Microbes bind complement inhibitor factor H via a common site.
Microbes bind complement inhibitor factor H via a common site.
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DOI：
10.1371/journal.ppat.1003308
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Jokiranta TS
中科院分区：
文献类型：
--
作者：
Meri T;Amdahl H;Lehtinen MJ;Hyvärinen S;McDowell JV;Bhattacharjee A;Meri S;Marconi R;Goldman A;Jokiranta TS
为了引起感染，微生物需要逃避宿主防御系统，其中之一是进化上古老而重要的先天免疫手臂，补体的替代途径。它可以攻击各种靶点，在血浆和宿主细胞中受血浆补体调节因子H(FH)的严密调控。FH通过结构域20与宿主细胞表面结构如肝素或糖胺多聚糖结合，通过结构域19与主要补体调理蛋白C3b结合。许多病原微生物通过招募宿主FH来保护自己免受补体的侵害。我们分析了不同的微生物如何以及为什么通过结构域19-20(FH19-20)结合FH。我们利用FH19-20点突变株揭示了几种微生物蛋白和整个微生物(流感嗜血杆菌、百日咳杆菌、铜绿假单胞菌、肺炎链球菌、白色念珠菌、伯氏疏螺旋体和赫氏疏螺旋体)的结合位点。我们发现所有被研究的微生物都使用位于结构域20一侧的相同结合区。肝素抑制了FH与微生物蛋白的结合，表明共同的微生物结合部位与FH与宿主细胞有效结合所需的肝素部位重叠。令人惊讶的是，微生物蛋白增强了FH19-20与C3b的结合，并下调了补体激活。我们表明，这是由微生物蛋白、FH和C3b之间形成的三方复合体引起的。在这项研究中，我们揭示了代表不同门的七种微生物利用FH结构域20上的共同结合部位来逃避补体。通过这个位点的结合不仅模仿宿主细胞的糖胺多聚糖，而且通过三方复合体形成的新机制增强了FH在微生物表面的功能。这是一个独特的收敛进化的例子，通过利用“超级逃避位点”，增强了对重要病原体的免疫逃避。补体是先天免疫的重要组成部分。这种血浆蛋白级联的激活导致吞噬靶标的调理，直接裂解革兰氏阴性菌，增强炎症和获得性免疫反应。不需要特定的信号来激活补体的替代途径，导致其在所有未受保护的表面上被激活。病原微生物需要避开这一途径，已知有几种物种招募宿主补体抑制因子H(FH)来防止激活。FH对宿主细胞的保护也很重要，因为FH的缺陷会导致一种严重的自身反应性疾病，非典型溶血性尿毒症综合征。我们现在已经在分子水平上确定了七种不同的微生物--流感嗜血杆菌、百日咳杆菌、铜绿假单胞菌、肺炎链球菌、白色念珠菌、伯氏疏螺旋体和赫氏杆菌--招募FH的共同机制。所有微生物都通过结构域20上的一个共同位点与FH结合，这有助于在微生物蛋白、主要补体调理蛋白C3b和FH之间形成三方复合体。我们表明，通过利用FH20上共同的微生物结合部位，微生物可以更有效地抑制补体。这种对补体逃逸机制的详细了解可用于开发新的抗菌化疗。
To cause infections microbes need to evade host defense systems, one of these being the evolutionarily old and important arm of innate immunity, the alternative pathway of complement. It can attack all kinds of targets and is tightly controlled in plasma and on host cells by plasma complement regulator factor H (FH). FH binds simultaneously to host cell surface structures such as heparin or glycosaminoglycans via domain 20 and to the main complement opsonin C3b via domain 19. Many pathogenic microbes protect themselves from complement by recruiting host FH. We analyzed how and why different microbes bind FH via domains 19–20 (FH19-20). We used a selection of FH19-20 point mutants to reveal the binding sites of several microbial proteins and whole microbes (Haemophilus influenzae, Bordetella pertussis, Pseudomonas aeruginosa, Streptococcus pneumonia, Candida albicans, Borrelia burgdorferi, and Borrelia hermsii). We show that all studied microbes use the same binding region located on one side of domain 20. Binding of FH to the microbial proteins was inhibited with heparin showing that the common microbial binding site overlaps with the heparin site needed for efficient binding of FH to host cells. Surprisingly, the microbial proteins enhanced binding of FH19-20 to C3b and down-regulation of complement activation. We show that this is caused by formation of a tripartite complex between the microbial protein, FH, and C3b. In this study we reveal that seven microbes representing different phyla utilize a common binding site on the domain 20 of FH for complement evasion. Binding via this site not only mimics the glycosaminoglycans of the host cells, but also enhances function of FH on the microbial surfaces via the novel mechanism of tripartite complex formation. This is a unique example of convergent evolution resulting in enhanced immune evasion of important pathogens via utilization of a “superevasion site.” Complement is an important arm of innate immunity. Activation of this plasma protein cascade leads to opsonization of targets for phagocytosis, direct lysis of Gram-negative bacteria, and enhancement of the inflammatory and acquired immune responses. No specific signal is needed for activation of the alternative pathway of complement, leading to its activation on all unprotected surfaces. Pathogenic microbes need to evade this pathway, and several species are known to recruit host complement inhibitor factor H (FH) to prevent the activation. FH is important for protection of host cells, too, as defects in FH lead to a severe autoreactive disease, atypical hemolytic uremic syndrome. We have now identified at the molecular level a common mechanism by which seven different microbes, Haemophilus influenzae, Bordetella pertussis, Pseudomonas aeruginosa, Streptococcus pneumoniae, Candida albicans, Borrelia burgdorferi and B. hermsii, recruit FH. All microbes bind FH via a common site on domain 20, which facilitates formation of a tripartite complex between the microbial protein, the main complement opsonin C3b, and FH. We show that, by utilizing the common microbial binding site on FH20, microbes can inhibit complement more efficiently. This detailed knowledge on mechanism of complement evasion can be used in developing novel antimicrobial chemotherapy.
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DOI：
10.4049/jimmunol.0804031
发表时间：
2009-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ferreira VP;Herbert AP;Cortés C;McKee KA;Blaum BS;Esswein ST;Uhrín D;Barlow PN;Pangburn MK;Kavanagh D
通讯作者：
Kavanagh D
影响因子：
3.1
作者：
Hovis, Kelley M.;Schriefer, Martin E.;Marconi, Richard T.
通讯作者：
Marconi, Richard T.
影响因子：
3.2
作者：
Hovis, KM;McDowell, JV;Marconi, RT
通讯作者：
Marconi, RT
影响因子：
56.9
作者：
Edwards, AO;Ritter, R;Farrer, LA
通讯作者：
Farrer, LA
DOI：
10.1073/pnas.1017087108
发表时间：
2011-02-15
影响因子：
11.1
作者：
Kajander, Tommi;Lehtinen, Markus J.;Jokiranta, T. Sakari
通讯作者：
Jokiranta, T. Sakari