University of Dundee

MRC DTP 4 Year PhD Programme: Understanding the difference between inflammasome activation in neutrophils and macrophages

This project is offered as part of the University of Dundee 4-year MRC DTP Programme “Quantitative and Interdisciplinary approaches to biomedical science”. This PhD programme brings together leading experts from the School of Life Sciences (SLS), the School of Medicine (SoM) and the School of Science and Engineering (SSE) to train the next generation of scientists at the forefront of international science.  The outstanding biomedical research at the University of Dundee was recognised by its very high rankings in REF 2014, with Dundee rated as the top University for Biological Sciences in the UK.  A wide range of projects are available within this programme crossing exceptional strengths in four key areas: Infection and Disease; Responses to Cellular Stresses; Development, Stem Cells and Neurobiology; and Big Data and Translation.  All students on this programme will receive training in computational biology, mathematical biology and statistics to equip with the quantitative skills in tackling complex biological questions.  In the 1st year, students will carry out 3 rotation projects prior to selection of the final PhD project.

Supervisors: Dr Gabriel Sollberger and Prof Simon Arthur.

The innate immune system uses a broad variety of sensors to detect cues of infections (pathogen-associated molecular patterns, PAMPs) or signs of cell and tissue damage (danger-associated molecular patterns, DAMPs). Recognition of PAMPs and DAMPs usually results in the production and release of pro-inflammatory mediators. Often, the activation of sensors and their downstream effectors also results in lysis and death of the activated cell, which makes it paramount that this activation is tightly controlled. If control mechanisms fail and excessive immune cell death occurs, this has detrimental consequences for the host, such as septic shock or the development of autoimmune diseases.An example of such processes is activation of inflammasomes. Inflammasomes are multiprotein complexes, which –upon sensing ofPAMPs or DAMPs –induce the release of IL-1b, a very potent pro-inflammatory cytokine (1). Inflammasomes are mostly studied in macrophages and much less is known in the most abundant human immune cell, the neutrophil. Neutrophils, rather than secreting IL-1b, undergo a special form of cell death when activated, they form neutrophil extracellular traps (NETs). NETs consist of DNA and protein; dying neutrophils expel them as web-like structures and thereby catch extracellular pathogens (2). Remarkably, we previously found that there is crosstalk between the molecular machinery mediating inflammasome activation in macrophages and NET formation in neutrophils (3).This project therefore aims to study, what the differences are between inflammasomes in neutrophils and macrophagesand if these differences affect the outcome of infections and inflammasome or NET-driven pathology.The project will use human cells and a combination of cell biological and genetic techniques to answer these important immunological questions from a mechanistic perspective. It will thereby contribute to our understanding of inflammation, infection and sterile pathologies and help to identify possible new drug targets to tackle such pathologies.

(1) Broz P., Dixit V.M. Inflammasomes: mechanism of assembly, regulation and signalling, Nat Rev Immunol, 16:417-20

(2) Sollberger G., Tilley D.O., Zychlinsky A. Neutrophil Extracellular Traps: The Biology of Chromatin Externalization Dev Cell, 44:542-553

(3) Sollberger G., Choidas A., Burn G.L., Habenberger P., Di Lucrezia R., Kordes S., Menninger S., Eickhoff J., Nussbaumer P., Klebl B., Krüger R., Herzig A., Zychlinsky A. Gasdermin D plays a vital role in the generation of neutrophil extracellular traps Sci Immunol, 3:eaar6689