Project description
An intracellular fight for nutrients could inspire novel therapies against microbes
All 'machines' need fuel to do their work. Cells rely on mitochondria, the organelles that produce energy for metabolic activities. Interestingly, mitochondria have several features suggesting they were once single-celled organisms that likely survived endocytosis by another species. It turns out that they are now a target of another invader: Toxoplasma gondii, the human parasite that causes toxoplasmosis. Toxoplasma gondii attempt to steal fatty acids they need to grow, and the mitochondria join forces to enhance fatty acid uptake themselves, restricting the parasite's growth. The EU-funded MITOvTOXO project is investigating the mechanisms of this phenomenon as well as whether mitochondria play a role in defence against microbes in general. Perhaps nature can teach us how to fight parasites and other microbes in vivo.
Objective
Once a pathogen has eluded immune defences to establish a replicative niche in the cytosol, it requires nutrients to grow—the same nutrients that host organelles need for their biogenesis and to perform cellular metabolic processes. The microbe must therefore compete with organelles for these nutrients.. This organelle-microbe competition for metabolites is a fundamental, but little understood aspect of the host–pathogen interaction. I recently defined one example of this competition, between mitochondria and the human parasite Toxoplasma gondii. During infection, Toxoplasma exploits host lipophagy to gain access to cellular fatty acids essential for its growth. To counter this, host mitochondria fuse to enhance fatty acid uptake, limiting Toxoplasma access to a key host resource and thus restricting its growth. This work shows that mitochondria—essentially domesticated parasites—metabolically defend the cell during infection, and opens several key questions that I will address in this proposal, including: a) by what mechanism do mitochondria enhance fatty acid oxidation to defend the cell against fatty acid siphoning by microbes?; b) can mitochondrial fatty acid oxidation be exploited to restrict microbial growth in vivo?; and c) do mitochondria play a broader role in cellular defence by sequestering other essential metabolites from microbes? The answers to these questions will lead to a deeper understanding of the role of mitochondria in the cellular response to microbes, and begin to address our long-term goal of understanding how human metabolism influences the progression of infectious disease. The innovative approaches I describe here are broadly applicable to dissecting the metabolic interactions between other organelles and diverse infectious agents.
Fields of science
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Funding Scheme
ERC-STG - Starting GrantHost institution
80539 Munchen
Germany