Unraveling novel molecular mechanisms of iron-sensing in African trypanosomes (360G-Wellcome-208780_Z_17_Z)

This proposal aims to understand intracellular iron homeostasis in Trypanosoma brucei, a parasitic pathogen that causes African Sleeping Sickness in humans and nagana in animals. Iron is an essential micronutrient for all organisms and serves as a regulatory signal for virulence factors in prokaryotic and eukaryotic systems. Its homeostasis is tightly regulated and extensively studied in these systems revealing specific mechanisms in each domain. However, it remains relatively understudied in T. brucei despite its crucial role in pathogenesis. Using a genome-wide transcriptome profiling pilot study of T. brucei under transferrin/iron-starvation conditions, I identified novel parasite-specific iron-deficiency responsive genes. Based on these findings, I hypothesize that novel intracellular iron-dependent regulatory and signaling processes exist in T. brucei that control expression of iron-responsive genes. I will investigate this hypothesis in-depth by: characterizing the function of these novel iron-responsive genes, probing global proteomic changes under transferrin/iron-starvation, and systematically mapping the post-transcriptional iron-sensing regulatory network using genetic and biochemical approaches. Functional characterization of these regulators/effectors will reveal how an iron-stress signal is converted into a biological response, how this process in T. brucei is distinct from those of mammalian hosts, and will potentially provide new insights for development of novel therapeutic targets