Dionne

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Welcome to the Dionne lab!

That is to say, Marc Dionne's lab, at King's College London; not to be confused with any other Dionne lab.

We are interested in (1) the effects of host genetics on the biology of infection; and (2) cytokine signalling and its effects on immune and non-immune tissues. Drosophila melanogaster is our animal model of choice.

Work in the lab has been funded by the Biotechnology and Biological Sciences Research Council and the Wellcome Trust.

Host genetics and the biology of infection

Different individuals show different levels of resistance to infections and develop different pathologies in response to infections. We are interested in why this is the case. We use the fruitfly Drosophila melanogaster as a model host to study these questions; this allows us to screen for genes that affect the progress of infection in a rapid and unbiased fashion.

All of our experiments originate from a simple genetic screen. Mutant flies are infected with Mycobacterium marinum, a bacterium closely-related to the causative agent of tuberculosis, or with Mycobacterium smegmatis, a related non-pathogen. We select lines of flies that die more quickly or more slowly than wild-type controls and identify the mutation that gives rise to this phenotype. We then try to understand what this phenotype tells us about the function of the mutated gene.

So far, our work on this system has focused on the mechanisms of pathogenesis. We have found that this infection causes progressive loss of metabolic stores, broadly similar to the wasting seen in people with tuberculosis. We have shown that, in the fly, this wasting effect is caused partly by systemic failures in anabolic signals via the insulin effector Akt and the TOR effector p70 S6 kinase.

Most recently, we have shown that the transcription factor MEF2 responds to nutrient signals to regulate expression of both immune effectors and anabolic enzymes. Remarkably, though MEF2 promotes the expression of both groups of genes, its choice of targets is regulated by a conserved phosphorylation that alters its affinity for the TATA binding protein. This work has recently been published in Cell.

Cytokines and cytokine signalling

In the course of screening, we find a lot of molecules and pathways that end up being involved in cytokine signalling and its consequences. One aspect of this is the metabolic effects of infection, which appear to result from high levels of cytokine expression over several days. Cytokines also regulate the realized immune response of the fly, much as they do in mammals.

Some time back, we published some of this work in Current Biology, showing that two different TGF-betas regulate fly immunity, each inhibiting a specific arm of the immune response, and each being produced by only a subset of phagocytes. Check it out!


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