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的生长引导到正在萌芽的子细胞，然后必须复制并正确地分享其DNA，给子细胞一个副本，自己保留一个副本。没有这些事件的紧密协调，子细胞和母细胞就会死亡。因此，细胞已经进化出详细的机制来紧密协调生长、DNA复制和DNA分布。然而，一些细胞找到了另一种解决这个问题的方法：即使它们的DNA数量不对，它们也能存活。这种生存被称为基因组可塑性，因为在这些细胞中，DNA拷贝的数量，也就是基因组，是可塑的。癌症是细胞显示基因组可塑性的一个重要例子。在这些细胞中，基因组的许多拷贝给细胞提供了更多的工具来生长和逃避药物治疗。细胞具有基因组可塑性的另一个例子是真菌病原体新隐球菌。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。在健康人群中，免疫系统能够对抗这种生长，但在患有潜在疾病的人群中，包括艾滋病毒和自身免疫性疾病，免疫系统被削弱了。在长期使用免疫抑制剂的人群中，如使用类固醇来对抗器官移植排斥反应，每20人中就有1人患隐球菌病。在这些个体中，隐球菌逃离肺部进入大脑，如果不及时治疗，它会导致脑膜炎和死亡。正常的隐球菌细胞只有一个DNA副本，但隐球菌也有一种独特的结构，叫做泰坦细胞，它包含许多DNA副本。特别引人注目的是，泰坦细胞仍然能够保持这种DNA的组织，并且在萌芽期间只给它们的后代一个拷贝。顾名思义，泰坦隐球菌细胞比普通细胞大得多——大10倍。这类似于一个樱桃气球膨胀到一个足球大小。这些巨大的细胞对我们的免疫细胞来说太大了，它们也会产生新的小细胞，这些小细胞会逃逸到血液中，导致疾病。没有人知道隐球菌泰坦细胞是如何形成的。一条线索是隐球菌利用ROS分子作为细胞中的信使。在其他生物体中，ROS发送信号来帮助协调生长。我已经证明，在ROS中有缺陷的隐球菌突变体在生长中也有缺陷。此外，控制ROS的相同因子也控制着基因组的可塑性。总之，这表明活性氧、生长和基因组可塑性可能相关。例如，ROS可能在出芽期间充当信使，告诉母细胞何时该分配DNA。当这个信号被改变时，泰坦细胞就会形成。本奖学金的研究将探讨隐球菌如何完成这一任务。因为隐球菌使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防止它们的形成将有助于我们开发更好的药物。

项目成果

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

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: 10.1101/2020.07.30.229070
• 发表时间: 2020
• 作者: Ballou E

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

• DOI: 10.1101/190587
• 发表时间: 2017-09
• 期刊: PLoS Pathogens
• 影响因子: 6.7
• 作者: I. Dambuza;Thomas A. Drake;A. Chapuis;L. Taylor-Smith;Nathalie M. Legrave;T. Rasmussen;M. Fisher;T. Bicanic;T. Harrison;M. Jaspars;R. May;Gordon D. Brown;R. Yuecel;D. MacCallum;Elizabeth R. Ballou

Biphasic zinc compartmentalisation in a human fungal pathogen.

• DOI: 10.1371/journal.ppat.1007013
• 发表时间: 2018-05
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Crawford AC;Lehtovirta-Morley LE;Alamir O;Niemiec MJ;Alawfi B;Alsarraf M;Skrahina V;Costa ACBP;Anderson A;Yellagunda S;Ballou ER;Hube B;Urban CF;Wilson D
• 通讯作者: Wilson D

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

• DOI: 10.1371/journal.ppat.1006978
• 发表时间: 2018-05
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Dambuza IM;Drake T;Chapuis A;Zhou X;Correia J;Taylor-Smith L;LeGrave N;Rasmussen T;Fisher MC;Bicanic T;Harrison TS;Jaspars M;May RC;Brown GD;Yuecel R;MacCallum DM;Ballou ER
• 通讯作者: Ballou ER