Analysing antibacterial immunity from two sides: host versus pathogen

细菌感染是人类健康的一个主要问题；通常会导致危及生命的疾病和持续感染，需要广泛的抗生素治疗。沙门氏菌在人类中引起一系列疾病，从胃肠炎到伤寒，在牛等动物中也很普遍，这可能造成严重的经济后果和公共卫生影响。正常情况下，一旦感染，宿主细胞对细菌产物作出反应，激活一系列事件，最终产生分子，触发强大的免疫防御程序，使细菌失活。许多细菌，包括沙门氏菌，通过所谓的毒力因子的作用来操纵宿主的这些反应，在宿主的免疫反应和进入的病原体之间产生复杂的相互作用。该项目一方面旨在了解细菌毒力因子的产生和转运到宿主细胞中如何改变感染的结果，使其有利于病原体。我们已经确定了几种调节宿主细胞反应的毒力因子，现在我们将详细描述它们的作用机制。破译这些毒力因子如何影响感染期间的免疫信号级联反应，为了解细菌致病性提供了有价值的见解，为病原体靶向的宿主过程提供了重要信息，并可能为疫苗设计和新疗法提供有价值的信息。为了补充这一点，需要在分子细节上了解限制细菌病原体的新宿主机制的研究努力。因此，该项目还将研究被称为TRIMs的宿主分子家族（一组蛋白质）的作用。研究工作主要集中在病毒感染期间TRIM的功能，但很少有详细的研究，并且在细菌感染期间该家族的特征仍然很差。尽管如此，一些证据表明它们对宿主感染细菌有重要作用。因此，我将研究这组蛋白质对细菌感染的反应，并确定它们是否可以限制细胞内细菌的生长。这些发现将揭示这些蛋白质的新功能，其中许多蛋白质在突变时会导致疾病。最终，随着对宿主免疫反应的了解的提高，我们可以更好地了解对抗细菌感染的最佳方法。鉴于抗生素耐药细菌种类的迅速增加，这是一个重要的考虑因素。

Bacterial infections represent a major problem to human health; often causing life-threatening diseases and persistent infections that can require extensive treatment with antibiotics. Salmonella causes a range of disease in humans, from gastro-enteritis to typhoid fever and is also prevalent in animals such as cattle, which can have serious economic consequences as well as public health implications. Normally, upon infection, host cells respond to bacterial products, activating a cascade of events that culminate in the production of molecules that trigger a robust immune defence programme to inactivate the bacteria. Many bacteria, including Salmonella, manipulate these host responses by the action of so-called virulence factors, producing a complex interaction between the host immune response and the incoming pathogen. This project on the one hand aims to understand how bacterial virulence factors produced and transported into host cells alter the outcome of infection to the advantage of the pathogen. We have identified several virulence factors that modulate host cell responses and we will now characterise their mechanism of action in detail. Deciphering how these virulence factors influence immune signalling cascades during infection provides valuable insight into what makes the bacteria pathogenic, provides important information on host processes that are targeted by the pathogen and is likely to provide valuable information for vaccine design and novel therapeutics. To complement this, research efforts are required to understand in molecular detail novel host mechanisms that restrict bacterial pathogens. Therefore, this project will also investigate the role of a family of host molecules (a group of proteins) that are called TRIMs. Research efforts have focused on TRIM function during viral infection but few have been studied in detail and the family remains poorly characterised during bacterial infection. Despite this, several lines of evidence suggest they have important functions upon host infection with bacteria. Therefore, I shall study how this group of proteins responds to bacterial infection and determine whether they can restrict the growth of bacteria within cells. These findings will reveal new functions for these proteins, many of which when mutated cause disease. Ultimately, with the improved understanding of host immune responses we are better informed on the best methods to combat bacterial infection. This is an important consideration given the rapidly developing rise in antibiotic resistant bacterial species.