The emerging pathogen Moraxella catarrhalis interacts with complement inhibitor C4b binding protein through ubiquitous surface proteins A1 and A2
The emerging pathogen Moraxella catarrhalis interacts with complement inhibitor C4b binding protein through ubiquitous surface proteins A1 and A2
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DOI：
10.4049/jimmunol.173.7.4598
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发表时间：
2004-10-01
影响因子：
4.4
通讯作者：
Riesbeck, K
中科院分区：
文献类型：
--
作者：
Nordström, T;Blom, AM;Riesbeck, K
卡他莫拉菌普遍存在的表面蛋白A2（UspA 2）介导对正常人血清杀菌活性的抗性。在这项研究中，经典途径的补体液相调节因子C4 b结合蛋白（C4 BP）和M。通过流式细胞术和RIA分析缺乏UspA 1和/或UspA 2的卡他突变体。两株临床分离的M.卡他菌表达UspA 2的密度高于UspA 1。UspA 1突变体显示出降低C4 BP结合（减少37.6%），而UspA 2缺陷型莫拉氏菌突变体显示出强烈减少（94.6%）C4 BP？与野生型相比，此外，用重组表达的UspA 1（50-770）和UspA 2（30-539）进行的实验表明，C4 BP（范围，1-1000 nM）以剂量依赖性方式结合这两种蛋白。USpA 1（50-770）和USpA（30-539）与C4 BP单亚基相互作用的平衡常数（K-D）分别为13 μ M和1.1 μ M。COP的主要同种型含有通过二硫桥连接在一起的七条相同的α链和一条β链，并且α链含有八个补体控制蛋白（CCP）模块。UspA 1和A2与C4 BP的α链结合，并且用缺少CCP 2、CCP 5或CCP 7的C4 BP进行的实验表明，这三个CCP对于Usp结合是重要的。重要的是，C4 BP结合到M的表面。卡他菌保留其辅因子活性，如通过C4 b降解分析所测定。在一起，M。卡他病通过将C4 BP与UspA 1和UspA 2结合来干扰经典的补体激活途径。
Moraxella catarrhalis ubiquitous surface protein A2 (UspA2) mediates resistance to the bactericidal activity of normal human serum. In this study, an interaction between the complement fluid phase regulator of the classical pathway, C4b binding protein (C4BP), and M. catarrhalis mutants lacking UspA1 and/or UspA2 was analyzed by flow cytometry and a RIA. Two clinical isolates of M. catarrhalis expressed UspA2 at a higher density than UspA1. The UspA1 mutants showed a decreased C4BP binding (37.6% reduction), whereas the UspA2-deficient Moraxella mutants displayed a strongly reduced (94.6%) C4BP? binding compared with the wild type. In addition, experiments with recombinantly expressed UspA1(50-770) and UspA2(30-539) showed that C4BP (range, 1-1000 nM) bound to the two proteins in a dose-dependent manner. The equilibrium constants (K-D) for the USpA1(50-770) and USpA(30-539) interactions with a single subunit of C4BP were 13 muM and 1.1 muM, respectively. The main isoform of COP contains seven identical alpha-chains and one beta-chain linked together with disulfide bridges, and the a-chains contain eight complement control protein (CCP) modules. The UspA1 and A2 bound to the a-chain of C4BP, and experiments with C4BP lacking CCP2, CCP5, or CCP7 showed that these three CCPs were important for the Usp binding. Importantly, C4BP bound to the surface of M. catarrhalis retained its cofactor activity as determined by analysis of C4b degradation. Taken together, M. catarrhalis interferes with the classical complement activation pathway by binding C4BP to UspA1 and UspA2.