Deletion of the ATP2 Gene in Candida albicans Blocks Its Escape From Macrophage Clearance.
Deletion of the ATP2 Gene in Candida albicans Blocks Its Escape From Macrophage Clearance.
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白色念珠菌中 ATP2 基因的缺失阻止其逃避巨噬细胞清除
DOI：
10.3389/fcimb.2021.643121
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发表时间：
2021
影响因子：
5.7
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Zhang Y;Tang C;Zhang Z;Li S;Zhao Y;Weng L;Zhang H
巨噬细胞是抵抗侵袭性真菌感染的第一道防线，因此，逃避巨噬细胞成为白念珠菌侵袭性感染建立的基础。我们发现C.白色念珠菌导致体外逃逸率从69.2%（WT）急剧下降至1.2%。ATP 2对巨噬细胞清除的作用在目前已知影响清除的基因中脱颖而出。在正常小鼠中，atp 2 Δ/Δ细胞在全身感染后72 h在主要器官中检测不到，而WT细胞在体内持续存在。然而，在巨噬细胞耗竭的小鼠中，atp 2 Δ/Δ可以以与24 h相当的量持续72 h。关于机制，WT细胞在模拟巨噬细胞中葡萄糖缺乏环境的培养基中持续生长并转变为菌丝形式，这更有利于从巨噬细胞中逃逸。相比之下，atp 2 Δ/Δ细胞可以保持存活，但不能在这些培养基中完成形态发生，导致它们以酵母形式被捕获在巨噬细胞内。同时，atp 2 Δ/Δ细胞在替代碳源中被氧化应激杀死的程度比WT细胞高2- 3倍。综上所述，ATP 2缺失阻止了C.因此，ATP 2具有作为干扰巨噬细胞清除的药物靶标的功能基础。
Macrophages provide the first-line defense against invasive fungal infections and, therefore, escape from macrophage becomes the basis for the establishment of Candida albicans invasive infection. Here, we found that deletion of ATP2 (atp2Δ/Δ) in C. albicans resulted in a dramatic decrease from 69.2% (WT) to 1.2% in the escape rate in vitro. The effect of ATP2 on macrophage clearance stands out among the genes currently known to affect clearance. In the normal mice, the atp2Δ/Δ cells were undetectable in major organs 72 h after systemic infection, while WT cells persisted in vivo. However, in the macrophage-depleted mice, atp2Δ/Δ could persist for 72 h at an amount comparable to that at 24 h. Regarding the mechanism, WT cells sustained growth and switched to hyphal form, which was more conducive to escape from macrophages, in media that mimic the glucose-deficient environment in macrophages. In contrast, atp2Δ/Δ cells can remained viable but were unable to complete morphogenesis in these media, resulting in them being trapped within macrophages in the yeast form. Meanwhile, atp2Δ/Δ cells were killed by oxidative stress in alternative carbon sources by 2- to 3-fold more than WT cells. Taken together, ATP2 deletion prevents C. albicans from escaping macrophage clearance, and therefore ATP2 has a functional basis as a drug target that interferes with macrophage clearance.