Grant: Discovery Grants Program - Individual

Our research program is to understand the fundamental mechanisms that govern the cell biology and immunobiology of host-pathogen interactions. We use a protozoan parasite of genus Leishmania as our model pathogen, and human macrophages as host cells. Our long term objective is to identify the strategies used by Leishmania to manipulate the host macrophage environment to be permissive for their survival inside phagolysosomes. We recently made two major advances. First, we discovered Leishmania hijacks the host PI3K-Akt cell signaling pathway to generate macrophage proparasitic phenotypes. Second, we discovered that Leishmania induces selective host macrophage autophagy, and fine-tunes this process to promote their survival by activating the PI3K-Akt pathway. Our short term objectives are to investigate the mechanisms of regulation of macrophage autophagy used by Leishmania to promote their survival.Autophagy is a fundamental, essential catabolic process characterized by the active degradation of cytoplasmic constituents that are engulfed by double membrane structures, known as autophagosomes. It was long thought that autophagy was a non-selective recycling pathway. However, recently it has been established that autophagy can selectively and efficiently degrade specific cellular constituents.Our hypothesis is that Leishmania needs specific host macromolecules to survive and grow inside host cells. These are obtained by inducing selective autophagy to transfer required cargo to Leishmania-containing phagolysosomes. We have three objectives:Objective 1. To biochemically characterize protein constituents of Leishmania induced autophagosomes and to study their roles in Leishmania-macrophage interaction.Objective 2. To investigate the mechanism of selective autophagy induction by Leishmania.Objective 3. To identify Leishmania PI3K activator(s) involved in the attenuation of classical host autophagy.This basic science research program will significantly advance our knowledge of host defense and microbial pathogenesis by characterizing a novel mechanism used to evade intracellular immunity. We anticipate that the knowledge generated will be broadly applicable to the area of host-pathogen interactions. One of the immediate outcomes of this research program will be the training of two doctoral students. They will have opportunities to work with a wide range of advanced techniques such as quantitative proteomics, molecular and cell biology and to develop critical thinking required in designing and executing complex sets of experiments. This will equip them for careers as scientists in academia or in the private sector. Together this research program will foster research excellence in the natural sciences and engineering, stimulate high quality training and create new employment opportunities.