Mechanisms Governing Translational Regulation During Plasmodium Transmission

Abstract Malarial infections are still one of today's great global health problems, with nearly 600,000 deaths and millions of new infections occurring annually. Plasmodium parasites (the causative agents of malaria) are transmitted between a mosquito vector and their mammalian host, and they have developed intricate systems to adequately prepare for transmission, and to then to firmly establish an infection. Because relatively few parasites are passed between the host and the mosquito vector, these two transmission events have long been prioritized as optimal points for interventions with drugs and vaccines. Recent work has demonstrated that Plasmodium parasites have evolved to use selective translational repression just prior to transmission events to store the mRNAs that it will need for the next steps of development. The adaptation of translational repression for these purposes is a logical choice, as the transmitted gametocytes and sporozoites cannot anticipate when they will be transmitted, and this system allows the parasite to always remain ready for that moment of transmission to occur. While some of the key proteins and mRNAs involved in these events have been identified, many important questions still remain. What proteins are responsible for selecting mRNAs for translational repression? What proteins act to repress them? What attributes of an mRNA will flag it to be selected for translational repression? In this proposed work, we will leverage new technological and experimental approaches to answer these questions, and by doing so, we will better understand the fundamental mechanisms that the parasite has evolved to be efficiently transmitted in both the gametocyte and sporozoite stages. Moreover, we will observe similarities and differences in how the parasite uses translational repression at these two stages in both rodent- infectious, and human-infectious parasites. Taken together, these findings will provide the first mechanistic studies of protein/RNA complexes in sporozoites, will allow a functional comparison across stages and species, and will highlight molecular components and functions that the parasite requires for transmission that may exploited in the future as targets for new therapeutic agents.