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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.

Science Graduate School
As a PhD student in one of the science departments at the University of Sheffield, you’ll be part of the Science Graduate School. You’ll get access to training opportunities designed to support your career development by helping you gain professional skills that are essential in all areas of science. You’ll be able to learn how to recognise good research and research behaviour, improve your communication abilities and experience the breadth of technologies that are used in academia, industry and many related careers. Visit http://www.sheffield.ac.uk/sgs to learn more.

Funding Notes

This position is open to self-funded students and also has the possibility of being funded by a fees scholarship, further details can be found here: View Website

First class or upper second 2(i) in a relevant subject. To formally apply for a PhD, you must complete the University's application form using the following link: View Website

All applicants should ensure that both references are uploaded onto their application as a decision will be unable to be made without this information.

References

https://www.sheffield.ac.uk/bms/research/humphreys

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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