KSEF RDE: Autophagy in the parasitic protozoan Toxoplasma gondii

Autophagy is a normal physiological process in eukaryotes involved in the digestion of the cytoplasm and defunct organelles, particularly in the context of starvation. Our recent work (Ghosh et al. 2011, in press) has established autophagy as a primary mechanism of programmed cell death. Given that triggering this pathway leads to parasite death, the primary objective in chemotherapeutic intervention highlights the importance of understanding autophagic processes. In yeast, at least 31 genes (designated ATG) have been identified as being involved in autophagy. Bioinformatic mining of the T. gondii genome reveals potential homologs of 15 ATG (TgATG) genes. Among these are TgATG8 (mammalian LCIII) and TgATG6 (mammalian Beclin-1). Both gene products play essential roles in regulating autophagy in the well developed systems. Analysis of the functions of these genes in Toxoplasma has not been done. With this study we propose functionally characterize TgATG8 and TgATG6 toward initiating a comprehensive dissection of autophagy related processes in the parasite. In light of our work indicating that autophagy is the key mechanism for programmed cell death in Toxoplasma, the proposed studies lay down the foundation for fundamental discoveries leading to novel chemotherapeutic targets. The need for new drug development is critical not only for Toxoplasma, an important AIDS-related pathogen and cause of birth defects but also for the related parasite Plasmodium that causes malaria. Our laboratory at UK has pioneered investigation of autophagy and autophagic death pathways in parasitic protozoa. Completion of the proposed foundational studies will provide the necessary preliminary data in support of RO1-level grant support to UK and the Commonwealth that has the potential to directly impact drug development against parasitic diseases for which there is an urgent global need.