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*EASTBIO* How does the cytokine ISG15 shape our immune response to infection?


School of Biology

, Wednesday, January 06, 2021 Competition Funded PhD Project (Students Worldwide)

About the Project

The evolutionarily conserved type I interferon (IFN-I) system is of fundamental importance for our defence against pathogens and forms a major arm of our innate immune response. IFN-I is also really important for the host response to cancer and cancer treatments and is critical for activating the adaptive immune response (which involves T cells and antibody producing B cells). Furthermore, IFNs are important immunomodulatory cytokines that regulate the magnitude of the host response and are therefore important for limiting tissue damage and an overexuberant inflammatory response. Intriguingly, many of the seminal discoveries in innate immunity regulation have come from the study of people with inherited defects in critical genes and the resulting disease phenotypes. One of these critical factors is the ubiquitin-like protein interferon stimulated gene 15 (ISG15). Importantly, inherited ISG15-deficiency causes autoinflammatory interferonopathy, where the type I IFN response is pathogenically activated in the absence of infection resulting in intracranial calcification, necrotising skin lesions and lung involvement.

Many of the regulatory roles of ISG15 occur inside the cell as it is involved in controlling IFN-I signalling. However, ISG15 is also secreted and functions as a cytokine. The most compelling evidence for this is that ISG15 loss-of-function is also one of the genetic etiologies of Mendelian susceptibility to mycobacterial disease (MSMD), a rare congenital condition associated with predisposition to infections caused by weakly virulent mycobacteria, including the attenuated BCG vaccine. Patients with MSMD are unable to produce a cytokine known as IFN-gamma (IFN-γ) from NK cells and so are unable to mount a proper T cell response to infection. It was later found that secreted ISG15 is required for NK cells to produce IFN-γ (NK cells are innate immune cells and are the major source of IFN-γ). It is also known that secreted ISG15 regulates the expression of several other factors implicated in the immune response to infection (such the chemokine CXCL10); but the molecular details of this are completely unknown.

Based on the hypothesis that ISG15 is a critical link between innate immunity (IFN-I) and the adaptive immune response, this project will address some of the fundamental questions related to how secreted ISG15 shapes our immune response to infection.

This highly focussed project, which has implications for our fundamental understanding of host defence, health and disease, is designed to provide training in molecular virology, recombinant protein purification and characterisation, CRISPR/Cas9 genome editing technologies, cutting-edge proteomics and FACS analyses.

You will be part of a productive and supportive research team that encourages personal development by providing training opportunities beyond the lab.

Application procedure
In order to apply for this position, please follow the application instructions under http://www.eastscotbiodtp.ac.uk/how-apply-0 to obtain the EASTBIO Application form.

Then, submit the EASTBIO application form and your academic transcripts as part of a formal online application- https://www.st-andrews.ac.uk/study/apply/postgraduate/research/

In the online application form, you will be asked to provide contact details for two academic references. Please ask your referees to use the EASTBIO reference form provided under the link above when preparing their support letter, and to ensure references are provided by the deadline on 6 January 2021.

Funding Notes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership View Website.

This opportunity is open to UK and International students and provides funding to cover stipend and UK level tuition. For international candidates, the University of St Andrews will cover the Home-International fee difference. Please refer to UKRI website and Annex B of the UKRI Training Grant Terms and Conditions for full eligibility criteria.

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