EASTBIO: The biological impact of anti-diabetic therapy on susceptibility to fungal infection

This fully funded, 4-year PhD project is part of a competition funded by the BBSRC EASTBIO Doctoral Training Partnership

Candidiasis rates have increased substantially worldwide in recent decades and is a significant cause of morbidity and mortality, especially amongst the aged, immunocompromised and those with metabolic disorders. Diabetics are more susceptible to fungal infection due to altered blood glucose levels. However, anti-diabetes therapies that decrease glucose levels can increase susceptibility to fungal infection. For example, in animal studies metformin lowers glucose levels, but consequently, immune cells depleted of glucose become dysfunctional. Similarly, SGLT2 inhibitors reduce reabsorption of glucose but in humans are associated with urinary tract fungal infections. The Wilson lab (1^st supervisor) have recently shown that a potential new anti-diabetic therapy, PTP1B inhibition, also increases susceptibility to fungal infection in experimental non-diabetic models where the fungus depletes glucose levels in susceptible organs.

We are just beginning to understand the role of immunometabolism in fungal infections and how fungi drive metabolic remodelling in immune cells in healthy subjects and the need for maintaining host glucose homeostasis to defeat fungal infections in normal physiology. However, the exact immunometabolic molecular mechanisms underpinning how anti-diabetic medicines, despite their health benefits, can increase infection susceptibility and whether this is different in diabetic and non-diabetic conditions is lacking.

The key aim of the studentship is to fully analyse and define the mechanisms that influence the functions of the immune cells, neutrophils and macrophages that fight fungal infection, by different anti-diabetic agents. This will provide a platform to establish how anti-diabetic medicines can be manipulated so they retain their health benefits but immune cell function is not compromised. This project offers an exciting and unique opportunity to bring together a multidisciplinary supervisory team with expertise in a wide range of cutting-edge technologies in immune cell biology and experimental models (Aberdeen), and omics and cell signalling (Dundee) to address the following:

1. What are the biological effects of anti-diabetic drugs on human neutrophil and macrophage function regarding their ability to engulf and kill invading fungi?
2. What are the alterations in metabolism, the proteome and intracellular signalling pathways in these immune cells, subsequently affecting functions relating to infection susceptibility, with expert guidance and training from the Arthur lab? (2^nd supervisor)
3. What are the key biological mechanisms by which anti-diabetic treatments change the levels of fungal infections in experimental models of diabetes and how could this be altered metabolically?

To address these aims, the student will receive extensive training in our well-established infection models, neutrophil and macrophage isolation and culture, multicolour flow cytometry, high powered confocal and real time imaging microscopy, fungal killing and phagocytosis assays, novel intracellular signalling analysis/metabolic and proteomic profiling and molecular biology techniques. A strong emphasis will be placed on training in experimental design, data analysis, bioinformatics, data management, report writing and presentations.

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ELIGIBILITY:

Applicants should hold a minimum of a 2:1 UK Honours degree (or international equivalent) in a relevant subject. Those with a 2:2 UK Honours degree (or international equivalent) may be considered, provided they have (or are expected to achieve) a Distinction or Commendation at master’s level.

All students must meet the eligibility criteria as outlined in the UKRI guidance on funding for postgraduate training and development. This guidance should be read in conjunction with the UKRI Training Grant Terms and Conditions.

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APPLICATION PROCEUDRE:

• Please visit this page for full application information: How to apply | eastbio (eastscotbiodtp.ac.uk)
• Please send your completed EASTBIO application form, along with academic transcripts to Alison Innes at [Email Address Removed]
• Two references should be provided by the deadline using the EASTBIO reference form. References should be sent to [Email Address Removed]
• Unfortunately, due to workload constraints, we cannot consider incomplete applications.
• CV's submitted directly through a FindAPhD enquiry WILL NOT be considered.
• If you require any additional assistance in submitting your application or have any queries about the application process, please don't hesitate to contact us at [Email Address Removed]