Abstract：
Candida albicans (C. albicans) is an opportunistic pathogen increasingly causing candidiasis worldwide. This study aims to investigate the pattern of systemic immune responses triggered by C. albicans with disease associated variation of Sap2, identifying the novel evasion strategies utilized by clinical isolates. Specifically, a variation in clinical isolates is identified at nucleotide position 817 (G to T). This homozygous variation causes the 273rd amino acid exchange from valine to leucine, close to the proteolytic activation center of Sap2. The mutant (Sap2-273L) generated from SC5314 (Sap2-273V) background carrying the V273L variation within Sap2 displays higher pathogenicity. In comparison to mice infected with Sap2-273V strain, mice infected with Sap2-273L exhibit less complement activation indicated by less serum C3a generation and weaker C3b deposition in the kidney. This inhibitory effect is mainly achieved by Sap2273L -mediated stronger degradation of C3 and C3b. Furthermore, mice infected with Sap2-273L strain exhibit more macrophage phenotype switching from M0 to M2-like and more TGF-β release which further influences T cell responses, generating an immunosuppressed cellular microenvironment characterized by more Tregs and exhausted T cell formation. In summary, the disease-associated sequence variation of Sap2 enhances pathogenicity by complement evasion and M2-like phenotype switching, promoting a more efficient immunosuppressed microenvironment.
摘要：
白色念珠菌(C.白色念珠菌）是一种机会性病原体，在全球范围内日益引起念珠菌病。本研究旨在研究由白色念珠菌引发的全身免疫反应与Sap2疾病相关变异的模式，确定临床分离株使用的新型逃避策略。具体来说,在核苷酸位置817(G至T)鉴定临床分离株的变异。这种纯合变异导致从缬氨酸到亮氨酸的第273个氨基酸交换，靠近Sap2的蛋白水解激活中心。从SC5314(Sap2-273V)背景产生的在Sap2内携带V273L变异的突变体(Sap2-273L)显示出更高的致病性。与感染Sap2-273V株的小鼠相比，感染Sap2-273L的小鼠表现出较少的补体激活,这由较少的血清C3a生成和较弱的C3b在肾脏中的沉积表明。这种抑制作用主要通过Sap2273L介导的C3和C3b的更强降解来实现。此外，感染Sap2-273L菌株的小鼠表现出更多的巨噬细胞表型从M0到M2样的转换和更多的TGF-β释放，这进一步影响T细胞反应，产生以更多Tregs和耗尽的T细胞形成为特征的免疫抑制细胞微环境。总之,Sap2的疾病相关序列变异通过补体逃避和M2样表型转换增强致病性，促进更有效的免疫抑制微环境。
