Junior Research Group Cellular Immunobiology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany.
J Immunol. 2010 Jan 15;184(2):912-21. doi: 10.4049/jimmunol.0901702. Epub 2009 Dec 11.
The host complement system plays an important role in protection against infections. Several human-pathogenic microbes were shown to acquire host complement regulators, such as factor H (CFH), that downregulate complement activation at the microbial surface and protect the pathogens from the opsonic and lytic effects of complement. Because CFH can also bind to host cells, we addressed the role of CFH and CFH-related proteins as adhesion ligands in host-pathogen interactions. We show that the CFH family proteins CFH, CFH-like protein 1 (CFHL1), CFH-related protein (CFHR) 1, and CFHR4 long isoform bind to human neutrophil granulocytes and to the opportunistic human-pathogenic yeast Candida albicans. Two major binding sites, one within the N-terminus and one in the C-terminus of CFH, were found to mediate binding to neutrophils. Complement receptor 3 (CD11b/CD18; alpha(M)beta2 integrin) was identified as the major cellular receptor on neutrophils for CFH, CFHL1, and CFHR1, but not for CFHR4 long isoform. CFH and CFHR1 supported cell migration. Furthermore, CFH, CFHL1, and CFHR1 increased attachment of neutrophils to C. albicans. Adhesion of neutrophils to plasma-opsonized yeasts was reduced when CFH binding was inhibited by specific Abs or when using CFH-depleted plasma. Yeast-bound CFH and CFHR1 enhanced the generation of reactive oxygen species and the release of the antimicrobial protein lactoferrin by human neutrophils, and resulted in a more efficient killing of the pathogen. Thus, CFH and CFHR1, when bound on the surface of C. albicans, enhance antimicrobial activity of human neutrophils.
宿主补体系统在抗感染中起着重要作用。已经证明,几种人类病原体微生物获得了宿主补体调节因子,如因子 H(CFH),从而下调微生物表面的补体激活,并保护病原体免受补体的调理和裂解作用。因为 CFH 还可以与宿主细胞结合,所以我们研究了 CFH 和 CFH 相关蛋白作为宿主-病原体相互作用中的粘附配体的作用。我们表明,CFH 家族蛋白 CFH、CFH 样蛋白 1(CFHL1)、CFH 相关蛋白(CFHR)1 和 CFHR4 长型异构体结合人中性粒细胞和机会性人类病原体酵母白色念珠菌。发现 CFH 与中性粒细胞结合的两个主要结合位点,一个位于 N 端,一个位于 C 端。补体受体 3(CD11b/CD18;α(M)β2 整合素)被鉴定为 CFH、CFHL1 和 CFHR1 在中性粒细胞上的主要细胞受体,但不是 CFHR4 长型异构体的主要细胞受体。CFH 和 CFHR1 支持细胞迁移。此外,CFH、CFHL1 和 CFHR1 增加了中性粒细胞与白色念珠菌的附着。当使用特异性抗体抑制 CFH 结合或使用 CFH 耗尽的血浆时,中性粒细胞对血浆调理的酵母的粘附减少。酵母结合的 CFH 和 CFHR1 增强了人类中性粒细胞产生活性氧物质和释放抗菌蛋白乳铁蛋白的能力,并导致病原体的更有效杀伤。因此,当结合在白色念珠菌表面时,CFH 和 CFHR1 增强了人类中性粒细胞的抗菌活性。