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

我们与传染病的斗争远未结束。全球化增加了流行病的风险，耐抗生素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出，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，估计在未来30年里，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越来越普遍，特别是肺炎克雷伯菌（本项目的重点），仅在英国，过去五年中发病率就增加了12%。鉴于对通常推荐用于克雷伯氏菌治疗的经验性抗生素的高耐药率，这尤其令人担忧。事实上，对“最后手段”抗微生物药物有耐药性的菌株越来越多地进行隔离，已大大缩小或在某些情况下完全消除了治疗克雷伯氏菌感染的治疗选择。毫不奇怪，这种病原体被英国政府、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”，原因是其菌株具有极强的耐药性。不幸的是，目前，我们无法确定用于治疗多药克雷伯氏菌感染的候选化合物。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型例子。令人担忧的是，最近的研究提醒人们，一些克雷伯氏菌强毒和耐多药分离株可以进入一个流动的毒力和抗微生物药物耐药性基因库；因此，有可能出现多药耐药、高毒力肺炎克雷伯菌分离物，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，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。在本提案中，通过结合Bengoechea， Moynagh和Schroeder实验室的分子和细胞微生物学，免疫学和生物化学等学科的独特但协同的专业知识，我们将发现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，这已被证明是克雷伯氏菌感染清除所必需的。我们的研究将揭示，这种免疫逃避策略也减弱了在感知感染的受体激活时启动的宿主防御信号。总的来说，这一建议将为病原体利用复杂手段克服宿主防御提供新的线索，同时为开发新的抗菌疗法开辟新的机会。干扰病原体的毒力和/或被病原体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，这种方法对耐药性的产生施加的选择性压力更小。对克雷伯氏菌靶向的途径进行了广泛的研究，目前正在开发新的药物。我们预计这一提议的结果将导致这些药物在克雷伯氏菌病的临床前模型中进行测试，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. 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.