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Unravelling the dynamic interactions between protective, probiotic Escherichia coli and pathogenic Salmonella


Project Description

Bacterial infections are a major cause of disease in humans. The ability to treat “minor” infections that arise after routine surgery or chemotherapy is the bedrock upon which modern medicine is based. The emergence of bacterial resistance to last resort antibiotics has exacerbated the impact of infections, and we now face a return to the “dark ages of medicine,” where even routine surgery carries life-threatening risks.

Salmonella are responsible for causing food-poisoning and remain a major global health problem. The bacteria reside in the intestines of humans and animals, and can subsequently enter the food chain. Our intestinal microbiota harbour trillions of commensal bacteria that play a pivotal role in maintaining good health. Bacterial probiotics provide huge health benefits to their hosts including protection against invading pathogens, thus preventing disease and helping to reduce antibiotic usage. Furthermore, screening extracellular metabolites produced by probiotic bacteria of anti-bacterial effects may provide a new pipeline for novel antibiotics.

The probiotic Escherichia coli Nissle 1917 strain has been shown to provide protection against food-borne pathogens and infectious diarrheal diseases, but our understanding of the underlying molecular mechanisms is limited. The aim of the studentship is to provide detailed molecular and cellular insights in to the fierce competition which takes place within the intestinal niche for nutrients and space between the probiotic Escherichia coli Nissle and invading Salmonella, as the probiotic bacterium successfully fights with the pathogen to maintain its niche. We hypothesise these interactions may involve direct intra-bacterial cell-to-cell contact, prophage products, and signalling through diffusible bacterial molecules.

Using a multidisciplinary team of scientists based in Newcastle, Liverpool, Nottingham and Norwich we will use the latest state-of-the-art technologies in molecular biology, chemical biology, and microbiology to address these hypotheses. The successful student will have the opportunity to spend time in the Co-supervisors and Collaborators laboratories to acquire complementary expertise and generate data.

The results generated will have important implications for mechanistically understanding, at the molecular and cellular levels, the biology of probiotic-pathogenic bacterial interactions. These will provide avenues for enhancing probiotic efficacy using synthetic biology and the development of novel antibiotics to control disease, now increasingly important with the growing threat of antibiotic-resistant bugs.

HOW TO APPLY

Applications should be made by emailing with a CV (including contact details of at least two academic (or other relevant) referees), and a covering letter – clearly stating your first choice project, and optionally 2nd and 3rd ranked projects, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University. Applications not meeting these criteria will be rejected.

In addition to the CV and covering letter, please email a completed copy of the Additional Details Form (Word document) to . A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.
Informal enquiries may be made to

Funding Notes

This is a 4 year BBSRC studentship under the Newcastle-Liverpool-Durham DTP. The successful applicant will receive research costs, tuition fees and stipend (£15,009 for 2019-20). The PhD will start in October 2020. Applicants should have, or be expecting to receive, a 2.1 Hons degree (or equivalent) in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support. Please note, there are 2 stages to the application process.

References

Salmonella Typhi sense host neuroendocrine stress hormones and release the toxin hemolysin E. EMBO Reports 2011, 12(3), 252-258

Distinct intra-species virulence mechanisms regulated by a conserved transcription factor. Proceedings of the National Academy of Sciences 2019. DOI:10.1073/pnas.1903461116

Host-associated niche metabolism controls enteric infection through fine-tuning of type 3 secretion and a co-ordinated suite of effector proteins. Nature Communications 2018 9(1):4187

Shiga-toxin encoding Bacteriophage phi 24(B) modulates bacterial metabolism to raise antimicrobial tolerance. Scientific Reports 2017. 7. doi:10.1038/srep40424, 2017

Transcriptomic Analysis of Shiga-Toxigenic Bacteriophage Carriage Reveals a Profound Regulatory Effect on Acid Resistance in Escherichia coli. Applied and Environmental Microbiology 2015. 81(23), 8118-8125. doi:10.1128/AEM.02034-15, 2015

Pathogen espionage: multiple bacterial adrenergic sensors eavesdrop on host communication systems. Molecular Microbiology 2013. 87(3) 455-65

Comparative genomics of Shiga toxin encoding bacteriophages. BMC Genomics 2012. 13.doi: 10.1186/ 1471-2164-13-311

A Highly Conserved Bacterial D-Serine Uptake System Links Host Metabolism and Virulence. PLoS Pathogens 2016. 12(1): e1005359.

The bacterial cystoskeleton modulates motility, type 3 secretion, and colonization in Salmonella. PLoS Pathogens 2012, 8(1), e1002500

Interkingdom crosstalk: host neuroendocrine stress hormones drive the hemolytic behavior of Salmonella typhi. Virulence 2011 2(4):371-4

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