PhD Studentship: Leukocyte polarisation during in vivo infection

Cells of the innate immune system (leukocytes) are in a constant balance during homeostasis and disease between activated and silenced states. Specifically, macrophages are now known to exist in a variety of activation states, from the M1-type inflammatory macrophage, to the M2-type wound-healing macrophage. These classes incorporate a broad spectrum of different phenotypes, classified largely in vitro, dependent on with which cytokines the monocytic precursors are stimulated with. Although there is a wealth of in vitro data on leukocyte activations states, there are few tractable animal models, especially ones in which we can genetically skew leukocyte phenotypes and follow their behaviour over the timecourse of disease-relevant infection models.

We have recently used the genetically tractable and visually transparent zebrafish embryo to show that hypoxia response genes, Hif-1α and Hif-2α, have opposing effects on leukocyte activation, and that we can manipulate Hif-αs genetically to skew leukocyte phenotype in the absence of other stimuli. In mammalian models the Kiss-Toth group has shown that Tribbles family member genes have similar leukocyte modulation effects and others have also demonstrated that they can skew macrophage polarisation. With these immune activators and repressors, we are now able to skew innate immune phenotype in disease models and observe their effects over the early timecourse of in vivo infections.

We hypothesise that via manipulation of Hif-α and Tribbles we can fine-tune leukocyte phenotype and alter disease outcomes in infection models to aid the host fight infection. The aim of this project is to utilise disease-relevant zebrafish models of human infections, and to modulate leukocyte function to aid understanding and to identify novel treatment avenues.

The behaviour of the leukocytes in the presence or absence of Hif/Tribbles manipulation will be observed in three well-characterised models of zebrafish infection; a Mycobacterium marinum-TB model, a Staphylococcus aureus model and a fungal Cryptococcus neoformans model. Leukocyte behaviour during infection will be studied using timelapse fluorescence microscopy, alongside infection outcomes measured by pathogen burden/death of host. Where suitable, findings will be extrapolated into mammalian cell line and/or bone marrow derived macrophage studies.

This work will take place in a young and vibrant research group (http://elkslab.weebly.com/) and the candidate will be well trained in a combination of cutting-edge molecular biology and microscopy techniques.

Funding Notes

Fully funded to include fees and annual stipend of £14,553.
Candidates must have a first or upper second class honors degree or significant research experience.
Interested candidates should in the first instance contact Dr Philip Elks, p.elks@sheffield.ac.uk

References

How to apply:
Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply
Please clearly state the prospective main supervisor in the respective box and select 'Infection, Immunity and Cardiovascular Disease' as the department.