Mechanisms of nutrient acquisition by malaria parasite mosquito stages

项目总结与摘要

PROJECT SUMMARY AND ABSTRACT Plasmodium parasites cause the disease malaria. According to the World Health Organization there were 216 million cases of the disease worldwide which led to 445,000 deaths in 2016. The disease is thus formidable in its global burden and in an arena of malaria eradication and elimination, it is sobering to point out that between 2015 and 2016, deaths from the disease only fell by 1,000. Furthermore, the frontline drug treatment for uncomplicated malaria, artemisinin combination therapy, is beginning to fail due to the emergence of drug resistant malaria parasites and thus the great gains in malaria control achieved over the last decade could be wiped out in the near future. Novel interventions are thus still required. The malaria parasite has a complex life cycle, and in the case of the human disease, this relies on both a mosquito vector and a human host. The mosquito vector transmits infectious sporozoites to the human host which ultimately leads to a fulminant blood stage infection that causes all associated disease mortality and morbidity. During the blood stage of infection, sexual blood stage gametocytes can be acquired by the mosquito vector during blood meal acquisition where they mature into gametes. Gametes fuse to form a zygote and then a motile ookinete within the mosquito midgut. The ookinete traverses midgut epithelial cells before exiting through the basal side of the epithelium and develops as an extracellular oocyst, that is in contact with the hemocoel cavity and its associated nutrition-rich hemolymph. Life in an extracellular environment presents distinct challenges, and very little is known about how exactly the oocyst parasitizes its mosquito host in order to mature and release sporozoites, which migrate to the salivary glands and lay in wait for transmission to the next human host. Research has demonstrated that lipophorin, a lipoprotein complex derived from the mosquito bloodmeal can be taken up by developing oocysts, likely for the purpose of providing lipids for sporozoite production. However, whether this process is required for oocyst development is unclear. We have shown that an oocyst-expressed ATP binding cassette (ABC) transporter plays a role in the uptake of lipophorin and the deletion of the gene encoding this transporter leads to a severe defect in oocyst development, resulting in a significant decrease in oocyst maturation and time to sporozoite release. This proposal aims to fully elucidate the role of ABC transporters in oocyst maturation and their involvement in the acquisition of nutrients required for sporozoite production. We will use reverse genetics, spatial and temporal expression analyses, lipid labelling and heterologous expression to achieve these goals. An increased knowledge of this process could aid in the development of novel intervention to target malaria mosquito stages.