Klebsiella pneumoniae type VI secretion system: a weapon for innate immunity warfare

VI型肺炎克雷伯菌分泌系统：先天免疫战的武器

• 批准号: BB/N00700X/1
• 负责人: Jose Bengoechea
• 金额: $ 55.84万
• 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: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN00700X%2F1
• 关键词: Klebsiella; pneumoniae; type; VI; secretion

The global problem of antimicrobial resistance (AMR) is fast becoming one of the major scientific and health issues of modern times. No surprisingly, AMR is included in the recently release UK government "National Risk Register of Civil Emergencies" that may directly affect the UK over the next 5 years. More than 80,000 deaths are estimated if there is a widespread outbreak of a resistant microbe. The development of new antibiotics is slow and difficult work but bacterial resistance is decreasing our arsenal of existing drugs. A post-antibiotic era - in which common infections and minor injuries can kill - far from being an apocalyptic fantasy, is a very real possibility for the 21st Century. The recent O'Neill review on AMR sets out the global threat by highliting that "drug-resistant infections already kill hundreds of thousands a year globally, and by 2050 that figure could be more than 10 million". Of particular concern is the mounting prevalence of infections caused by multidrug resistant Gram-negative bacteria, in particular Klebsiella pneumoniae. This pathogen has been singled out as an "urgent threat to human health" by the UK Government, the U.S. Centers for Disease Control and Prevention, and the World Health Organization due to extremely drug resistant strains. However, there is scant evidence on K. pneumoniae pathogenesis at the molecular and cellular level. Therefore, it is both urgent and necessary to better understand its pathophysiology to be able to design new strategies to treat Klebsiella infections.Previous studies from the laboratory support the notion that Klebsiella subverts the activation of host defence mechanisms to survive in the lung. While we have progressed on understanding the cellular pathways manipulated by the pathogen to block inflammation, there is a major gap on decoding the anti-immune factors employed by Klebsiella. By applying a multidisciplinar approach encompassing cellular and molecular microbiology, innate immunity, structural bioinformatics; and exploiting Saccharomyces cerevisiae to express heterologous proteins, we will embark on harnessing basic knowledge about how Klebsiella pneumoniae type VI secretion system (T6SS)-delivered effectors block the activation of cell intrinsic immunity. T6SS is a recently discovered nanomachinery that bacteria use to deliver proteins to a recipient cell (either a competitor bacteria and/or an eukaryotic cell). We will characterize Klebsiella T6SS at the molecular level. We will dissect how T66S-delivered proteins antagonize the activation of the signalling pathway controlling the majority of host defense responses upon infection. And, finally, we will illuminate a hithertho unknown Klebsiella virulence strategy based on targeting mitochondrial dynamics.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. It is therefore believed that such targets - if found and validated during the research - will meet big interest at pharmaceutical companies.

全球抗菌素耐药性（AMR）问题正迅速成为现代主要的科学和健康问题之一。不出意外，AMR被列入英国政府最近发布的《国家民事紧急情况风险登记册》，可能会在未来5年直接影响英国。如果耐药微生物大范围爆发，预计将导致超过 80,000 人死亡。新抗生素的开发是一项缓慢而艰巨的工作，但细菌耐药性正在减少我们现有的药物库。后抗生素时代——常见的感染和轻伤就可以致命——远非世界末日的幻想，而是 21 世纪非常现实的可能性。奥尼尔最近对 AMR 的评论指出了全球威胁，强调“耐药性感染每年已导致全球数十万人死亡，到 2050 年，这一数字可能超过 1000 万”。特别值得关注的是由多重耐药革兰氏阴性菌（特别是肺炎克雷伯菌）引起的感染流行率不断上升。由于这种病原体具有极强的耐药性，英国政府、美国疾病控制与预防中心和世界卫生组织已将这种病原体列为“对人类健康的紧急威胁”。然而，在分子和细胞水平上关于肺炎克雷伯菌发病机制的证据很少。因此，更好地了解其病理生理学以便能够设计治疗克雷伯氏菌感染的新策略既紧迫又必要。实验室之前的研究支持克雷伯氏菌破坏宿主防御机制的激活以在肺部生存的观点。虽然我们在了解病原体控制炎症的细胞途径方面取得了进展，但在解码克雷伯氏菌所使用的抗免疫因子方面仍存在重大差距。通过应用涵盖细胞和分子微生物学、先天免疫、结构生物信息学的多学科方法；并利用酿酒酵母表达异源蛋白，我们将着手利用有关肺炎克雷伯菌 VI 型分泌系统 (T6SS) 传递的效应子如何阻断细胞内在免疫激活的基础知识。 T6SS 是一种最近发现的纳米机械，细菌用它来将蛋白质传递到受体细胞（竞争细菌和/或真核细胞）。我们将在分子水平上表征克雷伯菌 T6SS。我们将剖析 T66S 传递的蛋白质如何拮抗感染时控制大多数宿主防御反应的信号通路的激活。最后，我们将阐明一种迄今为止未知的基于线粒体动力学的克雷伯氏菌毒力策略。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，它对耐药性发展施加的选择性压力较小。因此，人们相信，如果在研究过程中发现并验证这些目标，将会引起制药公司的极大兴趣。

项目成果

Meeting report - Cell dynamics: host-pathogen interface.

会议报告 - 细胞动力学：宿主-病原体界面。

• DOI: 10.1242/jcs.260456
• 发表时间: 2022
• 期刊: Journal of cell science
• 影响因子: 4
• 作者: Odendall C

A Klebsiella pneumoniae antibiotic resistance mechanism that subdues host defences and promotes virulence.

• DOI: 10.15252/emmm.201607336
• 发表时间: 2017-04
• 期刊: EMBO molecular medicine
• 影响因子: 11.1
• 作者: Kidd TJ;Mills G;Sá-Pessoa J;Dumigan A;Frank CG;Insua JL;Ingram R;Hobley L;Bengoechea JA
• 通讯作者: Bengoechea JA

A trans-kingdom T6SS effector induces the fragmentation of the mitochondrial network and activates innate immune receptor NLRX1 to promote infection.

• DOI: 10.1038/s41467-023-36629-3
• 发表时间: 2023-02-16
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Sa-Pessoa, Joana;Lopez-Montesino, Sara;Przybyszewska, Kornelia;Rodriguez-Escudero, Isabel;Marshall, Helina;Ova, Adelia;Schroeder, Gunnar N.;Barabas, Peter;Molina, Maria;Curtis, Tim;Cid, Victor J.;Bengoechea, Jose A.
• 通讯作者: Bengoechea, Jose A.

Klebsiella pneumoniae type VI secretion system-mediated microbial competition is PhoPQ controlled and reactive oxygen species dependent

• DOI: 10.1101/698415
• 发表时间: 2019-07
• 期刊: PLoS Pathogens
• 影响因子: 6.7
• 作者: Danielle Storey;A. McNally;M. Åstrand;Joana Sá-Pessoa Graca Santos;I. Rodríguez-Escudero;Bronagh Elmore;Leyre Palacios;H. Marshall;L. Hobley;M. Martin;V. J. Cid;T. Salminen;J. Bengoechea

Klebsiella pneumoniae type VI secretion system-mediated microbial competition is PhoPQ controlled and reactive oxygen species dependent.

VI 型肺炎克雷伯菌分泌系统介导的微生物竞争受 PhoPQ 控制且依赖于活性氧。

• DOI: 10.1371/journal.ppat.1007969
• 发表时间: 2020
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Storey D