Calcineurin governs thermotolerance and virulence of Cryptococcus gattii.
Calcineurin governs thermotolerance and virulence of Cryptococcus gattii.
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DOI：
10.1534/g3.112.004242
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发表时间：
2013-03
期刊：
影响因子：
--
通讯作者：
Heitman J
中科院分区：
文献类型：
--
作者：
Chen YL;Lehman VN;Lewit Y;Averette AF;Heitman J
致病酵母隐球菌gattii正在北美太平洋西北部地区引起疫情，它会在健康人中引起危及生命的肺部感染和脑膜脑炎，而不像新生隐球菌通常会感染免疫功能低下的患者。除了更容易感染健康宿主外，与新生隐球菌相比，盖蒂氏隐球菌基因组序列计划揭示了广泛的染色体重排，显示了这两个隐球菌种之间的基因组差异。我们研究了Cattii Cacineurin在三种分子类型中的作用：VGIIa(R265)、VGIIb(R272)和VGI(WM276)。我们发现钙调神经磷酸酶在37°固体培养基上表现出不同的生长要求，因为R265产生的钙调神经磷酸酶突变株比R272和WM276产生的突变株具有更强的耐热性。我们证明了37°时对钙调神经磷酸酶抑制剂(FK506、CsA)的耐受性与VGIIa分子类型有关。来自R272背景的钙调神经磷酸酶突变体表现出最广泛的生长和形态缺陷(多囊泡和较大的环状细胞)，以及增加对氟康唑的敏感性。我们的细胞结构检测显示，加蒂氏隐球藻和新生隐球藻钙调神经磷酸酶突变体表现出质膜的破坏。Gattii VGII分子型的钙调神经磷酸酶在控制阳离子动态平衡方面的作用比Cattii VGI和新生弧菌H99的更大。重要的是，我们证明了C.gattii钙调神经磷酸酶对于小鼠吸入模型的毒力是必不可少的，支持C.gattii钙调神经磷酸酶作为一个有吸引力的抗真菌药物靶点。
The pathogenic yeast Cryptococcus gattii, which is causing an outbreak in the Pacific Northwest region of North America, causes life-threatening pulmonary infections and meningoencephalitis in healthy individuals, unlike Cryptococcus neoformans, which commonly infects immunocompromised patients. In addition to a greater predilection for C. gattii to infect healthy hosts, the C. gattii genome sequence project revealed extensive chromosomal rearrangements compared with C. neoformans, showing genomic differences between the two Cryptococcus species. We investigated the roles of C. gattii calcineurin in three molecular types: VGIIa (R265), VGIIb (R272), and VGI (WM276). We found that calcineurin exhibits a differential requirement for growth on solid medium at 37°, as calcineurin mutants generated from R265 were more thermotolerant than mutants from R272 and WM276. We demonstrated that tolerance to calcineurin inhibitors (FK506, CsA) at 37° is linked with the VGIIa molecular type. The calcineurin mutants from the R272 background showed the most extensive growth and morphological defects (multivesicle and larger ring-like cells), as well as increased fluconazole susceptibility. Our cellular architecture examination showed that C. gattii and C. neoformans calcineurin mutants exhibit plasma membrane disruptions. Calcineurin in the C. gattii VGII molecular type plays a greater role in controlling cation homeostasis compared with that in C. gattii VGI and C. neoformans H99. Importantly, we demonstrate that C. gattii calcineurin is essential for virulence in a murine inhalation model, supporting C. gattii calcineurin as an attractive antifungal drug target.
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影响因子：
2.8
作者：
Jinhee, Choi;Kim, Yangseon;Lee, Yong-Hwan
通讯作者：
Lee, Yong-Hwan
影响因子：
3.6
作者：
Narasipura, SD;Ault, JG;Chaturvedi, S
通讯作者：
Chaturvedi, S
DOI：
10.1534/g3.112.002279
发表时间：
2012-06
期刊：
G3 (Bethesda, Md.)
影响因子：
--
作者：
Chen YL;Konieczka JH;Springer DJ;Bowen SE;Zhang J;Silao FG;Bungay AA;Bigol UG;Nicolas MG;Abraham SN;Thompson DA;Regev A;Heitman J
通讯作者：
Heitman J
影响因子：
11.8
作者：
Datta K;Bartlett KH;Baer R;Byrnes E;Galanis E;Heitman J;Hoang L;Leslie MJ;MacDougall L;Magill SS;Morshed MG;Marr KA;Cryptococcus gattii Working Group of the Pacific Northwest
通讯作者：
Cryptococcus gattii Working Group of the Pacific Northwest
影响因子：
3.1
作者：
Cruz, MC;Sia, RAL;Heitman, J
通讯作者：
Heitman, J