Molecular characterisation of bacterium-macrophage interactions: immune evasion, host-specificity and therapeutic potential

细菌感染的早期阶段是细菌和先天免疫细胞之间的关键“战场”，其结果通常决定感染或清除。因此，细菌病原体已经进化出许多复杂的机制来对抗嗜中性粒细胞和巨噬细胞的吞噬作用。金黄色葡萄球菌是一种全球主要的人类和牲畜病原体，与一系列疾病有关，从人类的皮肤感染和坏死性肺炎、反刍动物的乳腺炎到鸡的关节感染。重要的是，金黄色葡萄球菌的多重耐药菌株已经出现并在人类和动物中全球传播，限制了有效治疗的选择。迫切需要发现新的治疗靶点以减少我们对抗生素的依赖。金黄色葡萄球菌可以产生一系列专门针对先天免疫反应的分子，我们最近已经确定并表征了一类毒素的原型，这些毒素与白细胞上的特定受体结合以抑制吞噬。该毒素对淋巴细胞和白细胞类型具有多种不同的活性，在感染的实验模型中是一个毒力因子。我们现在已经确定了几种由金黄色葡萄球菌菌株产生的相关分泌蛋白，这些蛋白对不同宿主具有致病性，它们与先天免疫细胞相互作用，可能有助于特定宿主的存活。在一个跨学科项目中使用最先进的技术，该项目将涉及蛋白质与人、牛、猪和鸡来源的巨噬细胞的分子相互作用的特征。特别是宿主特异性的相互作用和来自不同宿主物种的先天免疫细胞的差异反应，将被检查。此外，将在适当的感染模型中检查蛋白质在发病机制中的作用。总的来说，该项目将为主要细菌病原体避免被吞噬细胞杀死的能力提供新的见解，并在人类和牲畜宿主物种中建立感染。此外，将测试细菌蛋白用作疫苗成分或作为新疗法靶点的潜力。该项目是跨学科的，受益于领先的细菌病原体和巨噬细胞生物学家的指导，成功的候选人将接受免疫学，细菌发病机制和宿主-病原体相互作用方面的广泛培训。罗斯林研究所和爱丁堡大学总体上为开展传染病分子发病机制的研究提供了良好的环境，拥有世界一流的科学家，出色的支持和培训机会。也有可能在欧洲或美国的合作实验室进行短期培训实习。

The early stages of bacterial infections represent a critical 'battle-ground' between bacteria and innate immune cells, the outcome of which often determines infection or clearance. Accordingly, bacterial pathogens have evolved numerous sophisticated mechanisms for counteracting phagocytic killing by neutrophils and macrophages. Staphylococcus aureus is a major global human and livestock pathogen associated with an array of diseases from skin infections and necrotising pneumonia in humans, mastitis in ruminants, to joint infections in chickens. Importantly, multi-drug resistant strains of S. aureus have emerged and disseminated globally in humans and animals, limiting the options for effective treatment. The identification of novel therapeutic targets to reduce our dependence on antibiotics is urgently required. S. aureus can produce an array of molecules which specifically target the innate immune response and we have recently identified and characterised the prototype of a family of toxins which bind to specific receptors on leucocytes to inhibit phagocytosis. The toxin has multiple distinct activities for lymphocyte and leucocyte cell types and is a virulence factor in in an experimental model of infection. We have now identified several related secreted proteins made by S. aureus strains pathogenic for different host species that interact with innate immune cells and likely contribute to survival in specific hosts. Using state-of-the-art techniques in an interdisciplinary project, the project will involve characterisation of the molecular interaction of the proteins with macrophages of human, bovine, porcine and chicken origin. In particular the host-specificity of the interactions and the differential response of the innate immune cells from different host species, will be examined. Furthermore, the role in pathogenesis of the proteins will be examined in appropriate models of infection. Overall, the project will provide new insights into the capacity of a major bacterial pathogen to avoid killing by phagocytes, and to establish infections in human and livestock host species. In addition, the potential for the bacterial proteins to be used as vaccine components or to represent targets for novel therapeutics, will be tested. The project is interdisciplinary , benefiting from supervision by leading bacterial pathogen and macrophage biologists, and the successful candidate will receive a broad training in immunology, bacterial pathogenesis and host-pathogen interactions. The Roslin Institute and the University of Edinburgh in general is an outstanding environment to carry out research into the molecular pathogenesis of infectious diseases with world-leading scientists, excellent support and training opportunities. There will also be the potential for short-term training internships in collaborating laboratories in Europe or the USA.