Regulation of autophagy by Salmonella

A combined computational and wet lab approach to understand how <i>Salmonella</i> is controlling our cells in the gut.

Project Summary.

Led by: Korcsmáros Group

Start date: 17 March 2014

Duration: Ongoing

Grant: EI CSP WP2 / QIB Gut Microbes and Health ISP

Our key research aim is to examine how the functions of intestinal cells are compromised as a consequence of autophagy down-regulation, caused by Salmonella infection. Autophagy is a common recycling process in which cells degrade their unnecessary or damaged parts. It is important in the defence against infections, which is why pathogens like Salmonella hijack it. Bacteria such as Salmonella enter gut cells and then aim to avoid those cells’ degradation. A better understanding of how they do it would help us to develop new drugs or treatments for several illnesses.

We develop new bioinformatics resources and combine existing technologies for studying the host response to infection (ARN and SalmoNet). We identify human gut cell autophagy proteins whose quantity changes with Salmonella infection. Using bioinformatics tools and resources we search for the affected proteins’ associated regulators, and test the likely candidates in experiments. Rather than experiment with actual human gut, we use cell culture, organ cultures (‘organoids’), which are near-physiological 3D model systems that facilitate studying a range of in vivo biological processes including cell differentiation, anti-microbial peptide production, and host-microbe interactions.

The validated autophagy regulators affected by Salmonella could enable drug development projects of pharmaceutical companies to design novel drugs against Salmonella infection (which is the second most common cause of childhood mortality in the developing world), and the list of Salmonella-affected proteins can be used to develop gut health promoting treatments and personalised medicine-based strategies to identify risk for certain diseases.

Impact statement.

With this project we will identify the systems level, dynamic relationship between a gut pathogen, Salmonella and a host defense mechanism, autophagy. The complex interplay between Salmonella and autophagy has been investigated in the last two decades, providing a substantial amount of data for this project. We will advance our understanding by investigating the multi-scale nature of the Salmonella-autophagy connection, focusing specifically on pathways in intestinal cells and the homeostasis of the gut.

Throughout the project, we iteratively combine state-of-the-art and novel computational and experimental methods (network analysis and organoid infection works) and build on existing in silico and wet lab resources. The results will extend our understanding of Salmonella infection (from causing mild food poisoning to life-threatening gastrointestinal diseases in humans and animal livestock) and the role of intestinal cells during infection and, in general, to the maintenance of gut homeostasis.