Understanding the immunometabolic response to Klebsiella pneumonia infection

项目摘要/摘要 耐碳青霉烯类肺炎克雷伯菌(KP)序列类型(ST)258菌株已蔓延 在过去的几十年里，在全球范围内。他们与经常致命的呼吸机相关肺炎的关系是紧急公众关注的问题 卫生问题，特别是考虑到目前的新冠肺炎大流行。虽然许多研究都集中在 在研究抗菌素耐药策略时，仍然缺乏有效的治疗药物，这促使 需要更好地了解对KP ST258持久性至关重要的其他因素。KP ST258菌株不同 来自超强毒力的菌株，通过引起亚急性慢性感染而导致迅速致命的感染。 未能清除KP ST258与单核细胞(髓系来源的抑制细胞， MDSCs)具有类似于促进肿瘤细胞生长的抗炎特性 致癌作用。鉴于代谢活动支配免疫细胞的功能，我们假设Kp ST258 与肿瘤代谢类似的代谢方式会产生宿主代谢应激和有利于 免疫抑制细胞的产生和扩增。我们发现KP ST258能刺激一种独特的宿主 肺部感染时的代谢反应，其特征是葡萄糖迅速耗尽、刺激 谷氨酰胺分解和脂肪酸氧化(FAO)途径的燃料氧化磷酸化(OXPHOS)和 活性氧(ROS)的产生和抗氧化代谢物衣康酸的积累。这 项目提供了一种新的方法来开发治疗策略，利用宿主的代谢反应 KPST258为慢性肺部感染的主要致病因素。具体地说，《目标1》探索了动态 宿主对KP ST258的免疫代谢反应。Aim 2试图调查这种反应是如何促进 免疫抑制，而目标3则侧重于其对细菌适应和在呼吸道中生存的直接影响 通过推动细菌基因表达的全球变化，包括上调第六型分泌物 系统(T6SS)，以中和氧化应激。

Project summary/abstract Carbapenem-resistant Klebsiella pneumoniae (Kp) strains belonging to sequence type (ST) 258 have spread globally in the past decades. Their association with often-fatal ventilator-associated pneumonia is of urgent public health concern especially in light of the current COVID-19 pandemic. While numerous studies have focused on investigating antimicrobial resistance strategies, there is still a lack of effective therapeutic agents, which urges the need to better understand other factors that are crucial for Kp ST258 persistence. Kp ST258 strains differ from hypervirulent strains that induce rapidly fatal infections by instead causing subacute chronic infections. Failure to clear Kp ST258 is associated with the recruitment of monocytes (myeloid-derived suppressor cells, MDSCs) with anti-inflammatory properties similar to those that promote the growth of tumor cells during oncogenesis. Given that metabolic activities govern the function of immune cells, we hypothesize that Kp ST258 metabolism in a manner similar to tumor metabolism generates host metabolic stress and a milieu conducive to the generation and expansion of immunosuppressive cells. We found that Kp ST258 stimulates a unique host metabolic response during pulmonary infection that is characterized by the rapid depletion of glucose, stimulation of glutaminolysis and fatty acid oxidation (FAO) pathways that fuel oxidative phosphorylation (OXPHOS) and reactive oxygen species (ROS) production, and the accumulation of the antioxidative metabolite itaconate. This project offers a novel approach to develop therapeutic strategies drawing upon the host metabolic response to Kp ST258 as the main factor promoting chronic pulmonary infection. Specifically, aim 1 explores the dynamics of the host immunometabolic response to Kp ST258. Aim 2 seeks to investigate how this response promotes immunosuppression while aim 3 focuses on its direct effect on bacterial adaptation to and survival in the airway by driving global changes in bacterial gene expression including the upregulation of the Type Six Secretion System (T6SS) to counteract oxidative stress.