Department of Hygiene, Microbiology and Social Medicine, Innsbruck Medical University, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria.
Mol Immunol. 2010 Apr;47(7-8):1438-49. doi: 10.1016/j.molimm.2010.02.010. Epub 2010 Mar 19.
Complement represents a central immune weapon in the brain, but the high lethality of cerebral aspergillosis indicates a low efficacy of the antifungal complement attack. Studies with cerebrospinal fluid (CSF) samples derived from a patient with cerebral aspergillosis showed a degradation of complement proteins, implying that Aspergillus might produce proteases to evade their antimicrobial potency. Further investigations of this hypothesis showed that Aspergillus, when cultured in CSF to simulate growth conditions in the brain, secreted a protease that can cleave various complement proteins. Aspergillus fumigatus, the most frequent cause of cerebral aspergillosis, destroyed complement activity more efficiently than other Aspergillus species. The degradation of complement in CSF resulted in a drastic reduction of the capacity to opsonize fungal hyphae. Furthermore, the Aspergillus-derived protease could diminish the amount of complement receptor CR3, a surface molecule to mediate eradication of opsonized pathogens, on granulocytes and microglia. The lack of these prerequisites caused a significant decrease in phagocytosis of primary microglia. Additional studies implied that the complement-degrading activity shares many characteristics with the previously described alkaline protease Alp1. To improve the current therapy for cerebral aspergillosis, we tried to regain the antifungal effects of complement by repressing the secretion of this degrading activity. Supplementation of CSF with nitrogen sources rescued the complement proteins and abolished any cleavage. Glutamine or arginine are of special interest for this purpose since they represent endogenous substances in the CNS and might be included in a future supportive therapy to reduce the high lethality of cerebral aspergillosis.
补体是大脑中一种重要的免疫武器，但大脑曲霉病的高致死率表明抗真菌补体攻击的效果较低。对来自大脑曲霉病患者的脑脊液（CSF）样本的研究表明，补体蛋白发生了降解，这意味着曲霉可能会产生蛋白酶来逃避其抗菌效力。进一步研究该假说表明，曲霉在 CSF 中培养以模拟大脑中的生长条件时，会分泌一种可以切割各种补体蛋白的蛋白酶。曲霉菌，最常见的大脑曲霉病的病因，比其他曲霉物种更有效地破坏补体活性。CSF 中补体的降解导致对真菌菌丝的调理作用能力急剧下降。此外，曲霉衍生的蛋白酶可以减少粒细胞和小胶质细胞上调理病原体清除的表面分子补体受体 CR3 的数量。缺乏这些前提条件导致初级小胶质细胞吞噬作用显著减少。进一步的研究表明，这种补体降解活性与先前描述的碱性蛋白酶 Alp1 具有许多共同特征。为了改善大脑曲霉病的当前治疗方法，我们试图通过抑制这种降解活性的分泌来恢复补体的抗真菌作用。用氮源补充 CSF 可挽救补体蛋白并阻止任何切割。谷氨酰胺或精氨酸对此特别感兴趣，因为它们是中枢神经系统中的内源性物质，可能包含在未来的支持性治疗中，以降低大脑曲霉病的高致死率。
