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MRC DiMeN Doctoral Training Partnership: Tuning the innate immune response to antimicrobial resistant infections


MRC DiMeN Doctoral Training Partnership

Sheffield United Kingdom Biochemistry Bioinformatics Cell Biology Genetics Immunology Microbiology Molecular Biology

About the Project

Life-threatening invasive fungal infection is a major health problem, especially in people with impaired immunity, and emerging drug resistance is a major threat to global health. Fungal pathogens, such as Candida, Cryptococcus and Aspergillus, are experts at immune evasion. Neutrophils - the most abundant white blood cell in humans - are vital in immunity to fungal infection, and optimising their function is a novel and powerful strategy to combat infection. The role of the neutrophil in fungal infection has been well studied in vitro but in vivo models of neutrophils in infection are limited. 

We have shown that if properly activated, neutrophils are very effective at controlling fungal infection, highlighting their potential as therapeutic targets. We are especially interested in low oxygen (hypoxia) signalling (via the transcription factor Hif-a). Infection sites are profoundly hypoxic and neutrophils have evolved to function well in this environment. Targeting Hif-a therapeutically to activate and tune neutrophils could be used against fungal infection, subverting antimicrobial resistance. You will use the transparent zebrafish embryo infected with Candida albicans and Cryptococcus neoformans and fluorescence microscopy techniques to understand how hypoxia signalling might be targeted to treat fungal infection. 

Using zebrafish models we already know that the two Hif-a variants, Hif-1a and Hif-2a, have opposing effects on neutrophil control of bacterial infection. In this project we aim to understand whether neutrophils can be molecularly ‘tuned’, by modulating Hif-1a and Hif-2a appropriately, to better kill invading fungi. Using cutting-edge molecular biology and fluorescence microscopy techniques you will address:

            1. How Hif-a signalling is protective against fungal infection

            2. How modulating Hif-a variants can fine-tune neutrophil behaviour during fungal infection

This project synergises the expertise of a number of internationally leading groups at Sheffield Medical School, using techniques that are well-established in our groups that have so far produced exciting results and require an enthusiastic PhD student to take forwards. You will join a young and vibrant research lab (http://elkslab.weebly.com/) and you will be well trained in molecular biology, zebrafish and microscopy techniques, as well as learning how to write and present your science. The research will take place in brand new, state-of-the-art, zebrafish infection facilities.

You should possess a high 2.1 or 1st class degree in a relevant biological degree. Relevant laboratory experience is not required, but a passion for tackling the growing problem of antimicrobial resistance is a must!

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 and how to apply can be found on our website:

https://bit.ly/3lQXR8A 


Funding Notes

Studentships are funded by the Medical Research Council (MRC) for 3.5yrs. Funding will cover UK tuition fees and stipend only. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Please read additional guidance here: View Website
Studentships commence: 1st October 2021
Good luck!

References

Hammond FR, Lewis A, Elks PM (2020) If it’s not one thing, HIF’s another: immunoregulation by hypoxia inducible factors in disease. The FEBS Journal. https://doi.org/10.1111/febs.15476
Evans RJ, Pline K, Loynes CA, Needs S, Aldrovandi M, Tiefenbach J, Bielska E, Rubino RE, Nicol CJ, May RC, Krause HM, O'Donnell VB, Renshaw SA, Johnston SA. (2019) 15-keto-prostaglandin E2 activates host peroxisome proliferator-activated receptor gamma (PPAR-γ) to promote Cryptococcus neoformans growth during infection. Plos Pathog, 28;15(3), e1007597.
Elks PM, Brizee S, van der Vaart M, Walmsley SR, van Eeden FJ, Renshaw SA & Meijer AH (2013) Hypoxia inducible factor signaling modulates susceptibility to mycobacterial infection via a nitric oxide dependent mechanism.. PLoS Pathog, 9(12), e1003789.

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