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-a). Infection sites are profoundly hypoxic and neutrophils have evolved to function in this environment. Targeting Hif-a 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-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 targeting different 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 and microscopy techniques, as well as writing and presenting your science. The research will take place in a newly refurbished bespoke zebrafish infection laboratory.
This is an exciting new project in collaboration with Alison Condliffe, Violaine See (Liverpool), and Simon Johnston labs.
See details below. Closing date is the 6th January 2020