Boosting immunity in chronic lung disease and antimicrobial resistant infection via the IL-33-ST2 axis

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Macrophages are effector cells that directly kill microbes and regulatory cells that coordinate the wider immune response. Due to the complex nature of macrophage function, how their different roles are integrated during infection and inflammation is still poorly understood. Increased numbers of patients living with immunocompromise, chronic inflammatory disease and the threat of antimicrobial resistance means that new and improved treatments that modulate macrophage function are required. This project is a collaborative project between the Johnston lab at the University of Sheffield (http://johnstonlab.group.shef.ac.uk/index.html) with an industrial partner, MedImmune (https://www.medimmune.com/), that will use our ex vivo lung imaging approaches to address questions of macrophage function during infection and inflammation.We have recently shown that the IL-33-ST2 axis plays a non-redundant role in regulating monocyte differentiation and alternative activated macrophage-mediated epithelial repair during naphthalene-induced injury of the airways (Dagner et al, in revision, Nat Immunol). In addition, macrophages from COPD patients demonstrate defective macrophage phagocytosis which may potentially contribute to why these patients suffer from repeated exacerbations which are linked with disease progression. We would like to extend these observations and determine whether IL-33-ST2 pathway is required for effective monocyte/macrophage recruitment, differentiation and function during lung infection.We will use established in vivo infection challenge studies (e.g. Staphylococcal aureus, Streptococcus pneumoniae, Cryptococcal neoformans and influenza nasal inhalation route lung infection) coupled to ex vivo live fluorescent imaging of lung. We will use fluorescent labelled antibodies (eg. CCR2;ST2;MHCII;Ly6C;CD3;CD4;CD11c) to mark and distinguish recruited and differentiating immune cells. We will assess macrophage responses by measuring phagocytic capacity, intracellular killing and pathogen growth by time lapse imaging.This PhD position offers an opportunity to work in a vibrant and successful biomedical research laboratory at The University of Sheffield with at least three months of industrial placement at our partner MedImmune. The Johnston lab is focused on the study infectious disease to improve patient treatment and to understand the fundamental mechanisms of how the immune system functions to fight infection. We use a diverse set of experimental models to understand human disease and collaborate with physicists, clinicians and engineers. This PhD position will give you the opportunity to learn a range of techniques and skills in biomedical research as well as broader training in research science. As an iCASE PhD student you will have the additional opportunity of working with MedImmune and seeing the benefits of partnering academic research with the development new treatments in industry.