The assembly of multimeric protein complexes in the sexual stages of the human malaria parasite Plasmodium falciparum

疟疾寄生虫的有性繁殖是在吸血期间从人类宿主传播到蚊子载体之后开始的。性阶段是寄生虫生命周期中唯一能够在蚊子中建立感染的阶段，因此对热带疾病的传播起着重要作用。寄生虫的传播是由性前体细胞（配子母细胞）介导的，在蚊子的中肠中，配子母细胞转化为可育配子。在配子母细胞分化过程中，大量的表面相关粘附蛋白表达，其组装成多聚体蛋白复合物（MPC），随后暴露在配子表面上。针对MPC蛋白的抗体导致蚊子中肠中的有性阶段寄生虫的补体介导的裂解，从而阻断寄生虫在载体中的进一步发育。因此，MPC蛋白代表了传播阻断疫苗的有希望的候选者。MPCs是介导有性阶段寄生虫接触的多功能单位，可能在配子发生以及寻找和融合交配伴侣中发挥作用。然而，到目前为止，对蚊子中肠寄生虫发育过程中MPC的组装及其命运还没有很好的了解。因此，这一建议的目的是调查性阶段MPC的分子组成，以确定一个可能的连接MPC与配子体细胞骨架的膜下元素，并调查MPC蛋白的加工，搬迁和降解。

Sexual reproduction of the malaria parasite is initiated following its transmission from the human host to the mosquito vector during a blood meal. The sexual stages are the only life-cycle stages of the parasite that are able to establish an infection in the mosquito and thus play an important role for spread of the tropical disease. Parasite transmission is mediated by sexual precursor cells, the gametocytes, that in the midgut of the mosquito transform into fertile gametes. During gametocyte differentiation, a high number of surface-associated adhesion proteins are expressed, which assemble to multimeric protein complexes (MPCs) and which are subsequently exposed on the gamete surface. Antibodies directed against MPC proteins result in complement-mediated lysis of sexual stage parasites in the mosquito midgut, thereby blocking further development of the parasite in the vector. MPC proteins therefore represent promising candidates for transmission blocking vaccines. MPCs are multifunctional units mediating contact of sexual stage parasites and possibly play a role in gametogenesis as well as in finding and fusion of mating partners. The assembly of MPCs and their fate during parasite development in the mosquito midgut, however, are up to date not well understood. It is therefore the aim of this proposal to investigate the molecular composition of sexual stage MPCs, to identify a possible connection of MPCs with the submembranous elements of the gametocyte cytoskeleton and to investigate processing, relocation and degradation of MPC proteins.