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EASTBIO Role of metabolism-related islets in Salmonella pathogenesis


Project Description

Royal (Dick) School of Veterinary Studies / The Roslin Institute

Salmonella is an animal and zoonotic pathogen of global importance. An estimated 78 million cases of human nontyphoidal salmonellosis occur annually causing 59,000 deaths. Human infections are frequently acquired via the food chain through the consumption or handling of contaminated meat products. Salmonella also causes enteric and systemic salmonellosis in farmed animals that constrains their productivity and welfare. Over 2600 Salmonella serovars exist and a need exists for more effective and cross-protective vaccines to control Salmonella in farmed animals and enhance food safety. Toward this aim, we have used transposon-directed insertion-site sequencing to assign roles to thousands of Salmonella enterica serovar Typhimurium genes in intestinal colonisation of chickens, pigs and cattle [1, 2]. Moreover, we have used novel surgical methods to assign spatiotemporal roles to Salmonella genes during systemic translocation in cattle [3]. These studies identified a core subset of genes that play conserved roles across species, but also identified host-, serovar- and niche-specific virulence factors, which can be used as targets for intervention. Many attenuating mutations are located in islets of metabolism-related genes of poorly defined function. Variation in metabolism-related genes has also been associated with the host tropism and invasive potential of Salmonella.

Here we propose to:

1. Generate mutations in metabolism-related islets implicated in Salmonella pathogenesis.
2. Define the impact of such mutations on the metabolome of Salmonella by mass spectrometry.
3. Characterise mutant phenotypes in vitro, for example, in relation to the use of specific metabolites and using cell-based assays of virulence-associated phenotypes.
4. Use novel 3Rs methods to assign phenotypes to mutants in farmed animals, for example, using ligated intestinal loop models to quantify net replication, inflammation and secretory responses.
5. Use computational approaches to study the relationship between metabolism-related islets and the differential tropism and virulence of S. Typhimurium pathovariants and S. enterica serovars.
The project will instil training in diverse areas, including microbial genetics, metabolomics, laboratory-based assays and vulnerable and strategically important in vivo skills.

Eligibility:
All candidates should have or expect to have a minimum of an appropriate upper 2nd class degree. To qualify for full funding students must be UK or EU citizens who have been resident in the UK for 3 years prior to commencement.

Funding Notes

Applications:
Completed application form along with your supporting documents should be sent to our PGR student team at

References:
Please send the reference request form to two referees. Completed forms for University of Edinburgh, Royal (Dick) School of Veterinary Studies and the Roslin Institute project should be returned to by the closing date: 5th January 2020.

It is your responsibility to ensure that references are provided by the specified deadline.
Download application and reference forms via:
View Website

References

[1] Chaudhuri RR et al. 2013. Comprehensive assignment of roles for Salmonella Typhimurium genes in intestinal colonization of food-producing animals. PLoS Genetics 9:e1003456.
[2] Vohra P et al. 2019. Retrospective application of transposon-directed insertion-site sequencing to investigate niche-specific virulence of Salmonella Typhimurium in cattle. BMC Genomics 20:20.
[3] Pullinger GD et al. 2007. Systemic translocation of Salmonella enterica serovar Dublin in cattle occurs predominantly via efferent lymphatics in a cell-free niche and requires type III secretion system 1 (T3SS-1) but not T3SS-2. Infect Immun 75:5191-9.

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