Calcineurin is required for virulence of Cryptococcus neoformans
Calcineurin is required for virulence of Cryptococcus neoformans
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DOI：
10.1093/emboj/16.10.2576
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发表时间：
1997-05-15
期刊：
影响因子：
11.4
通讯作者：
Heitman, J
中科院分区：
文献类型：
--
作者：
Odom, A;Muir, S;Heitman, J
环孢菌素A(CsA)和FK506是抑制信号转导的抗微生物、免疫抑制的天然产物。在T细胞和酿酒酵母中，CsA和FK506与亲环素A和FKBP12结合，生成的复合体抑制钙调节的蛋白磷酸酶钙调神经磷酸酶。我们发现，机会性真菌病原体新生隐球菌在37℃时对CSA和FK506敏感，但在24℃时不敏感，这表明CSA和FK506抑制了新生隐球菌在高温下生长所需的蛋白质。遗传证据支持一种模型，在该模型中，免疫亲和素药物复合体抑制钙调神经磷酸酶，以阻止37℃的生长。编码新生梭菌钙调神经磷酸酶A催化亚基的基因被克隆并被同源重组破坏。钙调神经磷酸酶突变株是活的，但不能在模拟宿主环境(高温、5%二氧化碳或碱性pH)的体外条件下存活，并且在隐球菌性脑膜炎的动物模型中不再具有致病性。野生型钙调神经磷酸酶A基因的引入弥补了这些生长缺陷并恢复了毒力。我们的研究结果表明，钙调神经磷酸酶是新生葡萄球菌毒力所必需的，并可能定义真菌发病所需的信号转导元件，这些元件可能成为治疗干预的靶点。
Cyclosporin A (CsA) and FK506 are antimicrobial, immunosuppressive natural products that inhibit signal transduction. In T cells and Saccharomyces cerevisiae, CsA and FK506 bind to the immunophilins cyclophilin A and FKBP12 and the resulting complexes inhibit the Ca2+-regulated protein phosphatase calcineurin. We find that growth of the opportunistic fungal pathogen Cryptococcus neoformans is sensitive to CsA and FK506 at 37 degrees C but not at 24 degrees C, suggesting that CsA and FK506 inhibit a protein required for C.neoformans growth at elevated temperature. Genetic evidence supports a model in which immunophilin-drug complexes inhibit calcineurin to prevent growth at 37 degrees C. The gene encoding the C.neoformans calcineurin A catalytic subunit was cloned and disrupted by homologous recombination. Calcineurin mutant strains are viable but do not survive in vitro conditions that mimic the host environment (elevated temperature, 5% CO2 or alkaline pH) and are no longer pathogenic in an animal model of cryptococcal meningitis. Introduction of the wild-type calcineurin A gene complemented these growth defects and restored virulence. Our findings demonstrate that calcineurin is required for C.neoformans virulence and may define signal transduction elements required for fungal pathogenesis that could be targets for therapeutic intervention.