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MRC DiMeN Doctoral Training Partnership: Targeting pathogen subversion of cellular ageing to combat antimicrobial-resistant typhoid fever


Project Description

- Antimicrobial-resistant typhoid fever is fuelled by chronic Salmonella carriage

The world faces epidemics of untreatable typhoid fever caused by antimicrobial-resistant strains of Salmonella Typhi (~27 million cases/year). This is exemplified by ongoing outbreaks of extensively drug-resistant typhoid in South Asia. To spread disease, S.Typhi establishes chronic infections in humans who contaminate the food-chain and transmit antimicrobial-resistant typhoid. Understanding how chronic infection develops, and identifying effective diagnostic, treatment and prevention strategies to detect chronic S.Typhi carriers is a research priority of the World Health Organisation and is vital to typhoid elimination efforts. To address this global health challenge, we seek an enthusiastic PhD student to advance a new area of research on pathogen subversion of cellular ageing, which will be exploited to identify novel diagnostic biomarkers that can combat chronic carriage and typhoid.


- Typhoid toxin triggers cellular ageing and release of putative diagnostic biomarkers

A major virulence factor implicated in chronic carriage is the typhoid toxin of S.Typhi. In our recent Nature Communications article (doi:10.1038/s41467-019-12064-1), we discovered that the toxin induces DNA replication stress in human cells and accelerates an ageing-like process called senescence. Remarkably, senescent cells secrete unidentified proteins that induce senescence in neighbouring cells, which are rendered more susceptible to infection. We propose that the unidentified secreted proteins underlying transmissible senescence represent novel diagnostic biomarkers. Moreover, our data suggest that the toxin accelerates cellular ageing via senescence to establish chronic carriage. This makes sense as infections are harder to combat as we age but how pathogens hijack ageing to cause disease is unclear.


- PhD project

The PhD project aims to break new ground in an emerging field on pathogen subversion of cellular ageing and use knowledge gained to elucidate diagnostic biomarkers that can identify and treat chronic carriers to combat the spread of antimicrobial-resistant typhoid.

The project combines molecular cell biology, infection, proteomic and epidemiological approaches. By challenging cultured human cells with toxigenic Salmonella or purified toxin, the project will replicate host-pathogen interactions underlying typhoid and chronic carriage. This will enable proteomic identification of senescent biomarkers (objective 1), the study of DNA damage and senescence mechanisms (objective 2), e.g. using fluorescence microscopy in siRNA/knockout cells, and investigation of diagnostic senescence biomarkers in patients samples (objective 3).

The studentship will be supported by leaders from the typhoid and diagnostic fields including primary supervisor Dr. Daniel Humphreys (https://www.sheffield.ac.uk/bms/research/humphreys) and co-supervisors Prof. Stephen Baker (https://www.tropicalmedicine.ox.ac.uk/team/stephen-baker) and clinician Dr. Tom Darton (https://www.sheffield.ac.uk/iicd/profiles/darton). The project provides opportunity for placements and field work at Oxford University and its Clinical Research Unit in Vietnam. The project aims to contribute to the fight against typhoid and antimicrobial resistance, and improve the health and wealth of vulnerable communities.

Contact Dr. Daniel Humphreys () for more information and assistance.


- Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs.
Includes:
- Stipend at national UKRI standard rate
- Tuition fees
- Research training and support grant (RTSG)
- Travel allowance

Studentships commence: 1st October 2020.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website

Good luck!

References

Ibler AEM, ElGhazaly M, Naylor KL, Bulgakova NA, El-Khamisy SF & Humphreys D (2019) Typhoid toxin exhausts the RPA response to DNA replication stress driving senescence and Salmonella infection. Nature Communications, 10(1), 4040. https://doi.org/10.1038/s41467-019-12064-1

Park SE, Pham DT… Baker S. (2018) The phylogeography and incidence of multi-drug resistant typhoid fever in sub-Saharan Africa. Nature Communications, 9: 5094. https://doi.org/10.1038/s41467-018-07370-z

Malick M Gibani … Thomas C Darton, Andrew J Pollard. (2018). The Impact of Vaccination and Prior Exposure on Stool Shedding of Salmonella Typhi and Salmonella Paratyphi in 6 Controlled Human Infection Studies. Clinical Infectious Diseases, 68 (8), 1265–1273. https://doi.org/10.1093/cid/ciy670

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