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

巨噬细胞是直接杀死微生物的效应细胞，也是协调更广泛免疫反应的调节细胞。由于巨噬细胞功能的复杂性，它们在感染和炎症过程中的不同作用如何整合仍然知之甚少。越来越多的患者患有免疫功能低下、慢性炎症性疾病和抗菌素耐药性的威胁，这意味着需要新的和改进的治疗方法来调节巨噬细胞的功能。该项目是谢菲尔德大学约翰斯顿实验室与工业合作伙伴医学免疫((http://johnstonlab.group.shef.ac.uk/index.html))(https://www.medimmune.com/)，)合作的项目，该项目将使用我们的体外肺成像方法来解决感染和炎症期间巨噬细胞功能的问题。我们最近已经表明，IL-33-ST2轴在调节单核细胞分化和替代激活的巨噬细胞介导的上皮修复过程中扮演着非多余的角色(Dagner等人，修订，NAT免疫学)。此外，COPD患者的巨噬细胞显示出巨噬细胞吞噬功能缺陷，这可能是这些患者反复加重的潜在原因，而反复加重与疾病进展有关。我们希望扩大这些观察范围，并确定在肺部感染期间，IL-33-ST2途径是否需要有效的单核/巨噬细胞募集、分化和功能。我们将使用已建立的体内感染挑战研究(例如金黄色葡萄球菌、肺炎链球菌、新型隐球菌和流感鼻腔吸入途径肺部感染)，并结合体外肺的实时荧光成像。我们将使用荧光标记的抗体(例如。CCR2；ST2；MHCII；Ly6C；CD3；CD4；CD11c)来标记和区分招募和分化的免疫细胞。我们将通过时间推移成像测量巨噬细胞的吞噬能力、细胞内杀伤和病原体生长来评估巨噬细胞的反应。这个博士职位提供了在谢菲尔德大学充满活力和成功的生物医学研究实验室工作的机会，并在我们的合作伙伴MedImmune至少有三个月的工业安置。约翰斯顿实验室专注于研究传染病，以改善患者的治疗，并了解免疫系统如何发挥作用以对抗感染的基本机制。我们使用一套不同的实验模型来了解人类疾病，并与物理学家、临床医生和工程师合作。这个博士职位将使你有机会学习生物医学研究中的一系列技术和技能，以及更广泛的研究科学培训。作为一名iCASE博士生，您将有更多的机会与MedImmune合作，并看到学术研究与工业新疗法开发的合作所带来的好处。

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.