Macrophage sabotage: undermining macrophage signalling by Klebsiella pneumoniae

呼吸道感染是英国传染病死亡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、越来越多的免疫抑制患者和耐多药微生物，这一健康负担正在增加。特别令人关注的是，由革兰氏阴性细菌引起的呼吸道感染的流行率不断上升，特别是肺炎克雷伯氏菌(本项目的重点)，仅在英国过去五年的发病率就增加了12%。这尤其令人担忧，因为克雷伯氏菌治疗通常建议使用经验性抗生素的高耐药率。事实上，越来越多的耐“最后手段”抗菌素菌株的分离已经大大缩小了治疗克雷伯氏菌感染的选择范围，甚至在某些情况下完全取消了这一选择。不幸的是，目前，我们还不能在治疗多药克雷伯氏菌感染的后期开发中确定候选化合物；这种病原体是未得到满足的医疗需求与当前抗菌素研发管道之间不匹配的典范。此外，在分子和细胞水平上对肺炎克雷伯菌致病机制的研究还很少。新的治疗策略的发展需要在细菌病原体与宿主之间复杂的相互作用的背景下更好地了解肺炎克雷伯菌的病理生理学。一个多世纪以来，巨噬细胞一直是免疫研究的核心，是天然免疫的组成部分。毫不奇怪，巨噬细胞在体内清除肺炎克雷伯菌的过程中也发挥了关键作用。然而，在实验室的一项里程碑式的贡献中，我们发现肺炎克雷伯菌存活在巨噬细胞内，因此表明克雷伯菌可能利用巨噬细胞来提高其生存能力，同时避免免疫控制。在这个项目中，通过将细胞微生物学和免疫学联系起来，我们将全面了解肺炎克雷伯菌在肺炎期间操纵巨噬细胞生存的策略。此外，通过建立这个知识平台，我们还着手提供证据，证明拮抗这一毒力策略将有利于病原体清除。利用宿主-病原体界面为新的抗菌疗法开辟了道路。干扰病原体的毒力和/或被病原体为了自身利益劫持的信号通路是一种特别引人注目的方法，因为与旨在杀死病原体或防止其生长的传统策略相比，这被认为对发展抗药性施加的选择性压力较小。已经有被批准用于人类的药物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，这大大绕过了药物开发过程，从而实现了从基础研究到临床开发的潜在快速过渡。总之，我们预计我们的结果将鼓励其他学者以及制药公司遵循这一研究途径，以解决对抗生素耐药微生物缺乏治疗的问题。

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.