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


School of Biology

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Dr DJ Hughes , Dr SJ Powis No more applications being accepted 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 (particularly viruses) 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 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 one of the genetic causes of Mendelian susceptibility to mycobacterial disease (MSMD), a rare condition associated with predisposition to weakly virulent mycobacteria, including the 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. It is also known that secreted ISG15 regulates the expression of several other factors implicated in the immune response (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.

Infection and immunity is clearly a subject considered a priority area of research across the world. The skills developed during this studentship will place the successful candidate in a strong position to pursue a career in this area (which may include employment in healthcare, the private sector or to continue in academia). Students at St Andrews University have access to award-winning training that recognises the value of an integrated workforce as well as providing personal development programmes that complement their laboratory training.

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

Please direct informal enquiries to Dr David Hughes ([Email Address Removed])
Applications can be made online via our online portal- https://www.st-andrews.ac.uk/study/apply/postgraduate/research/

Visit: https://hugheslab.weebly.com/



Funding Notes

Funded by the School of Biology, University of St Andrews. The studentship covers the tuition fees (Home and Overseas) and a living allowance for a duration of 3.5 years.

References

Holthaus, D, Vasou, A, Bamford, C, Andrejeva, J, Paulus, C, Randall, RE, McLauchlan, J & Hughes, DJ 2020, 'Direct antiviral activity of interferon stimulated genes is responsible for resistance to paramyxoviruses in ISG15-deficient cells', The Journal of Immunology. https://doi.org/10.4049/jimmunol.1901472
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