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远没有结束。全球化增加了大流行病的风险，抗生素耐药的微生物的兴起有可能使现有药物无用。特别令人担忧的是，呼吸道感染的健康负担是英国在急性呼吸道感染中死亡的25个国家，高于大多数其他欧洲国家。因此，基于新的概念和方法开发新的治疗剂是迫切和必要的。对于克雷伯氏菌感染的情况下，这一点尤其重要，表明仅英国在过去五年内发病率增加了12％。实际上，抗抗性抗菌药物的抗菌菌株的分离越来越明显变窄，或者在某些情况下完全消除了治疗克雷伯菌感染的治疗选择。不幸的是，目前，我们无法确定晚期发育中的候选化合物来治疗多药克雷伯菌感染。这种病原体是未满足医疗需求与当前抗菌研究和发育管道之间不匹配的典范。令人震惊的是，最近的研究已经认识到，几种毒和多药耐药株可以进入毒力和抗菌耐药基因的移动池。因此，使多种抗药性，高毒性的K.肺炎分离株的出现能够引起健康个体无法治疗的感染。但是，我们对克雷伯氏病发病机理的理解仍然包含很大的空白，从而在细菌病原体与其宿主之间复杂的相互作用的背景下，可以更好地理解克雷伯氏菌感染生物学。在这项建议中，通过结合了独特的但协同但协同的专业和经验的分子和细胞微生物学（Imbe），以及BBENGERAGY，BBENGEAGY（BBENG），以及BBENGERAGY（BB）的范围，以及BBE）的范围，以及BBE） （爱尔兰）实验室，我们将更好地了解宿主防御的各种致命弱点，从而更精确地掩盖这些脆弱的热点，同时解构克雷伯氏菌在感染组织中生存的策略。我们的努力将基于与抗菌防御有关的共同功能（受体和免疫信号），暴露基于抗毛的抗毛策略。这种非凡的策略与其他经过良好研究的细菌病原体所采用的策略完全不同，这些病原体破坏了宿主防御，而不是像克雷伯氏菌一样劫持它们。利用宿主病原体界面为新的抗菌治疗方法开辟了大街。与传统策略相比，旨在杀死病原体或防止其成长的传统策略，对病原体劫持的病原体毒力和/或信号传导途径的干扰是一种特别令人信服的方法。关于克雷伯菌（Klebsiella）瞄准的途径有广泛的研究，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，因此可以从基础研究到临床发展的潜在快速轨道过渡。

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.