Investigation of the impact of the mosquito immune system on shaping the transmitted malaria parasite populations

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Malaria is a devastating disease transmitted by mosquitoes. It infects about 220 million and kills about 430,000 people every year, mostly children in sub-Saharan Africa. This is a much better situation than 15 years ago, when deaths were almost twice as many, and is due to the combination of more effective medicines, improved health care and, above all, enhanced mosquito control. However, the latest data indicate that these measures can have no further impact as numbers have remain unchanged in the past few years. Importantly, widespread resistance to insecticides has seriously hampered mosquito control. Therefore, it has become evident that research that could lead to new interventions must be intensified. While efforts to manufacture an effective vaccine continues, focus is now placed in identifying new ways to halt malaria parasites before they are transmitted to humans. To this purpose, genetic modification of mosquitoes preventing them from transmitting the disease and manufacturing vaccines that act against parasites inside mosquitoes have received great attention and funding. This project aims to map the molecular and evolutionary landscape in which mosquito-parasite interactions take place and provide an informed list of targets of new antimalarial interventions.Our research is based on earlier findings that only few of the malaria parasites entering a mosquito upon blood feeding on an infected human survive to be transmitted to a new host. Most parasites are eliminated by mosquito immune responses before infection is established. Recently, we discovered that a specialised mosquito immune response, called the complement-like system, attacks and removes already compromised and unfit parasites. Therefore, we hypothesised that this response can act as an evolutionary sieve that purifies malaria parasite populations from compromising mutations.To examine our hypothesis, we will use a library of over 150 rodent malaria parasite lines, each carrying a deleterious mutation in a gene expressed during early stages of mosquito infection. Pools of these mutant parasites will infect a mouse and be transmitted to mosquitoes that are normal or have parts of their immune system disrupted. This includes the complement-like pathway and another pathway that attacks parasites soon after they enter the mosquito. Parasites that manage to survive will be transmitted back to mice through mosquito bites, and the mouse-mosquito-mouse transmission will continue for four additional cycles. In each cycle, the population of parasites in the mice will be characterised to identify genes of which mutations did or did not affect transmission. We expect that some parasites carrying deleterious mutations will be transmitted only when the mosquito immune system is disrupted. A proof-of-concept experiment with parasites carrying mutations in six such genes corroborated our hypothesis. The outcome of these experiments will be twofold: it will reveal novel parasite genes important in interactions with the mosquito, which can be targets of interventions aiming to block disease transmission, and it will identify the impact the mosquito immune system can have on shaping parasite populations transmitted between hosts. The latter can be very important in delineating the forces that determine the composition of the malaria parasite populations circulating among people.In Africa, some mosquitoes have more robust immune systems than others, and in some cases these mosquitoes occupy different geographic regions; hence, we hypothesise that they can transmit different parasites. A second research line will directly investigate this question using species of mosquitoes with different geographic distributions and playing different roles in malaria epidemiology. Determining which gene mutations can be transmitted by some mosquito species but not others can provide unprecedented insights into the malaria transmission landscape.