Characterization of Klebseilla pneumoniae T6SS nanoweapon and its role in the dissemination of antimicrobial genes and virulence factors.

肺炎克雷伯氏菌 T6SS 纳米武器的表征及其在抗菌基因和毒力因子传播中的作用。

• 批准号: BB/V007939/1
• 负责人: Jose Bengoechea
• 金额: $ 67.18万
• 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: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV007939%2F1
• 关键词: Characterization; Klebseilla; pneumoniae; T6SS; nanoweapon

Our struggle against infectious diseases is far from over. Globalisation has increased the risk of pandemics, and the rise of antibiotic-resistant microbes threatens to render existing drugs useless. Of particular concern is the health burden of respiratory infections being the UK in the top 25 countries for deaths from acute respiratory infections, above most other European countries. Of great concern is the mounting prevalence of respiratory infections caused by Gram-negative bacteria, in particular Klebsiella pneumoniae (the focus of this project). Worryingly, there are reports showing a 15% increased in incidence of Klebsiella infections 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. More than a third of the K. pneumoniae isolates reported to the European Centre for Disease Prevention and Control were resistant to at least one antimicrobial group, being the most common resistance phenotype the combined resistance to fluoroquinolones, third-generation cephalosporins and aminoglycosides. Of note, in Klebsiella, like in other microbes, the transfer of antimicrobial resistance genes occurs via sharing plasmids between different microbes. Epidemiological studies have demonstrated that Klebsiella strains have access to a mobile pool of antimicrobial genes and virulence factors, enabling the emergence of a multidrug, hypervirulent K. pneumoniae clone capable of causing untreatable infections in healthy individuals. Not surprisingly, Klebsiella 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. Recently, the Bengoechea laboratory has demonstrated that K. pneumoniae employs a nanowaepon, the type VI secretion system (T6SS), to antagonize other microbes. Therefore, the antimicrobial action of the T6SS is at odds with the dissemination of antimicrobial genes and virulence factors. In this project, our research will uncover how Klebsiella resolves the conflict between the transfer of genetic material and the activity of the T6SS. We will also provide new insights into the T6SS assemblies that Klebsiella produces to deliver the antimicrobial toxins to other bacteria, and identify the portfolio of toxins that Klebsiella deploys. We will also highlight a hitherto unknown connection between the T6SS and the lipopolysaccharide, a glycolipid located in the surface of all Gram-negative bacteria. A better understanding of the barriers and limitations of the transfer of material between microbes is invaluable to predict outbreaks of resistant microbes in the health care setting, and may result in developing new therapeutics to limit the process. In addition, our research will provide a global vision of the antimicrobial strategies deployed by Klebsiella. Finding new toxins and determining their mechanisms of action shall be a gold mine of usable antibacterial targets that pharmaceutical companies could consider to develop much needed new drugs against multidrug resistant infections.

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，而抗生素耐药微生物的增加可能使现有药物变得毫无用处。特别值得关注的是呼吸道感染的健康负担，英国是急性呼吸道感染死亡人数最多的 25 个国家之一，高于大多数其他欧洲国家。令人高度关注的是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）。令人担忧的是，有报告显示，过去五年里，仅在英国，克雷伯氏菌感染的发病率就增加了 15%。鉴于对通常推荐用于克雷伯氏菌治疗的经验性抗生素的耐药率很高，这一点尤其令人震惊。欧洲疾病预防和控制中心报告的肺炎克雷伯菌分离株中，超过三分之一对至少一种抗菌药物具有耐药性，这是最常见的耐药表型，即对氟喹诺酮类、第三代头孢菌素和氨基糖苷类药物的联合耐药。值得注意的是，在克雷伯氏菌中，与其他微生物一样，抗菌素耐药性基因的转移是通过不同微生物之间共享质粒而发生的。流行病学研究表明，克雷伯氏菌菌株能够获得可移动的抗菌基因和毒力因子库，从而能够出现一种多药、高毒力的肺炎克雷伯氏菌克隆，能够在健康个体中引起无法治疗的感染。毫不奇怪，克雷伯氏菌因其极度耐药的菌株而被英国政府、美国疾病控制与预防中心和世界卫生组织列为“对人类健康的紧急威胁”。最近，Bengoechea 实验室证明肺炎克雷伯菌利用纳米武器，即 VI 型分泌系统 (T6SS) 来对抗其他微生物。因此，T6SS 的抗菌作用与抗菌基因和毒力因子的传播不一致。在这个项目中，我们的研究将揭示克雷伯菌如何解决遗传物质转移和 T6SS 活性之间的冲突。我们还将提供有关克雷伯氏菌生产的 T6SS 组件的新见解，该组件可将抗菌毒素传递给其他细菌，并确定克雷伯氏菌部署的毒素组合。我们还将强调 T6SS 和脂多糖（一种位于所有革兰氏阴性细菌表面的糖脂）之间迄今为止未知的联系。更好地了解微生物之间物质转移的障碍和限制对于预测医疗保健环境中耐药微生物的爆发非常有价值，并且可能导致开发新的疗法来限制这一过程。此外，我们的研究将为克雷伯氏菌部署的抗菌策略提供全球视野。寻找新的毒素并确定其作用机制将成为可用抗菌靶点的金矿，制药公司可以考虑开发急需的针对多重耐药感染的新药。

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.

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

体内单细胞高维质谱流式分析追踪肺炎克雷伯菌与骨髓细胞之间的相互作用。

• DOI: 10.1101/2023.12.14.571618
• 发表时间: 2023
• 作者: Calderon-Gonzalez R

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.

Modelling the gastrointestinal carriage of Klebsiella pneumoniae infections

肺炎克雷伯菌感染的胃肠道运输模型

• DOI: 10.1101/2022.10.03.510744
• 发表时间: 2022
• 作者: Calderon-Gonzalez R