Dr Daniel Humphreys

Dan HumphreysUKRI Future Leaders Research Fellow
Department of Biomedical Science
University of Sheffield
Western Bank
Sheffield S10 2TN
United Kingdom

Room: C08 Florey building
Telephone: +44(0) 114 222 4632
Email: d.humphreys@sheffield.ac.uk

CMIAD


Cell Biology and Cancer

General

Biography

My research focusses on the host cell biology underlying infectious diseases with the aim of discovering new ways to combat globally important bacterial pathogens. I am a UKRI Future Leaders Research Fellow studying DNA damage responses and senescence in typhoid fever and its transmission by chronic bacterial carriage. I obtained my PhD and gained postdoctoral training at the University of Cambridge before being appointed as a lecturer in 2016 at the Department of Biomedical Science, University of Sheffield, where I received an MRC New Investigator Research Grant. Before that I studied Microbiology at the University of Liverpool (BSc) and Biological Sciences at the University of Manchester (Masters).

  • 2019 - present: UKRI Future Leaders Research Fellow
  • 2016 - present: Lecturer, Department of Biomedical Science, University of Sheffield
  • 2014 - 2016: Research Fellow, Department of Pathology, University of Cambridge
  • 2008 - 2013: Postdoctoral Research Associate, University of Cambridge
  • 2003 - 2007: PhD in Cellular Microbiology, Department of Pathology, University of Cambridge
  • 2002 - 2003: Masters of Biological Research, University of Manchester
  • 1999 - 2002: BSc in Microbiology, University of Liverpool

Awards and funding

  • UKRI Future Leaders Research Fellowship (2019)
  • HIC-Vac GCRF Grant (2019)
  • Royal Society Research Grant (2017)
  • MRC New Investigator Research Grant (2016)
  • Pathology Research Fellowship (2014)

Teaching

I am undergraduate module co-ordinator for Pathobiology BMS106/BMS109 in which I teach infection and immunity. I also lecture on the MSc for Molecular Medicine and the MSc for Antimicrobial Resistance.

Research interests

Typhoid fever and its transmission by chronic bacterial carriage
Typhoid fever is a major disease in low- and middle-income countries resulting in ~11 million cases and ~128,000 deaths each year. Typhoid is caused by the human-restricted pathogen Salmonella Typhi that has evolved antibiotic-resistance with multi- and extremely-resistant strains causing current epidemics.

Dan Humphreys page

Salmonella Typhi establishes infections through a wide repertoire of toxins and virulence effectors that mediate bacterial invasion of human cells, intracellular survival and immune evasion. A major focus of our laboratory is a key virulence determinant called the typhoid toxin that enters human cells where it causes breaks in our DNA, which activates a cellular alarm system known as the DNA damage response .

Our research also investigates how S.Typhi and its typhoid toxin cause chronic infections in humans - ‘chronic carriage’. Chronic carriers transmit the pathogen in the population and are difficult to control due to the lack of obvious clinical symptoms. The most infamous ‘chronic carrier’ was a household cook called Typhoid Mary who caused numerous outbreaks of typhoid between 1900 - 1906. This stealth strategy of S.Typhi continues today and helps S.Typhi perpetuate its infection cycle, which impedes global efforts to eradicate typhoid. By studying decisive disease mechanisms, our research contributes to global efforts combatting multidrug-resistant typhoid with the aim of improving the health and wealth of vulnerable communities in low- and middle-income countries.



Full publications

Research

Research projects on typhoid and chronic infection

Pathogenic bacteria manipulate the host DNA damage response (DDR) to execute virulence strategies and establish infections. This is exemplified by Salmonella Typhi that causes typhoid fever and fuels the infection cycle by chronic bacterial carriage. Upon infection, S.Typhi deploys the typhoid toxin, which is endocytosed by target host cells where the toxin activates the DDR. How the toxin hijacks the DDR and how this contributes to typhoid and chronic carriage is unclear. Understanding the toxin is especially important as related toxins are encoded by diverse bacterial pathogens that cause disease in humans and food-chain animals worldwide.

DNA damage responses underlying typhoid and chronic Salmonella carriage

Our laboratory is investigating the significance of DNA damage responses to infectious disease. We discovered a novel disease mechanism revealing that the typhoid toxin manipulates host cell machinery responsible for DNA replication and cell division. The typhoid toxin triggers accumulation of DNA repair protein γH2AX at the nuclear periphery - Response Induced by a bacterial Genotoxin (RING).

We found that the RING phenotype was caused by toxin subversion of replication protein A (RPA), which coats and protects single-strand DNA (ssDNA) at replication forks during DNA synthesis. By generating ssDNA breaks, toxin nuclease activity re-directs RPA from replication forks, which causes irreparable DNA damage (i.e. RING phenotype) resulting in DNA replication catastrophe and cellular senescence. Investigating this novel virulence mechanism is providing new information on disease while revealing potential therapeutic targets. Read the paper: http://rdcu.be/bQrD3

Dan Humphreys page

Investigating how pathogens accelerate the ageing of human host cells

Understanding how chronic infection develops, and identifying effective diagnostic, treatment and prevention strategies is vital to typhoid elimination efforts. We find that the typhoid toxin induces chronic DNA damage via the RING phenotype, which results in cellular senescence, a phenotype associated with ageing but whether pathogenic bacteria exploit senescence is unclear. Interestingly, protein secretions from intoxicated cells cause senescence in neighbouring cells but the identify of the secreted proteins and therefore the mechanism of this transmissible senescence is unresolved. Significantly, the senescent cells were rendered more susceptible to intracellular Salmonella infections.

Consequently, our findings support the view that pathogenic bacteria can speed up cellular ageing through a toxin and take advantage of this to establish infections. This makes sense as infections are often harder to combat and recover from as we age, which is partly due to senescence, but the idea that bacterial pathogens target this phenomenon could be important to infection and contribute to age-related pathologies such as cancer. We are investigating the significance of senescence in chronic infection and its diagnostic potential for typhoid and chronic carriage. Read more: http://rdcu.be/bQrD3

Dan Humphreys page

People

Dan Humphreys page

Dr. Angela Ibler
British Infection Association Research Fellow
Email: a.ibler@sheffield.ac.uk

Mohamed ElGhazaly
PhD student
Email: melghazaly1@sheffield.ac.uk

Daniel Stark
PhD student
Email: dsstark1@sheffield.ac.uk

Nadia Baseer
PhD student
Email: nbaseer1@sheffield.ac.uk

Salma Srour
PhD student
Email: shsrour1@sheffield.ac.uk

Alumni
Dr. Kate Naylor
Postdoctoral research associate

News

October 1, 2019

A big welcome to our new PhD student Salma Srour!

September 26, 2019

Daniel Humphreys awarded UKRI Future Leaders Fellowship
Thank you to the UKRI for supporting our research!

September 19, 2019

Typhoid Fever: an age-old problem
Behind the paper commentary posted on Nature Microbiology Communities

September 9, 2019

Thanks to Take on Typhoid for highlighting our research.

September 7, 2019

Typhoid toxin accelerates cell ageing to enhance killer infection, study reveals
University press release highlighting our Nature Communications paper!

September 6, 2019

Typhoid toxin exhausts the RPA response to DNA replication stress driving senescence and Salmonella infection
Read our Nature Communications paper on typhoid: http://rdcu.be/bQrD3

July 31, 2019

Daniel Humphreys and collaborators awarded HIC-Vac Research Grant
Thank you to HIC-Vac, which is supported by the GCRF Networks in Vaccines Research & Development that aims to advance human infection challenge (HIC) and vaccine (Vac) studies.

May 18, 2019

Dr. Angela Ibler - Congratulations on receiving your PhD at the University of Cambridge!

Opportunities

PhD Project Opportunity

Enquires for postdoc, fellowship and PhD positions are welcome.

We are advertising a post-doc position soon.


We advertise PhD opportunities (Funded or Self-Funded) on FindAPhD.com

For further information and details of other projects on offer, please see the department PhD Opportunities page:

PhD Opportunities

Selected publications

Journal articles