Molecular mechanisms of translational control in macrophages

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Macrophages are the sentinels of the innate immune system. As such, they play central roles in host defense against infections but also in the resolution of inflammation and wound healing after pathogen clearance. In order to accomplish these tasks, macrophages swiftly respond to changes in the environment by producing different types of proteins that render them pro-inflammatory and microbicidal or rather anti-inflammatory. Translational control (regulation of mRNA translation) allows cells to react to external triggers or cues by synthesizing proteins according to their needs. The advantage is that in contrast to other mechanisms that regulate gene expression, changes in mRNA translation can occur very rapidly because there is no need to synthesize new mRNA to produce proteins. Surprisingly, there are considerable gaps in our understanding of how translational control impacts macrophage functions. Therefore, my NSERC research program focuses on identifying the mRNAs and the cellular processes that are controlled at the level of translation in macrophages, and to investigate how they altered by invading pathogens. To this end, we will infect macrophages with Toxoplasma gondii, an intracellular protozoan parasite that is known to subvert numerous host cell functions to survive. In addition to target identification, we will define the intracellular signals that are blocked by Toxoplasma gondii in order to prevent translation of mRNAs required for normal macrophage responses. To achieve these goals, we will deploy a combination of biochemical, immunological and molecular biology approaches in macrophages genetically modified to alter the expression of different regulators of mRNA translation. Our screening will be performed by genome-wide RNA sequencing, and bioinformatic analysis using an algorithm specifically designed to capture changes in mRNA translation. Collectively, our study will provide insight on how protozoan parasites hijack the mRNA translation machinery of macrophages, and modify gene expression programs that ultimately contribute to the progression of the infection. A better understanding of the molecular mechanisms underlying the interactions of intracellular pathogens with their host cells is of paramount importance to design safe and efficient treatments to combat infections of clinical relevance, and thereby improve the life quality of Canadians.