The lectin pathway of complement activation is a critical component of the innate immune response to pneumococcal infection.
The lectin pathway of complement activation is a critical component of the innate immune response to pneumococcal infection.
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DOI：
10.1371/journal.ppat.1002793
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Schwaeble WJ
中科院分区：
文献类型：
--
作者：
Ali YM;Lynch NJ;Haleem KS;Fujita T;Endo Y;Hansen S;Holmskov U;Takahashi K;Stahl GL;Dudler T;Girija UV;Wallis R;Kadioglu A;Stover CM;Andrew PW;Schwaeble WJ
补体系统在宿主抵抗肺炎球菌感染中起着关键作用。三种不同的途径，经典途径，替代途径和凝集素途径，介导补体激活。关于补体的经典激活途径和替代激活途径在抗链球菌感染中的作用，现有的信息有限，但对凝集素途径的作用知之甚少，这主要是由于缺乏合适的凝集素途径缺陷的实验模型。我们最近建立了一个缺乏凝集素途径效应酶甘露聚糖结合凝集素相关丝氨酸蛋白酶-2(MASP-2)的小鼠品系，并表明该品系不能形成凝集素途径特异性的C3和C5转换酶。在这里，我们报告了MASP-2缺陷小鼠(它仍然可以通过经典途径和替代途径激活补体)对肺炎链球菌感染高度敏感，并且在非免疫宿主中无法调理肺炎链球菌。补体调理的这种缺陷严重影响凝集素途径缺陷宿主的病原体清除。利用补体缺陷小鼠和人的血清，我们证明了两个物种中的小鼠非编织素A、人L非编织素和胶凝素11是驱动肺炎链球菌表面凝集素途径激活的模式识别分子，而不是甘露聚糖结合凝集素(MBL)。我们进一步证明，通过凝集素途径的肺炎球菌调理可以在没有C4的情况下进行。这项研究证实了MASP-2在凝集素途径中的基本功能，并强调了MBL非依赖性凝集素途径激活在宿主防御肺炎球菌中的重要性。肺炎链球菌是引起肺炎、败血症和脑膜炎的主要人类病原体。宿主对肺炎球菌的防御在很大程度上依赖于补体，补体是一个血液蛋白系统，当被激活时，它会附着在细菌上，目标是让吞噬细胞清除细菌。补体激活有三种途径：经典途径、凝集素途径和替代途径。关于经典途径和替代途径在对抗肺炎球菌中的作用，现有的信息有限；凝集素途径的作用没有引起先前研究的注意。这项工作表明，凝集素途径在对抗肺炎球菌感染中起着关键作用。在人血清中的五种不同的凝集素途径识别分子中，只有L-无花果和胶凝素11激活肺炎球菌上的补体。人甘露糖结合凝集素(MBL)是最著名的凝集素途径模式识别分子，在对抗肺炎球菌方面没有任何作用。类似地，在小鼠血清中，只有无花果A和集合素11驱动肺炎链球菌的补体激活。因此，MBL缺陷小鼠在肺炎球菌感染中不会受到损害，而非花青素A缺陷小鼠和关键凝集素途径酶MBL相关丝氨酸蛋白酶-2(MASP-2)缺乏的小鼠对感染非常敏感。这项工作解释了为什么MBL缺陷，最常见的遗传免疫缺陷，不容易患肺炎球菌病。
The complement system plays a key role in host defense against pneumococcal infection. Three different pathways, the classical, alternative and lectin pathways, mediate complement activation. While there is limited information available on the roles of the classical and the alternative activation pathways of complement in fighting streptococcal infection, little is known about the role of the lectin pathway, mainly due to the lack of appropriate experimental models of lectin pathway deficiency. We have recently established a mouse strain deficient of the lectin pathway effector enzyme mannan-binding lectin associated serine protease-2 (MASP-2) and shown that this mouse strain is unable to form the lectin pathway specific C3 and C5 convertases. Here we report that MASP-2 deficient mice (which can still activate complement via the classical pathway and the alternative pathway) are highly susceptible to pneumococcal infection and fail to opsonize Streptococcus pneumoniae in the none-immune host. This defect in complement opsonisation severely compromises pathogen clearance in the lectin pathway deficient host. Using sera from mice and humans with defined complement deficiencies, we demonstrate that mouse ficolin A, human L-ficolin, and collectin 11 in both species, but not mannan-binding lectin (MBL), are the pattern recognition molecules that drive lectin pathway activation on the surface of S. pneumoniae. We further show that pneumococcal opsonisation via the lectin pathway can proceed in the absence of C4. This study corroborates the essential function of MASP-2 in the lectin pathway and highlights the importance of MBL-independent lectin pathway activation in the host defense against pneumococci. Streptococcus pneumoniae is a major human pathogen that causes pneumonia, septicemia and meningitis. The host defense against pneumococci is largely dependent on complement, a system of blood proteins which, when activated, attach to bacteria, targeting them for clearance by phagocytes. There are three routes of complement activation: The classical, lectin and alternative pathways. Limited information is available on the roles of the classical and alternative pathways in fighting pneumococci; the role of the lectin pathway has escaped the attention of previous research. This work demonstrates that the lectin pathway is critical in fighting pneumococcal infection. Of the five different lectin pathway recognition molecules in human serum, only L-ficolin and collectin 11 activate complement on pneumococci. Human mannose-binding lectin (MBL), the best-known lectin pathway pattern recognition molecule, has no role whatsoever in fighting pneumococci. Similarly, in mouse serum, only ficolin A and collectin 11 drive complement activation on S. pneumoniae. Hence, MBL deficient mice are not compromised in pneumococcal infection, while ficolin A deficient mice and mice deficient of the key lectin pathway enzyme MBL-associated serine protease-2 (MASP-2) are exquisitely susceptible to infection. This work explains why MBL deficiency, the most frequent hereditary immune deficiency, does not predispose to pneumococcal disease.
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影响因子：
3.1
作者：
Kadioglu, A;Gingles, NA;Andrew, PW
通讯作者：
Andrew, PW
影响因子：
4.4
作者：
Iwaki, Daisuke;Kanno, Kazuko;Fujita, Teizo
通讯作者：
Fujita, Teizo
影响因子：
2.8
作者：
Kenawy, Hany Ibrahim;Ali, Youssif Mohammed;Schwaeble, Wilhelm J.
通讯作者：
Schwaeble, Wilhelm J.
影响因子：
5.4
作者：
Girija, Umakhanth Venkatraman;Mitchell, Daniel A.;Wallis, Russell
通讯作者：
Wallis, Russell
影响因子：
3.6
作者：
Garred, P;Larsen, F;Koch, C
通讯作者：
Koch, C