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Phosphate sensing as a vital virulence determinant in a major pathogen of humans, Candida albicans


Biosciences Institute

Prof J Quinn , Dr B Suarez-Mantilla Friday, January 22, 2021 Competition Funded PhD Project (Students Worldwide)
Newcastle United Kingdom Biochemistry Genetics Microbiology Molecular Biology

About the Project

Human fungal pathogens are often described as ‘Hidden killers’ as they kill more people every year than malaria and many so called ‘super-bugs’, but are often overlooked. Current anti-fungal drugs are limited, and many fungal pathogens are developing resistance to these drugs, hence there is a clear unmet clinical need for novel drug treatments. To drive forward antifungal drug discovery we need to better understand the pathobiology of these ‘hidden killers’. Candida albicans is one of the major human fungal pathogens causing over 400,000 deaths per annum. In this project you will investigate how C. albicans acquires essential nutrients during infection of the human host, because this is intimately linked with virulence. Specifically you will explore exciting new findings from the research team that acquisition of the macronutrient phosphate is vital for C. albicans virulence. Strikingly, phosphate acquisition is essential for this fungus to survive host-imposed stresses during infection, and C. albicans cells unable to acquire phosphate are acutely sensitive to macrophage killing. The aim of this project is to build on these findings and dissect the signalling mechanisms that regulate phosphate homeostasis and activation of the PHO phosphate acquisition pathway in C. albicans. Using a multidisciplinary approach, you will be trained in molecular genomics, RNA-Sequencing, metabolic profiling (LC-MS), fluorescence microscopy, phosphate analysis, and virulence models, to delineate how a major human fungal pathogen acquires phosphate during infection. This combination of approaches will uncover new virulence determinants and initiate the development of improved therapeutic strategies for treating fungal infections. You will also join a vibrant research team committed to the promotion and career progression of early career researchers.

Informal enquiries may be made to

HOW TO APPLY 

Applications should be made by emailing with a CV and a covering letter, including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project/s and at the selected University. Applications not meeting these criteria will be rejected. We will also require electronic copies of your degree certificates and transcripts.

In addition to the CV and covering letter, please email a completed copy of the Newcastle-Liverpool-Durham (NLD) BBSRC DTP Studentship Application Details Form (Word document) to , noting the additional details that are required for your application which are listed in this form. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.


Funding Notes

Studentships are funded by the Biotechnology and Biological Sciences Research Council (BBSRC) for 4 years. Funding will cover tuition fees at the UK rate only, a Research Training and Support Grant (RTSG) and stipend. 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.

References

1. The type VI secretion system deploys antifungal effectors against microbial competitors. Nat Microbiol. 2018, 3(8):920-931.
2. Redox Regulation, Rather than Stress-Induced Phosphorylation, of a Hog1 Mitogen-Activated Protein Kinase Modulates Its Nitrosative-Stress-Specific Outputs. mBio 2018 9(2), e02229-17.
3. Phosphate Acquisition and Virulence in Human Fungal Pathogens. Microorganisms 2017, 5(3), 48.
4. Blocking two-component signalling enhances Candida albicans virulence and reveals adaptive mechanisms that counteract sustained SAPK activation. PLoS Pathogens 2017, 13(1), e1006131.
5. Stress-induced nuclear accumulation is dispensable for Hog1-dependent gene expression and virulence in a fungal pathogen. Scientific Reports 2017, 7, 14340.
6. Pho4 mediates phosphate acquisition in Candida albicans and is vital for stress resistance and metal homeostasis. Molecular Biology of the Cell 2016, 27(17), 2784-2801.
7. Mechanisms underlying the delayed activation of the Cap1 transcription factor in Candida albicans following combinatorial oxidative and cationic stress important for phagocytic potency. mBio 2016, 7(2), e00331-16.
8. Metabolomic profiling reveals a finely tuned, starvation-induced metabolic switch in Trypanosoma cruziepimastigotes. Journal of Biological Chemistry 2017 292(21): 8964-8977.
9. Proline Metabolism is Essential for Trypanosoma brucei brucei Survival in the Tsetse Vector. PLoS Pathogens 2017, 13(1): e1006158.
10. Role of Δ1-Pyrroline-5-Carboxylate Dehydrogenase Supports Mitochondrial Metabolism and Host-Cell Invasion of Trypanosoma cruzi. Journal of Biological Chemistry 2015, 290(12): 7767-7790.
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