Can malaria transmission be prevented through catastrophic failure of gametocyte quiescence?

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Despite recent gains in 2000-20016, progress has stalled and malaria is still a devastating disease, killing ~405,000 people each year and infecting 228 million. Plasmodium falciparum, the parasite causing the most deadly form of malaria spreads when a female mosquito ingests specialised parasite cells called male and female gametocytes whilst biting an infected person. These gametocytes have no control over when a mosquito might bite, therefore, to maximise their chances of transmission they become "quiescent" (i.e. dormant) for up to 22 days in human blood. Most antimalarial drugs are not effective against quiescent gametocytes thus allowing the disease (and drug resistance genes) to escape and spread throughout the population. Cellular quiescence is a process that is fundamental to all of life. In response to an unfavourable environment or a specific signal, cells can stop growing and become quiescent for a period of time. When conditions become more favourable, quiescent cells then exit this dormancy and resume their normal programmed growth. Cells carry out quiescence by a number of different methods, however common processes occur within the cell to keep them alive: 1. Reduced or efficient energy generation; 2. A shift in resource production from those needed for growth, to those necessary for survival; 3. Efficient damage and repair mechanisms.I hypothesise that interfering with gametocyte quiescence mechanisms will have catastrophic effects on their infectiousness, leaving them unable to transmit to mosquitoes. Studying these processes will help the design and discovery of new transmission-blocking antimalarial therapies targeting gametocyte quiescence.My fellowship focuses on how quiescent gametocytes regulate their energy production. Parasite stages in the mosquito generate energy by consuming glucose in a process called mitochondrial respiration, which is carried out in a specialised part of the cell called the mitochondrion. Mitochondrial respiration is essential for the parasite to survive in the mosquito but less important whilst it is in the human. Gametocytes must be ready to "switch on" mitochondrial respiration at a moment's notice. However, too much unwanted mitochondrial respiration is damaging for cells as it produces toxic "free radicals" that can kill the cell and thus would limit the lifespan of the gametocyte and lower its chances of transmission. Therefore, gametocytes appear to have several mechanisms to control their energy generation. It is hypothesised that one mechanism is to divert glucose away from the mitochondrion and out of the cell before it has been consumed. Alternatively, energy production could be reduced by replacing key enzymes (proteins that manufacture materials needed by the cell) involved in the process with less efficient alternatives. I have identified four enzymes made by gametocytes that may be responsible for this control. To study the role these play, I will genetically modify the parasite to lack these proteins and observe how this affects gametocytes and mosquito transmission. This will involve feeding parasites to live mosquitoes. I will also trace how glucose use by the parasite is affected in the mutant parasites using a technique called metabolomics which separates and identifies individual chemicals made by the cell. To identify additional proteins important for maintaining gametocytes in their quiescent state, I will label newly made proteins within the gametocyte with a chemical "tag" which will allow me to "capture" them and identify them using a technique called mass spectroscopy. By using this approach on male and female gametocytes individually, I will determine whether there is a sex difference in how gametocytes maintain quiescence. Finally, I will study how disrupting gametocyte energy metabolism impacts their ability to repair themselves.Ultimately, my research will identify which steps in the quiescence pathway could by targeted by new therapeutics.