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

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萌芽中的子细胞，然后必须复制并正确地分享其DNA，给子细胞一个副本，并为自己保留一个副本。如果没有这些事件的紧密协调，子代和母体细胞就会死亡。因此，细胞进化出详细的机制来密切协调生长、DNA复制和DNA分布。然而，一些细胞已经找到了解决这个问题的另一种方法：即使它们的DNA含量错误，它们也能够存活。这种存活被称为基因组可塑性，因为在这些细胞中，DNA的拷贝数，也被称为基因组，是可塑性的。癌症是细胞显示基因组可塑性的一个关键例子。在这些细胞中，拥有许多基因组副本为细胞提供了更多生长和逃避药物治疗的工具。另一个具有基因组可塑性的细胞例子是真菌病原体新生隐球菌。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。隐球菌在肺部生长。在健康人中，免疫系统能够对抗这种增长，但在患有包括艾滋病毒和自身免疫性疾病在内的潜在疾病的人中，免疫系统被削弱。在长期服用免疫抑制剂(如类固醇)以对抗器官移植排斥反应的人中，每20人中就有1人患上隐球菌病。在这些人中，隐球菌从肺中逃脱，进入大脑，如果不治疗，就会导致脑膜炎和死亡。正常的隐球菌细胞只有一个DNA副本，但隐球菌也会产生一种独特的结构，称为泰坦细胞，其中包含许多DNA副本。尤其令人惊讶的是，土卫六细胞仍然能够保持这种DNA的组织，并在萌芽期间只给他们的女儿一个拷贝。顾名思义，隐球菌泰坦细胞比普通细胞大得多--是普通细胞的10倍。这类似于一个足球大小的樱桃气球。这些巨大的细胞太大了，我们的免疫细胞无法摧毁，它们还会产生新的小细胞，这些细胞可以逃逸到血液中并导致疾病。没有人知道隐球菌泰坦细胞是如何形成的。一条线索是，隐球菌在细胞中使用称为ROS的分子作为信使。在其他生物体中，ROS发出信号来帮助协调生长。我已经证明，ROS缺陷的隐球菌变异体在生长方面也有缺陷。此外，控制ROS的相同因素也控制着基因组的可塑性。综上所述，这表明ROS、生长和基因组可塑性可能是相关的。例如，ROS可能在萌发过程中扮演信使的角色，告诉母细胞什么时候该分配DNA了。当这种信号改变时，泰坦细胞可能会形成。这项研究将调查隐球菌是如何完成这一任务的。因为隐球菌使用泰坦细胞来抵抗药物治疗，了解泰坦细胞是如何工作的，以及如何防止它们的形成，将有助于我们开发更好的药物。

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.