Mechanisms of nuclear translocation of IL-33 after stimulation of skin keratinocytes by S. aureus

Background: A quarter of children in the UK suffer from atopic dermatitis (eczema). IL-33 is an important alarmin usually released from injured cells, but we have recently found that this type 2 allergy-inducing cytokine is also actively secreted from uninjured skin cells stimulated with the Staphylococcus aureus virulence factor Sbi. The process seems to be independent of calcium influx but linked to nuclear histone binding and transfer.

Objectives: To determine the critical stimulatory cell signals and secretary pathways leading to active IL-33 secretion using a novel reporter cell system.

Methods: We aim to develop a novel IL-33 assay using system microscopy to monitor movement of this constitutive nuclear cytokine from the nucleus to the external milieu in live cells after bacterial stimulation. This will complement and build on established molecular methodology available here at the University of Manchester. Cell signalling pathways will be interrogated initially by RNAseq and phosphoarray, and subsequently using specific chemical inhibitors and siRNA knockdown using our primary keratinocyte in vitro model. In vitro results will then potentially be translated into in vivo mouse models currently available (NC/Tnd mice available via collaborators in Tokyo, Japan) and/or the flaky tail model of AD being developed as part of our current MRC project grant at the University of Manchester.

Potential outcome/impact: A better understanding of key pathways involved both initiation and active secretion of IL-33, a key early driver of atopic dermatitis should in the medium to long-term lead to the development of novel therapeutics for the treatment of severe allergic skin disease and related atopic conditions such as asthma.

Entry Requirements

Candidates should ideally have an MSc in Microbiology/Immunology/Cell Biology, although those with a BSc (Honours) in these subjects may also be accepted. 

How to Apply

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select the PhD Immunology or Microbiology.

For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit www.internationalphd.manchester.ac.uk

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