A facility for the analysis of the intrinsic and extrinsic regulation of Plasmodium falciparum development in mosquitoes, and the evaluation of pre-erythrocytic, and transmission-blocking. (360G-Wellcome-077640_Z_05_Z)

Ongoing studies on rodent malaria parasites have described the molecular basisfor, and regulation of, parasite development in Anopheles stephensi, and parasite interactions with the vector immune system. This proposal will extendthe hypotheses generated, to the important human pathogen P. falciparum in itsnatural vector A. gambiae. In addition the project will provide critical materials, sporozoites and assays, for the development of pre-erythrocytic, and transmission-blocking vaccines respectively. The project will: i) characterize parasite phenotypes in wild-type mosquitoes challenged with mutated parasites (gametocyte signalling-Billker; ookinete-vector interaction - Sinden); ii) provide P. falciparum sporozoite-infected mosquitoes for ongoing studies on the development of pre-erythrocytic stage vaccines (Hill); iii) evaluate new transmission-blocking monoclonal antibodies, and sera from phase I trials (Carter/Saul) and iv) study the responses of RNAi immune knock-down mosquitoes (Kafatos/Christophides). Specific outcomes include the better understanding of vaccine design and application; the discovery of noveltransmission-blocking targets in the parasite and vector, and a coincidental reduction in animal experimentation. Imperial College has established a majorinitiative in parasite-vector interactions/innate immunity, and now has one ofthe few units able to transmit P. falciparum (including genetically modified (GM) lines) with confidence through both Anopheles stephensi (susceptible or GM refractory) and A. gambiae (susceptible, refractory and GM). National and international demands for this resource now exceed the capacity of current staff. We request funds to support the work described above, and to fund an additional technician to support the key needs of others (see attached letters). Collaborators not funded by The Trust will be asked to pay full costs, and the monies used to establish a rolling fund to sustain the additional technician long-term.