Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom.
PLoS Pathog. 2012;8(7):e1002793. doi: 10.1371/journal.ppat.1002793. Epub 2012 Jul 5.
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.
补体系统在宿主防御肺炎球菌感染中起着关键作用。三条不同的途径，经典途径、替代途径和凝集素途径，介导补体激活。虽然关于补体经典和替代激活途径在对抗链球菌感染中的作用的信息有限，但关于凝集素途径的作用知之甚少，主要是因为缺乏适当的凝集素途径缺乏的实验模型。我们最近建立了一种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）缺陷的小鼠品系，并表明该小鼠品系无法形成凝集素途径特异性 C3 和 C5 转化酶。在这里，我们报告 MASP-2 缺陷型小鼠（仍然可以通过经典途径和替代途径激活补体）极易受到肺炎球菌感染，并且无法在非免疫宿主中调理肺炎链球菌。这种补体调理缺陷严重损害了凝集素途径缺陷宿主中病原体的清除。使用来自具有明确补体缺陷的小鼠和人类的血清，我们证明了小鼠 ficolin A、人类 L-ficolin 和两种物种中的 collectin 11，但不是甘露聚糖结合凝集素（MBL），是在 S. pneumoniae 表面驱动凝集素途径激活的模式识别分子。我们进一步表明，即使没有 C4，肺炎球菌的凝集素途径调理也可以进行。这项研究证实了 MASP-2 在凝集素途径中的重要功能，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。
