺旋体的CspA直系同源物充当多功能逃避分子，其在两个中心活化水平上抑制补体，C3b产生和末端补体复合物的组装。
CspA of the Lyme disease spirochete Borrelia burgdorferi represents a key molecule in immune evasion, protecting borrelial cells from complement-mediated killing. As previous studies focused almost exclusively on CspA of B. burgdorferi, here we investigate the different binding capacities of CspA orthologs of Borrelia burgdorferi, B. afzelii, and B. spielmanii for complement regulator factor H and plasminogen and their ability to inhibit complement activation by either binding these host-derived plasma proteins or independently by direct interaction with components involved in formation of the lethal, pore-like terminal complement complex. To further examine their function in serum resistance in vivo, a serum-sensitive B. garinii strain was used to generate spirochetes, ectopically producing functional CspA orthologs. Irrespective of their species origin, all three CspA orthologs impart resistance to complement-mediated killing when produced in a serum-sensitive B. garinii surrogate strain. To analyze the inhibitory effect on complement activation and to assess the potential to inactivate C3b by binding of factor H and plasminogen, recombinant CspA orthologs were also investigated. All three CspA orthologs simultaneously bound factor H and plasminogen but differed in regard to their capacity to inactivate C3b via bound plasmin(ogen) and inhibit formation of the terminal complement complex. CspA of B. afzelii binds plasmin(ogen) and inhibits the terminal complement complex more efficiently than CspA of B. burgdorferi and B. spielmanii. Taken together, CspA orthologs of serum-resistant Lyme disease spirochetes act as multifunctional evasion molecules that inhibit complement on two central activation levels, C3b generation and assembly of the terminal complement complex.