Website The University of Sheffield
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Antimicrobial-resistant typhoid fever
The world faces epidemics of antimicrobial-resistant (AMR) typhoid fever caused by Salmonella Typhi that underlies 12 million cases / 129 000 deaths each year. Understanding how infection develops and how human host cells combat Salmonella will improve control strategies that are vital to typhoid elimination efforts.
Typhoid toxin a tumour suppressor mechanism called senescence.
A major virulence factor implicated in typhoid is the typhoid toxin of Salmonella Typhi. We discovered that the toxin induces DNA damage responses in human cells that accelerates an ageing-like process called senescence (Ibler et 2019, Nature Communications). Senescence is an innate defence against cancer marked by cell-cycle arrest but we recently showed that p53-dependent senescence attacks Salmonella and suppresses the activities of typhoid toxin via the senescence-associated secretory phenotype (SASP) (Srour et al 2025, EMBO Mol Med; ElGhazaly et al 2023, Cell Reports). The findings indicate that DNA damage responses have co-evolved to not only protect mammalian cells from cancer but infections by bacterial pathogens. However, we do not understand how these host defences or how they are regulated. Thus, we seek an enthusiastic PhD researcher to study the mechanisms by which DNA damage responses activate innate defences against major pathogens such as Salmonella Typhi and related toxigenic Salmonella.
Objectives
Determine metabolic and proteomic senescence responses to DNA damage induced by typhoid toxin
Identify and resolve the senescence-associated antimicrobial mechanisms restricting Salmonella infection
The project combines molecular cell biology, infection, mass spectrometry (metabolic, proteomics) and immunological approaches. By challenging cultured human cells with Salmonella Typhi in a containment level 3 laboratory, the project will replicate infection mechanisms underlying typhoid. Typhoid toxin activation of senescence and its manipulation by intracellular Salmonella will be studied using fluorescent microscopes. Mass spectrometry will be exploited to identify DNA damage-associated antimicrobial pathways and provide a springboard for resolving how the host senses and combats Salmonella during infection. The mechanisms aim to be validated and further investigated using clinical samples from patients with typhoid fever.
Contact Dr. Daniel Humphreys (d.humphreys@sheffield.ac.uk) for more information and assistance with your application.
Funding Notes
Self-Funded Students only – You must have your own funding.
References
Supervisor references
Srour et al. 2025, EMBO Mol Med (https://doi.org/10.1038/s44321-025-00347-8)
ElGhazaly et al., 2023, Cell Reports (https://doi.org/10.1016/j.celrep.2023.113181)
Ibler et al. 2023, Nat Commun (https://doi.org/10.1038/s41467-019-12064-1)
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