Targeting pathogen subversion of cellular ageing to combat antimicrobial-resistant typhoid fever
Lead Research Organisation:
University of Sheffield
Department Name: Biomedical Science
Abstract
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 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).
Organisations
People |
ORCID iD |
| Daniel Humphreys (Primary Supervisor) | |
| Michelle King (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/N013840/1 | 01/10/2016 | 30/09/2025 | |||
| 2441952 | Studentship | MR/N013840/1 | 01/10/2020 | 31/03/2024 | Michelle King |