Macrophage sabotage: undermining macrophage signalling by Klebsiella pneumoniae

巨噬细胞破坏：肺炎克雷伯菌破坏巨噬细胞信号传导

• 批准号: BB/P006078/1
• 负责人: Jose Bengoechea
• 金额: $ 63.39万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FP006078%2F1
• 关键词: Macrophage; sabotage; undermining; macrophage; signalling

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.

呼吸道感染是英国传染病死亡率和发病率的主要原因，每年影响约 1% 的成年人口。由于人口老龄化、免疫抑制患者数量不断增加和多重耐药微生物，这种健康负担日益加重。特别值得关注的是，革兰氏阴性菌引起的呼吸道感染患病率不断上升，特别是肺炎克雷伯菌（本项目的重点），仅在英国，过去五年发病率就增加了 12%。考虑到通常推荐用于克雷伯菌治疗的经验性抗生素的耐药率很高，这一点尤其令人担忧。事实上，对“最后手段”抗菌药物耐药的菌株的日益分离已经显着缩小了克雷伯氏菌感染的治疗选择，或者在某些情况下完全消除了治疗选择。不幸的是，目前我们无法确定处于后期开发阶段的候选化合物用于治疗多药克雷伯氏菌感染；这种病原体是未满足的医疗需求与当前抗菌药物研发渠道之间不匹配的典型例子。此外，在分子和细胞水平上关于肺炎克雷伯菌发病机制的证据仍然很少。新治疗策略的开发需要在细菌病原体与其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，是先天免疫的一个组成部分。毫不奇怪，巨噬细胞在体内肺炎克雷伯菌的清除中也发挥着关键作用。然而，在实验室的一项具有里程碑意义的贡献中，我们发现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，证明这种毒力策略的拮抗将有利于病原体的清除。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，它对耐药性的发展施加的选择性压力较小。已经有一些药物被批准用于人类，这些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，这显着规避了药物开发过程，从而实现了从基础研究到临床开发的潜在快速过渡。总而言之，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，以解决缺乏抗生素耐药微生物疗法的问题。

项目成果

A Porcine Ex Vivo Lung Perfusion Model To Investigate Bacterial Pathogenesis

• DOI: 10.1128/mbio.02802-19
• 发表时间: 2019-11-01
• 期刊: MBIO
• 影响因子: 6.4
• 作者: Dumigan, Amy;Fitzgerald, Marianne;Bengoechea, Jose A.
• 通讯作者: Bengoechea, Jose A.

In vivo single-cell transcriptomics reveal Klebsiella pneumoniae skews lung macrophages to promote infection.

• DOI: 10.15252/emmm.202216888
• 发表时间: 2022-12-07
• 期刊: EMBO MOLECULAR MEDICINE
• 影响因子: 11.1
• 作者: Dumigan, Amy;Cappa, Oisin;Morris, Brenda;Pessoa, Joana Sa;Calderon-Gonzalez, Ricardo;Mills, Grant;Lancaster, Rebecca;Simpson, David;Kissenpfennig, Adrien;Bengoechea, Jose A.
• 通讯作者: Bengoechea, Jose A.

Natural killer cell-intrinsic type I IFN signaling controls Klebsiella pneumoniae growth during lung infection.

• DOI: 10.1371/journal.ppat.1006696
• 发表时间: 2017-11
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Ivin M;Dumigan A;de Vasconcelos FN;Ebner F;Borroni M;Kavirayani A;Przybyszewska KN;Ingram RJ;Lienenklaus S;Kalinke U;Stoiber D;Bengoechea JA;Kovarik P
• 通讯作者: Kovarik P

2-Hydroxylation of Acinetobacter baumannii Lipid A Contributes to Virulence

• DOI: 10.1128/iai.00066-19
• 发表时间: 2019-04-01
• 期刊: INFECTION AND IMMUNITY
• 影响因子: 3.1
• 作者: Bartholomew, Toby L.;Kidd, Timothy J.;Bengoechea, Jose A.
• 通讯作者: Bengoechea, Jose A.