Secreted Aspergillus fumigatus Protease Alp1 Degrades Human Complement Proteins C3, C4, and C5
Secreted Aspergillus fumigatus Protease Alp1 Degrades Human Complement Proteins C3, C4, and C5
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DOI：
10.1128/iai.01353-09
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发表时间：
2010-08-01
影响因子：
3.1
通讯作者：
Brakhage, Axel A.
中科院分区：
文献类型：
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作者：
Behnsen, Judith;Lessing, Franziska;Brakhage, Axel A.
机会性人类致病真菌烟曲霉是免疫功能低下患者真菌感染的主要原因。先天免疫在防御感染方面发挥着重要作用。补体系统代表先天免疫系统的重要组成部分。该级联系统在烟曲霉分生孢子和菌丝表面被激活，并增强分生孢子的吞噬作用。烟曲霉分生孢子而非菌丝与其表面宿主补体调节因子 H、FHL-1 和 CFHR1 结合，这些因子控制补体激活。在这里，我们证明烟曲霉菌丝具有额外的内源性活性来控制补体激活。 A. fumigatus 培养物上清液有效裂解补体成分 C3、C4、C5 和 C1q 以及免疫球蛋白 G。分泌组分析和蛋白酶抑制剂研究确定了分泌型碱性蛋白酶 Alp1（大量存在于培养物上清液中）是负责这种裂解的中心分子。生成了 alp1 缺失菌株，培养上清液具有最小的补体降解活性。此外，源自过量生产 Alp1 的大肠杆菌菌株的蛋白质提取物可裂解 C3b、C4b 和 C5。因此，蛋白酶 Alp1 负责观察到的切割并降解多种不同的底物。总之，我们在烟曲霉中发现了一种有助于逃避宿主补体攻击的新机制。
The opportunistic human pathogenic fungus Aspergillus fumigatus is a major cause of fungal infections in immunocompromised patients. Innate immunity plays an important role in the defense against infections. The complement system represents an essential part of the innate immune system. This cascade system is activated on the surface of A. fumigatus conidia and hyphae and enhances phagocytosis of conidia. A. fumigatus conidia but not hyphae bind to their surface host complement regulators factor H, FHL-1, and CFHR1, which control complement activation. Here, we show that A. fumigatus hyphae possess an additional endogenous activity to control complement activation. A. fumigatus culture supernatant efficiently cleaved complement components C3, C4, C5, and C1q as well as immunoglobulin G. Secretome analysis and protease inhibitor studies identified the secreted alkaline protease Alp1, which is present in large amounts in the culture supernatant, as the central molecule responsible for this cleavage. An alp1 deletion strain was generated, and the culture supernatant possessed minimal complement-degrading activity. Moreover, protein extract derived from an Escherichia coli strain overproducing Alp1 cleaved C3b, C4b, and C5. Thus, the protease Alp1 is responsible for the observed cleavage and degrades a broad range of different substrates. In summary, we identified a novel mechanism in A. fumigatus that contributes to evasion from the host complement attack.