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

我们与传染病的斗争远未结束。全球化增加了大流行的风险，抗药性微生物的崛起有可能使现有药物失效。尤其令人担忧的是，在急性呼吸道感染死亡人数最多的25个国家中，英国的呼吸道感染造成的健康负担高于其他大多数欧洲国家。因此，基于新的概念和方法开发新的治疗方法是迫切和必要的。这在克雷伯氏菌感染的情况下尤其重要，仅在英国，在过去五年中，克雷伯菌感染的发病率增加了12%。事实上，越来越多的耐“最后手段”抗菌素菌株的分离已经大大缩小了治疗克雷伯氏菌感染的选择范围，甚至在某些情况下完全取消了这一选择。不幸的是，目前，我们还不能在治疗多药克雷伯氏菌感染的后期开发中确定候选化合物；这种病原体是未得到满足的医疗需求与当前抗菌素研发管道之间不匹配的典范。令人担忧的是，最近的研究已经认识到，几个克雷伯氏菌毒力和多药耐药分离株可以访问毒力和抗菌素耐药基因库；因此，可能出现多药耐药、超强毒力的肺炎克雷伯菌分离株，能够在健康个体中造成无法治疗的感染。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提供了一个引人注目的案例。在这项建议中，通过结合本戈切亚(英国)和鲍伊(爱尔兰)实验室在分子和细胞微生物学、生物化学和免疫学领域独特但协同的专业知识和经验，我们将更好地了解宿主防御的各种跟腱，从而更准确地支撑这些脆弱的热点，同时解构克雷伯氏菌在感染组织中生存所使用的策略。我们的努力将揭示一种基于参与抗菌防御的增选功能(受体和免疫信号)的克雷伯氏菌抗免疫策略。这一显着的策略与其他经过充分研究的细菌病原体使用的策略截然不同，后者扰乱了宿主的防御，而不是像克雷伯氏菌那样劫持它们。利用宿主-病原体界面为新的抗菌疗法开辟了道路。干扰病原体的毒力和/或被病原体为了自身利益劫持的信号通路是一种特别引人注目的方法，因为与旨在杀死病原体或防止其生长的传统策略相比，这被认为对发展抗药性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，这项提议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。

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.