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

抗菌素耐药性（AMR）的全球性问题正在迅速成为现代主要的科学和健康问题之一。毫不奇怪，AMR被列入英国政府最近发布的“国家突发事件风险登记册”，可能在未来5年内直接影响英国。如果耐药微生物大范围爆发，估计将有8万多人死亡。新抗生素的开发是缓慢而困难的工作，但细菌耐药性正在减少我们现有的药物库。后抗生素时代--普通感染和轻微伤害都可能致命--远非世界末日的幻想，而是21世纪非常真实的可能性。奥尼尔最近对AMR的评论指出了全球的威胁，强调“耐药感染每年已经在全球范围内杀死数十万人，到2050年，这一数字可能超过1000万”。特别令人关切的是，由多重耐药革兰氏阴性菌，特别是肺炎克雷伯氏菌引起的感染的流行率不断上升。这种病原体已被英国政府、美国疾病控制和预防中心和世界卫生组织列为“对人类健康的紧迫威胁”，因为它具有极强的耐药性。然而，关于K的证据很少。在分子和细胞水平上研究肺炎的发病机制。因此，更好地了解其病理生理学是迫切和必要的，以便能够设计新的策略来治疗克雷伯氏菌感染。来自实验室的先前研究支持克雷伯氏菌破坏宿主防御机制的激活以在肺中存活的概念。虽然我们在理解病原体操纵的细胞通路以阻断炎症方面取得了进展，但在解码克雷伯氏菌所采用的抗免疫因子方面存在重大差距。通过应用多学科的方法，包括细胞和分子微生物学，先天免疫，结构生物信息学;并利用酿酒酵母表达异源蛋白，我们将着手利用关于克雷伯氏肺炎菌VI型分泌系统（T6 SS）传递的效应子如何阻断细胞内在免疫激活的基本知识。T6 SS是最近发现的一种纳米机器人，细菌用来将蛋白质递送到受体细胞（竞争细菌和/或真核细胞）。我们将在分子水平上表征克雷伯氏菌T6 SS。我们将剖析如何T66 S交付的蛋白质拮抗激活的信号通路控制大多数宿主的防御反应感染后。最后，我们将阐明一个迄今为止未知的克雷伯氏菌毒力策略的基础上靶向线粒体dynamics. Harizing宿主-病原体接口开辟了新的抗菌治疗的途径。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。因此，人们相信，如果在研究过程中发现并验证这些目标，将满足制药公司的巨大兴趣。

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.