Klebsiella anti-immunology: exploiting proteins with a eukaryotic SEFIR domain

克雷伯氏菌抗免疫学：利用具有真核 SEFIR 结构域的蛋白质

• 批准号: BB/T001976/1
• 负责人: Jose Bengoechea
• 金额: $ 66.3万
• 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: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT001976%2F1
• 关键词: Klebsiella; anti; immunology; exploiting; proteins

Our struggle against infectious diseases is far from over. Globalization has increased the risk of pandemics, and the rise of antibiotic-resistant microbes threatens to render existing drugs useless. Public Health England has calculated that the lack of effective antibiotics will render more than the three million operations and cancer treatments life threatening, and more than 90,000 people are estimated to die in the UK over the next 30 years due to antibiotic resistant infections. 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. Not surprisingly, 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. 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. Worryingly, recent studies have alerted that several Klebsiella virulent and multidrug resistant isolates have access to a mobile pool of virulence and antimicrobial resistance genes; hence making possible the emergence of a multidrug resistant, hypervirulent K. pneumoniae isolate capable of causing untreatable infections in healthy individuals. However, our understanding of Klebsiella pathogenesis still contains considerable gaps thereby making a compelling case to better understand Klebsiella infection biology in the context of the complex interactions between bacterial pathogens and their hosts.In this proposal, by combining the distinct but synergistic expertise across the disciplines of molecular and cellular microbiology, immunology and biochemsitry of the Bengoechea, Moynagh and Schroeder laboratories, we will uncover a hitherto unknown Klebsiella immune evasion strategy directed to blunt IL17-governed host defenses, which have been shown to be essential for the clearance of Klebsiella infections. Our research will reveal that this immune evasion strategy also attenuates host defense signalling launched upon activation of the receptors implicated in sensing infections. Collectively, this proposal will shed new light into the sophisticated means exploited by pathogens to overcome host defenses while opening new opportunities to develop 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 is extensive research on the pathways targeted by Klebsiella, and new drugs are currently under development. We anticipate that the outcomes of this proposal would lead to test these drugs in pre-clinical models of klebsiella disease, hence allowing a potential fast-track transition from the basic research to clinical development.

我们与传染病的斗争还远未结束。全球化增加了流行病的风险，而抗药性微生物的增加有可能使现有药物失效。英国公共卫生部计算，缺乏有效的抗生素将使300多万例手术和癌症治疗危及生命，预计未来30年英国将有9万多人死于抗生素耐药性感染。特别值得关注的是，由革兰氏阴性菌引起的呼吸道感染的患病率不断上升，特别是肺炎克雷伯菌（本项目的重点），仅在英国，过去五年的发病率就增加了12%。考虑到对通常推荐用于克雷伯菌治疗的经验性抗生素的高耐药性，这尤其令人担忧。事实上，对“最后手段”抗微生物剂耐药的菌株的分离增加已经显著缩小或在某些情况下完全消除了用于治疗克雷伯氏菌属感染的治疗选择。毫不奇怪，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。不幸的是，目前，我们无法确定用于治疗多药克雷伯菌感染的后期开发的候选化合物;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范。令人担忧的是，最近的研究已经警告说，几个克雷伯氏菌毒性和多药耐药分离株有机会获得一个移动的池的毒力和抗生素耐药基因，因此可能出现的多药耐药，高毒力的K。肺炎分离株，能够在健康个体中引起不可治疗的感染。然而，我们对克雷伯氏菌致病机理的理解仍然存在相当大的差距，因此，在细菌病原体与其宿主之间复杂相互作用的背景下，更好地理解克雷伯氏菌感染生物学是一个令人信服的案例。在这一提议中，通过结合本戈切亚、莫伊纳和施罗德实验室在分子和细胞微生物学、免疫学和生物化学等学科独特但协同的专业知识，我们将揭示一种迄今为止未知的克雷伯氏菌免疫逃避策略，该策略旨在削弱IL 17控制的宿主防御，这已被证明是清除克雷伯氏菌感染所必需的。我们的研究将揭示，这种免疫逃避策略也会减弱宿主防御信号，这些信号是在激活与感知感染有关的受体时发出的。总的来说，这一提议将为病原体克服宿主防御所利用的复杂手段提供新的启示，同时为开发新的抗微生物疗法开辟新的机会。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。对克雷伯氏菌靶向的途径进行了广泛的研究，目前正在开发新药。我们预计，该提案的结果将导致在克雷伯氏菌病的临床前模型中测试这些药物，从而允许从基础研究到临床开发的潜在快速过渡。

项目成果

In vivo single-cell high-dimensional mass cytometry analysis to track the interactions between Klebsiella pneumoniae and myeloid cells

• DOI: 10.1371/journal.ppat.1011900
• 发表时间: 2024-04-01
• 期刊: PLOS PATHOGENS
• 影响因子: 6.7
• 作者: Calderon-Gonzalez，Ricardo;Dumigan，Amy;Bengoechea，Jose A.
• 通讯作者: Bengoechea，Jose A.

Cooperative action of SP-A and its trimeric recombinant fragment with polymyxins against Gram-negative respiratory bacteria.

• DOI: 10.3389/fimmu.2022.927017
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3

Type I interferons drive MAIT cell functions against bacterial pneumonia

I 型干扰素驱动 MAIT 细胞对抗细菌性肺炎的功能

• DOI: 10.25418/crick.23799003
• 发表时间: 2023
• 作者: López-Rodríguez J

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.

Type I interferons drive MAIT cell functions against bacterial pneumonia.

• DOI: 10.1084/jem.20230037
• 发表时间: 2023-10-02
• 期刊: JOURNAL OF EXPERIMENTAL MEDICINE
• 影响因子: 15.3
• 作者: Lopez-Rodriguez, Juan Carlos;Hancock, Steven J.;Li, Kelin;Crotta, Stefania;Barrington, Christopher;Suarez-Bonnet, Alejandro;Priestnall, Simon L.;Aube, Jeffrey;Wack, Andreas;Klenerman, Paul;Bengoechea, Jose A.;Barral, Patricia
• 通讯作者: Barral, Patricia