白色念珠菌天冬氨酸蛋白酶突变与免疫逃避间关系和机理的研究

白色念珠菌(Candida albicans)是最常见的临床病原真菌，其表达的分泌型天冬氨酸蛋白酶2（Sap2）在该菌感染宿主过程中起关键作用，且表达水平在感染过程中明显增加。临床数据显示被C. albicans感染但未发病的人体内存在大量的抗Sap2的抗体，而被该菌成功感染的病人体内则很难检测到, 表明C. albicans感染宿主过程中Sap2的免疫原性可能出现变化。我们新近在临床分离的几株C. albicans中发现SAP2基因出现非中性突变，引起蛋白序列变化，且当用这些菌株感染小鼠后，其大脑和肺部出现局部血栓。申请项目拟以从系统感染的病人中大量分离收集的C. albicans临床菌株为研究材料，在基因和蛋白水平上研究Sap2的序列变化, 阐明这些变化对Sap2免疫原性的影响, 以期破译Sap2突变与C. albicans逃避免疫监视进而诱发局部血栓形成的关系和机理。

Candida albicans is the most frequently isolated human pathogenic fungus, which secrets aspartic protease 2(Sap2) playing multiple roles upon fungal infection, Sap2 is often up-regulated upon fungal infection. Clinical data show that specific antibody against Sap2 is always found in infected but disease-free healthy donors, but it is rarely identified in patients with C. albicans infection, indicating that Sap2 is highly immunogenic in healthy but not disease subjects. We recently identified four nonsynonymous nucleotide mutations in SAP2 gene in several clinical C. albicans isolates, leading to the amino acids changes. When intravenously injected these clinical isolates into mice, local thrombus was found in the brain and lung. In the present application, we plan to: (1) screen a lot of different clinical strains isolated from systemic C. albicans infected patients to identify the Sap2 mutations both on DNA and protein levels; (2) further analyze whether and how these mutations influence Sap2 immunogenicity and failure in B and T cell responses; (3) elucidate the relevance of C. albicans Sap2 and Sap2 mutations with fungal infection associated pathology (local thrombus formation). Finally we aim to identify the new fungal immune evasion strategy during the C. albicans systemic infection.