Bilateral BBSRC-SFI Innate immune signalling underpinning Klebsiella-host interactions

双边 BBSRC-SFI 先天免疫信号传导支撑克雷伯氏菌与宿主相互作用

• 批准号: BB/P020194/1
• 负责人: Jose Bengoechea
• 金额: $ 59.67万
• 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%2FP020194%2F1
• 关键词: Bilateral; BBSRC; SFI; Innate; immune

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. It is therefore urgent and necessary to develop new therapeutics based on new concepts and approaches. This is particularly important in the case of Klebsiella infections showing a 12% increased incidence over the last five years within the UK alone. 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. Alarmingly, recent studies have recognized 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 and experience across the disciplines of molecular and cellular microbiology, biochemistry, and immunology, of the Bengoechea (UK) and Bowie (Ireland) laboratories we will better understand the various Achilles heels of host defense, and thereby more precisely shore-up these vulnerable hot spots while deconstructing the strategies used by Klebsiella to survive within the infected tissue. Our efforts will expose a Klebsiella anti-immune strategy based on co-opting functions (receptors and immune signals) implicated in antimicrobial defense. This remarkable strategy is radically different to those employ by other well studied bacterial pathogens which disrupt host defenses instead of hijacking them like Klebsiella. 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 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没有结束。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。因此，迫切且有必要开发基于新概念和方法的新疗法。这对于克雷伯氏菌感染而言尤其重要，仅在英国，过去五年中克雷伯氏菌感染的发病率就增加了 12%。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。令人震惊的是，最近的研究已经认识到，一些克雷伯氏菌的强毒力和多重耐药菌株能够获得毒力和抗菌素耐药基因的移动库；因此，可能出现多重耐药性、高毒力的肺炎克雷伯菌分离株，能够在健康个体中引起无法治疗的感染。然而，我们对克雷伯氏菌发病机制的理解仍然存在相当大的差距，从而为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克雷伯氏菌感染生物学提供了令人信服的理由。在本提案中，通过结合不同但协同的专业知识和经验Bengoechea（英国）和 Bowie（爱尔兰）实验室的分子和细胞微生物学、生物化学和免疫学学科，我们将更好地了解宿主防御的各种致命弱点，以及从而更精确地支撑这些脆弱的热点，同时解构克雷伯氏菌在受感染组织中生存的策略。我们的努力将揭示克雷伯氏菌基于与抗菌防御相关的选择功能（受体和免疫信号）的抗免疫策略。这种非凡的策略与其他经过深入研究的细菌病原体所采用的策略截然不同，它们破坏宿主的防御，而不是像克雷伯氏菌那样劫持宿主。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。人们对克雷伯氏菌的靶向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疾病的临床前模型中测试这些药物，从而实现从基础研究到临床开发的潜在快速过渡。

项目成果

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

Myeloid cell nuclear differentiation antigen controls the pathogen-stimulated type I interferon cascade in human monocytes by transcriptional regulation of IRF7.

• DOI: 10.1038/s41467-021-27701-x
• 发表时间: 2022-01-10
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Gu L;Casserly D;Brady G;Carpenter S;Bracken AP;Fitzgerald KA;Unterholzner L;Bowie AG
• 通讯作者: Bowie AG

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.

Klebsiella pneumoniae hijacks the Toll-IL-1R protein SARM1 in a type I IFN-dependent manner to antagonize host immunity.

• DOI: 10.1016/j.celrep.2022.111167
• 发表时间: 2022-08-09
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Feriotti, Claudia;Sa-Pessoa, Joana;Calderon-Gonzalez, Ricardo;Gu, Lili;Morris, Brenda;Sugisawa, Ryoichi;Insua, Jose L.;Carty, Michael;Dumigan, Amy;Ingram, Rebecca J.;Kissenpfening, Adrien;Bowie, Andrew G.;Bengoechea, Jose A.
• 通讯作者: Bengoechea, Jose A.