Deciphering Klebsiella pneumoniae strategies to subvert host defences

对现有抗生素产生抗药性的微生物数量不断增加，已成为全球范围内的主要公共卫生威胁。从长远来看，由于缺乏有效的治疗药物，我们可能无法治疗传染病。因此，有必要基于新的靶点和方法开发有效的治疗方法。最有希望的方法之一是开发基于宿主-微生物界面调节的创新疗法，特别是针对微生物为其自身利益而操纵宿主防御反应的策略。肺炎克雷伯氏菌是一种引起从尿路感染到肺炎的广泛感染的微生物。后者在免疫功能低下的患者中尤其具有破坏性。肺炎克雷伯菌是所谓的ESKAPE微生物组中的一员，强调他们有效地“逃避”抗菌药物的影响。因此，更好地了解克雷伯菌感染生物学是迫切和必要的，以便能够设计新的策略来治疗肺炎克雷伯菌感染。实验室先前的研究支持这样的观点，即克雷伯菌以关键的细胞通路为靶点，以防止宿主防御反应的激活。对克雷伯氏菌靶向途径的分析应该会揭示用来颠覆免疫反应的策略，并导致识别宿主防御的各种跟腱。通过应用多学科方法，这项建议的总体目的是扩大我们目前对克雷伯菌在肺部生存所使用的策略的理解。我们将剖析克雷伯氏菌如何对抗感染后控制大多数宿主防御反应的主要途径的激活。我们将在分子水平上研究克雷伯氏菌如何扰乱宿主用来感知感染存在的受体的激活。最后，我们将破译克雷伯氏菌如何操纵细胞用来快速、局部和特定地修改与感知/响应感染有关的关键蛋白质的活性或相互作用的修饰。这项提案的预期结果应该会启动药物的开发进程，这些药物可以作为有效治疗克雷西氏菌感染的治疗剂，也许还可以治疗其他感染。可能有一些药物已经被批准用于人类，但用于与抗菌活性无关的目的，调节宿主-克雷伯氏菌相互作用中确定的靶标。这将大大缩短甚至绕过药物开发过程。因此，人们相信，如果在研究期间发现并验证这些靶点，将会引起参与抗感染药物开发的制药公司的极大兴趣。

The growing number of organisms resistant to currently available antibiotics has become a major public health threat worldwide. In the long-term we might not be able to treat infectious diseases due to the lack of effective therapeutic agents. Therefore there is a need to develop effective therapeutics based on new targets and approaches. One of the most promising approaches is to develop innovative therapies based on the modulation of the host-microorganism interface, specifically to target the strategies employed by the microorganisms to manipulate for their own benefit host defense responses. Klebsiella pneumoniae is a microorganism causing a wide range of infections, from urinary tract infections to pneumonia. The latter is particularly devastating among immunocompromised patients. K. pneumoniae is a member of the so-called ESKAPE group of microorganisms to emphasize that they effectively "escape" the effects of antibacterial drugs. Therefore it is both urgent and necessary to better understand Klebsiella infection biology to be able to design new strategies to treat K. pneumoniae infections.Previous studies from the laboratory support the notion that Klebsiella targets key cellular pathways to prevent the activation of host defense responses. Analysis of pathways targeted by Klebsiella should reveal the strategies used to subvert immune responses and lead to the identification of the various Achilles heels of host defence. By applying a multidisciplinary approach, the overall purpose of this proposal is to expand our current understanding of the strategies used by Klebsiella to survive in the lung. We will dissect how Klebsiella antagonizes the activation of the main pathways controlling the majority of host defense responses upon infection. We will study at the molecular level how Klebsiella perturbs the activation of the receptors that the host employs to sense the presence of an infection. And, finally, we will decipher how Klebsiella manipulates the modifications that the cells used to rapidly, locally and specifically modify activity or interactions of key proteins implicated in sensing/responding infections. The anticipated results of this proposal should initiate the process of the development of drugs which can serve as therapeutic agent to treat Klesiella infections effectively and perhaps other infections as well. It might be possible that there are drugs already approved for use in humans but used for purposes unrelated to antimicrobial activity, that modulate the target identified in the context of host-Klebsiella interactions. This will significantly short cut or even bypass the drug-development process. It is therefore believed that such targets - if found and validated during the research - will meet big interest at pharmaceutical companies, involved in the development of anti-infective agents.