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

Why did we fund this project?

This award aims to establish the infrastructure and techniques to use Drosophila at the University of Essex to investigate components of innate immunity.

The innate immune response is the first line of defence against pathogens. It is highly evolutionarily conserved. The system must be tightly controlled as failing to activate can result in infection, whereas overactivity can result in inflammation. Dr Patrick Varga-Weisz has previously shown that a chromatin remodeling protein, Smarcad1, is a critical component in innate immunity in mice. To further explore the protein function in mice would require breeding of transgenic lines for infection studies associated with pain and suffering using large numbers of animals. Patrick’s collaborator, Dr Dominique Ferrandon at the Institute de Biologie Moléculare et Cellulaire, has identified a homolog for Smarcad1 in Drosophila. Based on current thinking, Drosophila are incapable of experiencing suffering and so can provide a partial replacement for other animals.

To explore the function of Smarcad1 further, Patrick will set up the necessary infrastructure at the University of Essex to work with Drosophila. Dominique will train Patrick and colleagues in key techniques to study innate immunity in Drosophila. Patrick will then work with collaborators in Brazil, where Drosophila is not used widely as a model, to further advocate its use basic scientific research.

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.

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Skills and Knowledge Transfer grant

Status

Active

Institution

University of Essex

Grant reference number

NC/W001047/1

Award date

Jul 2021 - Jun 2023

Grant amount

£64,941