PhD Research Project: DiMeN Doctoral Training Partnership: Macrophage inflammatory activation and b

Macrophages are innate immune cells that kill microbes and are important regulators of immune signaling in both health and disease. Many macrophage types have been identified and how different macrophages interact and function is crucial to many diseases. For example, overactive inflammatory macrophages can drive cancer and cardiovascular disease while under activity may result in increased susceptibility to infection or a failure in wound healing e.g. in diabetes. In our lab we are interested in how different macrophages behave and how individual cell behaviors determine the outcome of infection.

Macrophages are both effector cells that directly kill pathogenic microbes and regulator cells that coordinate the response of the immune system to infection. In this project we want to understand how these two aspects of macrophage behaviour interact to decide the outcome of infection:
1) What is the relationship between individual macrophage behaviours and increased susceptibility to infection? 
2) What is the molecular basis for differences in macrophage behaviour and can this be targeted for new therapy?

The primary infection we will use in the project is the fungal pathogen Cryptococcus neoformans (goo.gl/bJaQco). Cryptococcal infection is both a significant opportunistic infection that causes hundreds of thousands of deaths worldwide each year and an excellent opportunity to understand the relationship between individual macrophage behaviour and infection due to the complicated interactions of Cryptococcus and macrophages (goo.gl/IkIf2V). Macrophages are essential for control of infection yet many microbes are highly resistant to macrophage mediated killing. For example, cryptococci can resist phagocytosis, grow within macrophages if they are taken up and can escape non-lytically by vomocytosis. Critically we have identified several key macrophage molecular immune modulators of behaviour interferon-gamma, bacterial peptidoglycan and prostaglandin E2) that we can measure and modulate genetically. Therefore, in this project we will test two hypotheses related to how the arms race between human immunity and pathogen evolution may provide clues for therapeutic intervention:
1) The control and clearance of cryptococcal infection is dependent on extracellular pro-inflammatory cues that modify macrophage behaviour to intracellular cryptococci.
2) Changing macrophage behaviour to a controlling phenotype will reverse uncontrolled infection.

Zebrafish have a number of advantages in studying human infections having a highly similar immune system and being able to study both cell and sub-cellular biology in a living organism during infection. This project will use our in vivo zebrafish models of immunity and infection (goo.gl/Vhe8hF) to gain high content imaging data of the immune response and progression of infection with interferon-gamma, bacterial peptidoglycan and prostaglandin E2. These three factors will be modulated using transgenic and mutant zebrafish and pathogen strains (e.g. plb and lac mutants that have altered prostaglandin secretion, bacterial cell wall mutants and interferon gamma receptor mutants). The project will be primarily wet lab-based in the Johnston lab (http://www.johnstonlabs.co.uk) but will use expertise from co-supervisors in engineering, mathematics and physics. We will use automated image analysis with Prof. Alex Frangi (http://www.cistib.org/cistib_shf/) to specify and track immune cell and pathogen behaviour during infection. Image analysis data will be used for individual-based and multiscale modeling of cryptococcal infection with Dr. Alex Fletcher (http://alex-fletcher.staff.shef.ac.uk/) and used to inform physical models of the macrophage pathogen macrophage interaction with Dr. Rhoda Hawkins (http://rhoda-hawkins.staff.shef.ac.uk/). We will then use our models to make experimental predictions and use these as a basis for exploring targeted therapy in personalized medicine for example in the stratification of cryptococcal meningitis patients with different inflammatory profiles for which there are currently no alternative treatments.

Funding Notes

DiMeN DTP studentships are funded for 3.5 years and include:

- Tax-free maintenance grant set at the UK Research Council's national rate.
- Full payment of tuition fees at the Home/EU rate.
- A Research Training Support Grant to support your research studies.

Successful Home students will receive a full studentship. EU students will be considered for a full studentship/fees only support depending on the excellence of their qualifications and their employment/residency status.

Please carefully read the instructions on eligibility and how to apply at our website and use the link on the page to submit an application: http://www.dimen.org.uk/how-to-apply/application-overview