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

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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.