Acquisition of the Drosophila model system to understand mechanisms of innate immunity regulation by chromatin dynamics

Our body fights off pathogens in multiple ways, which are broadly summarised as innate and adaptive immunity. Innate immunity comprises an array of cellular responses against pathogens that, by contrast to the adaptive immunity, is highly evolutionarily conserved and can be enacted by many cell types in our body that are not primarily immune cells. A functional innate immunity response is essential for life. Failure of innate immunity leads to pathogen-driven diseases and its deregulation to chronic inflammatory conditions.
Critical to innate immunity is the proper regulation of a cascade of genes. This regulation is largely mediated by how the DNA that contains those genes is packaged within cells by a plethora of proteins into a superstructure called chromatin. However, the knowledge of how 'chromatin remodelling' supports a functional innate immunity response is limited. In our research (Patrick Varga-Weisz), using mice, we have implicated a chromatin remodelling protein called Smarcad1 as a critical component in the innate immunity response in the gut. However, to elucidate this further using the mouse model is very expensive, slow and involves invasive procedures in these animals.
The fruit fly Drosophila melanogaster has been instrumental in the discovery of molecular processes of innate immunity, leading to the 2011 Nobel prize to Jules A. Hoffmann.
In this proposal, we wish to transfer world-class expertise in fly innate immunity from the lab of Dr Dominique Ferrandon (Institute de Biologie Moléculare et Cellulaire, Strasbourg) to our labs at the University of Essex. Dominique is a leading researcher in this field, having been trained in the lab of Jules A. Hoffmann and having established sophisticated approaches to study this important biological problem.
Using the methods from Dr Ferrandon, we can employ the powerful genetics of Drosophila to unravel details of how chromatin remodelling regulates innate immunity. These insights may provide targets for the pharmacological regulation of innate immunity to fight infections and during pathological inflammatory conditions. Meanwhile, these results from Drosophila will lead to the direct replacement of mice in these studies locally as well as potentially in the Brazilian network of collaborators of Dr Varga-Weisz.

Chromatin remodelling factors can control specific cellular processes through the coordinated regulation of cohorts of genes. However, how they achieve this specificity is still poorly understood. One process controlled by chromatin dynamics is the innate immune response, whose activity must be kept within set parameters. For instance, in the intestine, failure to properly activate innate immunity pathways may lead to dysbiosis and infection, while excessive activity could prevent colonisation by indigenous and lead to inflammation. This, understanding the molecular mechanisms behind this control holds great potential to fight a broad range of health issues. Work by Patrick Varga-Weisz has shown that chromatin modification of specific genomic regions by Smarcad1 is key to provide this fine-tuned regulation of innate immunity in the intestine of mice (Kazakevych et al., Genome Biology 2020). A genetic screen (Cronin et al., Science 2009) by our collaborator within this proposal, Dominique Ferrandon, identified fly homolog of Smarcad1, among several other chromatin remodelling factors, as a new candidate component of the innate immunity response to intestinal infections in Drosophila. However, Drosophila Smarcad1 function has not been elucidated yet, and we lack the molecular mechanism for these and other observations to realise their potential biomedical impact in mammals. We will establish a Drosophila platform to analyse in vivo the molecular mechanism whereby Smarcad1 modifies chromatin at specific loci, and their effect on the infection response. We expect this work to ultimately reveal novel, potentially druggable pathways of innate immunity at the level of gene expression regulation. This work will pave the way towards greater focus in future work involving mice, effectively leading to immediate local replacement in the PVW lab, local reduction in the near future, and potential reduction in the wider community of chromatin/immunity research.