Deciphering Klebsiella pneumoniae strategies to subvert host defences

越来越多的生物体对现有抗生素产生耐药性，已成为全球公共卫生的主要威胁。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，需要开发基于新靶点和方法的有效治疗剂。最有前途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自身利益操纵宿主防御反应所采用的策略。肺炎克雷伯氏菌是一种微生物，可引起从尿路感染到肺炎等多种感染。后者在免疫功能低下的患者中尤其具有破坏性。K.肺炎克雷伯氏菌是所谓的ESKAPE微生物组的成员，以强调它们有效地“逃避”抗菌药物的作用。因此，更好地了解克雷伯氏菌感染生物学以便能够设计新的治疗克雷伯氏菌的策略是既紧迫又必要的。来自实验室的先前研究支持克雷伯氏菌靶向关键细胞途径以防止宿主防御反应的激活的概念。对克雷伯氏菌靶向途径的分析应该揭示用于破坏免疫反应的策略，并导致识别宿主防御的各种阿基里斯之踵。通过应用多学科的方法，本提案的总体目的是扩大我们目前对克雷伯氏菌在肺中生存的策略的理解。我们将剖析克雷伯氏菌如何拮抗控制感染后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干扰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于快速，局部和特异性地修饰与感测/响应感染有关的关键蛋白质的活性或相互作用的修饰。这一建议的预期结果应该启动药物的开发过程，这些药物可以作为治疗剂有效地治疗克雷伯氏菌感染，也可能治疗其他感染。可能有一些药物已经批准用于人类，但用于与抗菌活性无关的目的，这些药物调节宿主-克雷伯菌相互作用背景下确定的靶标。这将大大缩短甚至绕过药物开发过程。因此，人们相信，如果在研究过程中发现并验证这些目标，将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.