Macrophage sabotage: undermining macrophage signalling by Klebsiella pneumoniae

在英国，呼吸道感染是传染病死亡和发病的主要原因，每年影响大约1%的成年人口。由于人口老龄化、免疫抑制患者人数增加和耐多药微生物，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越来越普遍，特别是肺炎克雷伯菌（本项目的重点），仅在英国，过去五年中发病率就增加了12%。鉴于对通常推荐用于克雷伯氏菌治疗的经验性抗生素的高耐药率，这尤其令人担忧。事实上，对“最后手段”抗微生物药物有耐药性的菌株越来越多地进行隔离，已大大缩小或在某些情况下完全消除了治疗克雷伯氏菌感染的治疗选择。不幸的是，目前，我们无法确定用于治疗多药克雷伯氏菌感染的候选化合物。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型例子。此外，肺炎克雷伯菌在分子和细胞水平上的发病机制尚缺乏证据。开发新的治疗策略需要更好地了解肺炎克雷伯菌在细菌病原体与其宿主之间复杂相互作用背景下的病理生理。一个多世纪以来，巨噬细胞一直是免疫研究的核心，是先天免疫的一个组成部分。毫不奇怪，巨噬细胞在体内清除肺炎克雷伯菌中也起着关键作用。然而，在一项里程碑式的实验室贡献中，我们发现肺炎克雷伯菌在巨噬细胞内存活，因此表明克雷伯菌可能利用巨噬细胞来提高其存活率，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，我们将全面了解肺炎克雷伯菌在肺炎期间操纵巨噬细胞存活的策略。此外，通过建立这个知识平台，我们还着手提供证据证明这种毒力策略的拮抗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/或被病原体劫持的信号通路是一种特别引人注目的方法，因为人们认为，与旨在杀死病原体或阻止其生长的传统策略相比，这种方法对耐药性的产生施加的选择性压力更小。已经有批准用于人类的药物可能针对克雷伯氏菌的毒力策略。从药物发现的角度来看，这大大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。总之，我们设想我们的结果将鼓励其他学者和制药公司遵循这一研究途径，以解决缺乏对抗生素耐药微生物治疗的问题。

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.