Understanding the immunometabolic response to Klebsiella pneumonia infection

项目概要/摘要 属于序列类型（ST）258的碳青霉烯类耐药肺炎克雷伯菌（Kp）菌株已传播 在过去的几十年里，全球。他们与经常致命的呼吸机相关性肺炎的关系是迫切的公众关注的问题。 特别是在当前COVID-19大流行的情况下。虽然许多研究都集中在 在研究抗菌素耐药性策略的同时，仍然缺乏有效的治疗药物，这促使 需要更好地了解对Kp ST 258持久性至关重要的其他因素。Kp ST 258菌株不同 从高毒力菌株，诱导迅速致命的感染，而不是引起亚急性慢性感染。 不能清除Kp ST 258与单核细胞（骨髓来源的抑制细胞， MDSC）具有抗炎特性，类似于在治疗过程中促进肿瘤细胞生长的抗炎特性。 肿瘤发生鉴于代谢活动控制免疫细胞的功能，我们假设Kp ST 258 以类似于肿瘤代谢的方式的代谢产生宿主代谢应激和有利于肿瘤生长的环境。 免疫抑制细胞的产生和扩增。我们发现Kp ST 258刺激了一种独特的宿主， 肺部感染期间的代谢反应，其特征在于葡萄糖的快速消耗，刺激 脂肪酸氧化（FAO）途径，促进氧化磷酸化（OXPHOS）， 活性氧（ROS）的产生和抗氧化代谢产物衣康酸的积累。这 该项目提供了一种新的方法来开发利用宿主代谢反应的治疗策略， Kp ST 258为促进慢性肺部感染的主要因素。具体来说，aim 1探索了 宿主对Kp ST 258的免疫代谢反应。目标2旨在研究这种反应如何促进 免疫抑制，而aim 3关注其对细菌适应和在气道中存活的直接影响。 通过驱动细菌基因表达的全球变化，包括六型分泌的上调， 系统（T6 SS），以抵消氧化应激。

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.