Macrophage sabotage: undermining macrophage signalling by Klebsiella pneumoniae

呼吸道感染是英国传染病死亡率和发病率的主要原因，每年影响大约1%的成年人口。由于人口老龄化、免疫抑制患者数量增加和多重耐药微生物，这种健康负担正在增加。特别值得关注的是，由革兰氏阴性菌引起的呼吸道感染的患病率不断上升，特别是肺炎克雷伯菌（本项目的重点），仅在英国，过去五年的发病率就增加了12%。考虑到对通常推荐用于克雷伯菌治疗的经验性抗生素的高耐药性，这尤其令人担忧。事实上，对“最后手段”抗微生物剂耐药的菌株的分离增加已经显著缩小或在某些情况下完全消除了用于治疗克雷伯氏菌属感染的治疗选择。不幸的是，目前，我们无法确定用于治疗多药克雷伯菌感染的后期开发的候选化合物;这种病原体是未满足的医疗需求与当前抗菌药物研发管道之间不匹配的典范。此外，K.在分子和细胞水平上研究肺炎的发病机制。新的治疗策略的发展需要更好地了解K。巨噬细胞世纪以来一直是免疫研究的核心，并且是先天免疫的组成部分。毫不奇怪，巨噬细胞在K的清除中也起着关键作用。pneumoniae in vivo.然而，在实验室的一个里程碑式的贡献，我们已经发现，K。肺炎克雷伯氏菌在巨噬细胞内存活，因此表明克雷伯氏菌可能利用巨噬细胞来增强其存活，同时避免免疫控制。在这个项目中，通过连接细胞微生物学和免疫学，我们将全面了解K。在肺炎期间操纵巨噬细胞存活。此外，通过建立这个知识平台，我们还着手提供证据，证明这种毒力策略的拮抗作用将有利于病原体清除。利用宿主-病原体界面为新的抗菌治疗开辟了道路。干扰病原体毒力和/或被病原体为了自身利益而劫持的信号通路是一种特别引人注目的方法，因为据认为，与旨在杀死病原体或防止其生长的传统策略相比，这种方法对耐药性的发展施加的选择压力较小。已经有药物被批准用于人类，可能针对这种克雷伯氏菌毒力策略。从药物发现的角度来看，这显著地规避了药物开发过程，从而允许从基础研究到临床开发的潜在快速过渡。总而言之，我们设想我们的研究结果将鼓励其他学者和制药公司遵循这一研究途径，以解决对抗生素耐药的微生物缺乏治疗方法的问题。

Respiratory infections are the leading cause of infectious disease mortality and morbidity in UK, affecting roughly 1% of the adult population per year. This health burden is increasing due to ageing of the population, growing numbers of immunosuppressed patients and multidrug-resistant microorganisms. Of particular concern is the mounting prevalence of respiratory infections caused by Gram-negative bacteria, in particular Klebsiella pneumoniae (the focus of this project), with a 12% increased in incidence in the last five years only in the UK.This is particularly alarming given the high rates of resistance to empirical antibiotics commonly recommended for Klebsiella treatment. In fact, the increasing isolation of strains resistant to "last resort" antimicrobials has significantly narrowed, or in some settings completely removed, the therapeutic options for the treatment of Klebsiella infections. Unfortunately, at present, we cannot identify candidate compounds in late-stage development for treatment of multidrug Klebsiella infections; this pathogen is exemplary of the mismatch between unmet medical needs and the current antimicrobial research and development pipeline. Furthermore, there is still scant evidence on K. pneumoniae pathogenesis at the molecular and cellular level. The development of new therapeutic strategies requires a better understanding of K. pneumoniae pathophysiology in the context of the complex interactions between bacterial pathogens and their hosts.Macrophages have been at the heart of immune research for over a century and are an integral component of innate immunity. Not surprisingly, macrophages also play a critical role in the clearance of K. pneumoniae in vivo. However, in a landmark contribution of the laboratory we have discovered that K. pneumoniae survives inside macrophages hence suggesting that Klebsiella may exploit macrophages to enhance its survival while avoiding immune control. In this project, by bridging cellular microbiology and immunology, we will gain holistic understanding of the strategies used by K. pneumoniae to manipulate macrophages to survive during pneumonia. Furthermore, and by building up upon this knowledge platform, we also set out to provide evidence demonstrating that antagonism of this virulence strategy will favour pathogen clearance. Harnessing the host-pathogen interface opens the avenue for new antimicrobial therapeutics. Interference with pathogen virulence and/or signalling pathways hijacked by pathogens for their own benefit is an especially compelling approach, as it is thought to apply less selective pressure for the development of resistance than traditional strategies, which are aimed at killing pathogens or preventing their growth. There are already drugs approved for use in humans which may target this Klebsiella virulence strategy. From the drug discovery point of view, this significantly circumvents the drug development process hence allowing a potential fast-track transition from the basic research to clinical development. Altogether, we envision that our results will encourage other academics as well as pharmaceutical companies to follow this avenue of research to tackle the problem of lack of therapies for microbes resistant to antibiotics.