The Cryptococcus neoformans Redoxome: The role of Rac GTPases in ROS Signal Transduction and Titanisation

新型隐球菌氧化还原体：Rac GTPases 在 ROS 信号转导和钛化中的作用

• 批准号: BB/M014525/2
• 负责人: Elizabeth Ballou
• 金额: $ 15.06万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM014525%2F2
• 关键词: Cryptococcus; neoformans; Redoxome; role; Rac

When cells grow and divide, they must simultaneously coordinate a number of complex events. The mother cell must direct all of its growth to the budding daughter cell and then must duplicate and correctly share out its DNA, giving one copy to the daughter and keeping one copy for itself. Without tight coordination of these events, daughter and mother cells die. As a consequence, cells have evolved detailed mechanisms to tightly coordinate growth, DNA duplication and DNA distribution. Some cells have found another way around this problem, however: They are able to survive even when they have the wrong amount of DNA. This survival is called genome plasticity because in these cells, the number of copies of DNA, also known as the genome, is malleable. Cancer is one key example of cells displaying genome plasticity. In these cells, having many copies of the genome gives the cell more tools to grow and to evade drug treatment. Another example of cells with genome plasticity is the fungal pathogen Cryptococcus neoformans. Cryptococcus affects nearly 1 million people each year worldwide, and kills nearly two thirds of those infected within three months of infection. Cryptococcus grows in the lungs. In healthy people, the immune system is able to combat this growth, but in people with underlying diseases, including HIV and auto-immune diseases, the immune system is weakened. Among people on long-term immune suppressors, such as steroids to combat organ transplant rejection, 1 in 20 develop cryptococcosis. In these individuals, Cryptococcus escapes the lung and goes to the brain, where it causes meningitis and death if left untreated.Normal Cryptococcus cells have a single copy of their DNA, but Cryptococcus also makes a unique structure called a Titan cell that contains many DNA copies. What is particularly striking is that Titan cells are still able to keep this DNA organised and give only one copy to their daughters during budding. As the name suggests, Cryptococcus Titan cells are much larger than ordinary cells -10 times bigger. This is similar to a cherry ballooning to the size of a football. These huge cells are too big for our immune cells to destroy, and they also produce new small cells that can escape into the blood and cause disease. No one knows how Cryptococcus Titan cells are formed. One clue is that Cryptococcus uses molecules called ROS as messengers in the cell. In other organisms, ROS send signals to help coordinate growth. I have shown that Cryptococcus mutants that are defective in ROS are also defective in growth. Additionally, the same factors that control ROS also control genome plasticity. Together, this suggests that ROS, growth and genome plasticity may be related. For example, ROS may act as messengers during budding that tell the mother cell when it is time to distribute DNA. Titan cells may form when this signal is altered. The research in this Fellowship will investigate how Cryptococcus accomplishes this task. Because Cryptococcus uses Titan cells to resist drug treatment, understanding how Titan cells work and how to prevent their formation will help us develop better drugs.

当细胞生长和分裂时，它们必须同时协调许多复杂的事件。母细胞必须将其所有生长引导至出芽的子细胞，然后必须复制并正确共享其 DNA，将一份副本提供给子细胞，并为自己保留一份副本。如果这些事件没有紧密协调，子细胞和母细胞就会死亡。因此，细胞进化出了详细的机制来紧密协调生长、DNA 复制和 DNA 分布。然而，一些细胞找到了解决这个问题的另一种方法：即使 DNA 数量错误，它们也能生存。这种生存被称为基因组可塑性，因为在这些细胞中，DNA 拷贝数（也称为基因组）是可塑的。癌症是细胞表现出基因组可塑性的一个重要例子。在这些细胞中，拥有许多基因组拷贝为细胞提供了更多生长和逃避药物治疗的工具。具有基因组可塑性的细胞的另一个例子是真菌病原体新型隐球菌。隐球菌每年影响全球近 100 万人，并在感染后三个月内杀死近三分之二的感染者。隐球菌生长在肺部。在健康人中，免疫系统能够对抗这种生长，但在患有基础疾病（包括艾滋病毒和自身免疫性疾病）的人中，免疫系统会被削弱。在长期服用类固醇等免疫抑制剂以对抗器官移植排斥反应的人群中，每 20 人中有 1 人患有隐球菌病。在这些个体中，隐球菌会从肺部逃逸并进入大脑，如果不及时治疗，会导致脑膜炎和死亡。正常的隐球菌细胞只有一个 DNA 副本，但隐球菌还产生一种称为泰坦细胞的独特结构，其中包含许多 DNA副本。特别引人注目的是，泰坦细胞仍然能够保持这种 DNA 的有序性，并在出芽期间只将一份拷贝传给它们的女儿。顾名思义，隐球菌泰坦细胞比普通细胞大得多 -10 倍。这类似于一颗膨胀到足球大小的樱桃。这些巨大的细胞太大，我们的免疫细胞无法破坏，它们还会产生新的小细胞，这些细胞可以逃入血液并引起疾病。没有人知道隐球菌泰坦细胞是如何形成的。一条线索是隐球菌使用称为 ROS 的分子作为细胞中的信使。在其他生物体中，ROS 会发送信号来帮助协调生长。我已经证明，ROS 有缺陷的隐球菌突变体在生长上也有缺陷。此外，控制 ROS 的因素也控制着基因组的可塑性。总之，这表明 ROS、生长和基因组可塑性可能相关。例如，ROS 可能在出芽过程中充当信使，告诉母细胞何时需要分配 DNA。当该信号改变时，可能会形成泰坦细胞。该奖学金的研究将调查隐球菌如何完成这项任务。由于隐球菌利用泰坦细胞来抵抗药物治疗，了解泰坦细胞如何工作以及如何阻止其形成将有助于我们开发更好的药物。

项目成果

Repeated evolution of inactive pseudonucleases in a fungal branch of the Dis3/RNase II family of nucleases

Dis3/RNase II 核酸酶家族真菌分支中无活性假核酸酶的重复进化

• DOI: http://dx.10.1101/2020.07.30.229070
• 发表时间: 2020
• 作者: Ballou E

Redistribution of a glucuronoxylomannan epitope towards the capsule surface coincides with Titanisation in the human fungal pathogen Cryptococcus neoformans

葡糖醛酸木甘露聚糖表位向胶囊表面的重新分布与人类真菌病原体新型隐球菌中的钛化一致

• DOI: http://dx.10.1101/431650
• 发表时间: 2018
• 作者: Probert M

The Cryptococcus neoformans Titan cell is an inducible and regulated morphotype underlying pathogenesis

新型隐球菌泰坦细胞是一种可诱导和调节的形态类型，是发病机制的基础

• DOI: http://dx.10.1101/190587
• 发表时间: 2017
• 作者: Dambuza I

mSphere of Influence: Positive Research Culture Enables Excellence and Innovation.

m影响力范围：积极的研究文化促进卓越和创新。

• DOI: http://dx.10.1128/msphere.00948-19
• 发表时间: 2020
• 期刊: mSphere
• 影响因子: 4.8
• 作者: Ballou ER

A Bright Future for Fluorescence Imaging of Fungi in Living Hosts.

活宿主真菌荧光成像的光明前景。

• DOI: http://dx.10.3390/jof5020029
• 发表时间: 2019
• 期刊: Journal of fungi (Basel, Switzerland)
• 作者: Chapuis AF