Phil Yates, PhD
Our research focuses on three related kinetoplastid parasites (Leishmania, Trypanosoma brucei, and Trypanosoma cruzi), which cause a broad spectrum of Neglected Tropical Diseases that affect ~12 million people worldwide. During their lifecycles, these parasites face substantial fluctuations in temperature, pH, and nutrient availability, both within and in the transition between their insect and human host. However, the sensing and signaling pathways used by kinetoplastids to adapt to changes in the host milieu are poorly defined. As kinetoplastid parasites lack many of the canonical sensing and signaling proteins found in higher eukaryotes (i.e., G-protein-coupled receptors and receptor tyrosine kinases), aspects of these pathways are likely novel. Additionally, kinetoplastids are somewhat unique in that all gene regulation occurs post-transcriptionally.
Our long-term goal is to elucidate environmental sensing and stress response pathways in these parasites by examining nutrient deprivation. Purines are essential nutrients obtained exclusively from the host, and we have used the adaptive response to purine starvation in both Leishmania donovani and Trypanosoma brucei as a readily tractable model of nutrient stress responses. In collaboration with other groups, we identified several proteins that are differentially regulated by purine availability in L. donovani. We have shown that purine-responsive protein abundance can be controlled via any combination of mechanisms operating at the level of mRNA abundance, translation, or post-translational protein stability. Current projects focus on three main areas: 1) identification of cis- and trans-acting factors controlling mRNA stability and/or translation efficiency in the mRNAs of purine-responsive genes in Leishmania; 2) identification of potential purine sensing and signaling pathways by comparing the Leishmania and T. brucei purine stress responses via whole proteome and phosphoproteome analyses; and 3) development of novel molecular genetic tools to facilitate the experimental manipulation of kinetoplastid parasites. Tools under development include methods for tagging genes at their endogenous loci, simple reporter systems for assessing the relative contributions of different modes of post-transcriptional regulation to protein abundance, and a variety of systems for inducible protein expression in Leishmania.