Life-threatening invasive fungal infection is a major health problem in the immunocompromised, 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 neutrophils in fungal infection has been well studied in vitro but is difficult to translate to in vivo models of infection.
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-). Infection sites are profoundly hypoxic and neutrophils have evolved to function in this environment. Targeting Hif- therapeutically to activate neutrophils could be used against fungal infection, subverting antimicrobial resistance. You will use the transparent zebrafish embryo infected with Candida albicans and Cryptococcus neoformans to understand how hypoxia signalling might be targeted to treat fungal infection.
Using zebrafish models we already know that the two Hif- variants, Hif-1 and Hif-2, 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-1 and Hif-2 appropriately, to better kill invading fungi. Using cutting-edge molecular biology and fluorescence microscopy techniques you will address:
1. How Hif- signalling is protective against fungal infection
2. How targeting different Hif- 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 and microscopy techniques, as well as writing and presenting your science. The research will take place in a newly refurbished bespoke zebrafish infection laboratory.
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 can be found on our website: http://www.dimen.org.uk/
1. Ogryzko NV, Lewis L, Wilson HL, Meijer AH, Renshaw SA, Elks PM (2019). Hif-1alpha-induced expression of Il-1beta protects against Mycobacterial infection in zebrafish. J Immunol December 14, 2018, ji1801139; DOI: https://doi.org/10.4049/jimmunol.1801139
2. 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.
3. 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.