Trypanosome parasites will glow different colours depending on whether they are dividing or arrested, allowing researchers to watch the cell cycle in real time for the first time. These single-celled parasites cause African sleeping sickness, Chagas disease, and leishmaniasis—three neglected tropical diseases that together infect over 8 million people each year. The parasites must stop dividing in the insect vector to become infectious, then restart division in the mammal host to cause disease. Some forms also arrest and persist undetected in mammals for long periods, potentially evading treatment. Despite this, scientists have virtually no understanding of how the parasites control whether to divide or arrest, because existing methods cannot efficiently distinguish cell cycle stages. The researcher will engineer a fluorescent parasite line that changes colour as it progresses through the cell cycle or stops glowing when arrested. Using this tool, she will screen hundreds of genes to identify those controlling division, track where dividing and arrested parasites are found in mammal and insect tissues, and test whether blocking cell-cycle arrest prevents transmission. This is fundamental science. If successful, it will reveal the molecular switches that govern trypanosome transmission cycles. The identified proteins could later become targets for drugs that force parasites into the wrong cell cycle stage, potentially blocking both disease progression and spread.
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Trypanosome parasites are spread between humans and other mammals by biting insects, and cause three World Health Organisation designated Neglected Tropical Diseases: African trypanosomiasis (Trypanosoma brucei), Chagas disease (Trypanosoma cruzi) and Leishmaniasis (Leishmania species), together responsible for over 8 million cases each year. Cases of human African trypanosomiasis have decreased from epidemic levels in the 1990's due to sustained surveillance and control programmes. Yet, T. brucei is still endemic in 36 countries and highly prevalent in livestock animals, where it causes an additional economic burden. Understanding the mechanisms these parasites use to proliferate and transmit between hosts is essential to meet the WHO's aims of eliminating African trypanosomiasis as a public health problem by 2030. Like all eukaryotic cells, trypanosomes undergo the tightly regulated cell cycle to divide and multiple. Critically, only trypanosome parasites that stop dividing in the insect mouthparts and preadapt to survive in the mammal are able to infect a new host when vector insects take a bloodmeal. Once injected into the skin and bloodstream, these parasites start rapidly dividing again and spread to various host tissues causing disease. In the case of T. brucei, a mirrored process occurs where some parasites in the human undergo cell cycle arrest and prepare for transmission back to the tsetse flies, which spread them to new hosts across sub-Saharan Africa. When arrested parasites are ingested by a tsetse fly, they being proliferating again to complete the life cycle. Additionally, some Trypanosoma and Leishmania species appear to arrest and persist as dormant forms in mammals for long periods of time without detection by the immune system and may escape treatment. The mechanisms controlling whether trypanosomes continue to divide or arrest are, therefore, highly integral to both the survival and spread of these destructive parasites. Despite its importance, we have virtually no understanding of how or where these processes are regulated, not least because current assays are unable to efficiently discriminate the cell division cycle stages. Using Trypanosoma brucei, I will address three fundamental questions: which genes control whether T. brucei divides or arrests; where in the mammal and tsetse fly are the dividing and arrested forms found; and is cell-cycle-arrest required for transmission? To achieve this, I will take advantage of the amenability of T. brucei to genetic manipulation. I will engineer a novel fluorescent parasite line that will change fluorescent colour as they progress through the different stages of the cell cycle, or stop fluorescing when arrested. The changes in fluorescence can be easily and quickly tracked using both microscopy and flow cytometry, a method which can detect fluorescence of thousands of cells in seconds. Using this approach I will, firstly, perform a targeted gene silencing screen of hundreds of genes to identify those needed to either drive or repress cell division. Secondly, I will track the cell cycle changes of parasites in the different mammal and tsetse fly tissues. Finally, I will test whether preventing cell-cycle-arrest by gene silencing, also prevents T. brucei completing its life cycle in the mammal and tsetse fly. Together, this work will reveal how T. brucei directs its intricate transmission cycles to spread disease, findings that will then be extended to related trypanosomatid parasites. Ultimately, the cell-cycle-regulating proteins identified will be assessed as potential therapeutic drug targets for the treatment of trypanosome diseases.
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