Host control mechanisms against K. pneumoniae infection in the lungs

肺部肺炎克雷伯菌感染的宿主控制机制

• 批准号: 9913387
• 负责人: Janet Sojung Lee
• 金额: $ 39.13万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913387
• 关键词: Acute; Affect; Africa; African; Alveolar Macrophages; Amyloid beta-Protein; Asia; Asians; Attenuated; Bacteria; Binding; CD36 gene; Cancer Patient; Cells; Clinical; Communities; Couples; Critical Illness; Cytoskeletal Modeling; DNA Binding Domain; Data; Environment; Event; Exhibits; Failure; Gene Activation; Gene Expression; Genes; Goals; Gram-Negative Bacteria; Guanosine Triphosphate Phosphohydrolases; Hematopoietic; Hospitals; Host Defense; Human; IL12B gene; IRF1 gene; Immune; Immune response; Immunocompromised Host; Impairment; In Vitro; Infection; Inflammation; Inflammatory Response Pathway; Intensive Care Units; Interferon Type II; Interferons; Interleukin-12; Invaded; Klebsiella pneumoniae; Knowledge; Lecithin; Leucine Zippers; Ligands; Ligation; Lower Respiratory Tract Infection; Lung; MAP Kinase Gene; Mediating; Microarray Analysis; Molecular; Morbidity - disease rate; Multi-Drug Resistance; Mus; Mutation; NF-kappa B; Oxides; Pathway interactions; Patients; Pattern Recognition; Pattern recognition receptor; Phagocytes; Phagocytosis; Phosphotransferases; Plant Roots; Population; Positioning Attribute; Production; Proteins; Regulation; Role; Sentinel; Serotyping; Signal Transduction; Small Interfering RNA; Source; Sterility; Stromal Cells; Surface; Syndrome; TLR4 gene; TLR6 gene; Testing; Tissues; Tyrosine; attenuation; bZIP Domain; base; carbapenemase; common cellular transcription factor ATF; cytokine; extracellular; healthy volunteer; improved; in vivo; knock-down; live cell imaging; macrophage; microbial; mortality; novel; older patient; oxidized low density lipoprotein; pathogen; programs; protein expression; receptor binding; response; scavenger receptor; targeted treatment; therapy design; transcription factor; transcription factor USF; transcriptome sequencing

Project Summary/Abstract: Acute lower respiratory tract infection from gram negative bacteria is a common problem affecting hospitalized patients, and the most common infection encountered in intensive care units worldwide. The global emergence of multidrug-resistant, carbapenemase-producing strains of Klebsiella pneumoniae (KP), an extracellular gram negative bacteria, is associated with significant morbidity and mortality that disproportionately affects older patients, cancer patients, the immunocompromised, and the critically ill. KP infection is also the root of community-acquired invasive syndrome in parts of Asia and Africa. A critical gap in knowledge exists in how macrophages, sentinel immune cells positioned strategically within tissue environments such as the lung, augments host defense against invading pathogen such as KP. Beyond the initial recognition by pattern recognition receptors such as TLR4, the host macrophage must coordinate a multitude of externally-triggered signals by the bacteria and execute an effective program of engulfment, cytokine response, and pathogen elimination. We recently showed that CD36, a scavenger receptor that binds endogenous DAMPs such as oxidized phosphatidylcholine of oxLDL or amyloid β peptides, provides host protection against KP intrapulmonary infection by enhancing LPS responsiveness and macrophage phagocytosis and is a critical determinant of host survival, lung bacterial burden, extrapulmonary dissemination, phagocytosis and inflammatory cytokine response. Although CD36 functional mutations are found in certain human populations where community-acquired invasive KP syndromes prevail, remarkably little is known about host control mechanisms that defend against this pathogen on a molecular level and this presents a critical barrier to progress. The broad, long term objective is to define distinct host determinants that control K. pneumoniae (KP) infection. Our major hypothesis is that the CD36 is pivotal in the proximal control of macrophage effector cytokine responses and phagocytosis to amplify host defense against K. pneumoniae in the lungs. Our preliminary findings suggest that CD36 amplifies macrophage interferon response through the induction of the basic leucine zipper transcription factor ATF-like 2 (Batf2) to promote an effective cytokine response and phagocytic program. Based upon these findings, we propose the following aims utilizing genetically deficient mice, primary cells, and KP clinical isolates to (1) identify the mechanism by which CD36 and BATF2 enhances downstream macrophage effector cytokine response, (2) evaluate the upstream molecular events that position CD36 for optimal phagocytosis and killing of KP using multi-drug resistant clinical isolates from the ICU, and (3) examine the role of BATF2 and interferon regulatory factor interactions during acute intrapulmonary infection in vivo. Successful completion of the aims will elucidate novel mechanisms of host control and aid in the long-term objective of understanding KP infection in susceptible hosts for rational, targeted therapy design.

项目摘要/摘要：革兰氏阴性菌引起的急性下呼吸道感染是一种常见的疾病 影响住院患者的问题，以及在重症监护病房遇到的最常见感染 全世界。全球出现多药耐药、产碳青霉烯酶克雷伯氏菌 肺炎杆菌(KP)是一种胞外革兰氏阴性菌，具有较高的发病率和死亡率。 这对老年患者、癌症患者、免疫功能低下的人和危重病人的影响不成比例。Kp 感染也是亚洲和非洲部分地区社区获得性侵袭性综合症的根源。在…方面的严重差距 关于巨噬细胞、前哨免疫细胞如何在组织内处于战略位置的知识 肺等环境增强了宿主对金黄色葡萄球菌等入侵病原体的防御。超越了 最初由模式识别受体(如TLR4)识别，宿主巨噬细胞必须协调 细菌的大量外部触发信号，并执行有效的吞噬程序， 细胞因子反应和病原体清除。我们最近发现CD36，一种结合清道夫受体的 内源性潮湿，如oxLDL的氧化磷脂酰胆碱或淀粉样蛋白β肽，提供宿主 增强内毒素反应性和巨噬细胞对肺炎克雷伯菌肺内感染的保护作用 吞噬作用是宿主存活的关键决定因素，肺细菌负荷，肺外 播散、吞噬和炎性细胞因子反应。尽管CD36功能突变是 在社区获得性侵袭性KP综合征盛行的某些人群中发现，值得注意的是 在分子水平上防御这种病原体的寄主控制机制知之甚少，而这 这是取得进展的关键障碍。广泛的、长期的目标是定义不同的宿主决定因素 控制肺炎克雷伯菌(Kp)感染。我们的主要假设是CD36在近端起着关键作用。 控制巨噬细胞效应细胞因子的反应和吞噬，以增强宿主对K。 肺部有肺炎。我们的初步发现表明CD36可以放大巨噬细胞干扰素 通过诱导碱性亮氨酸拉链转录因子ATF-like 2(BATF2)促进 有效的细胞因子反应和吞噬程序。基于这些发现，我们提出如下建议 旨在利用遗传缺陷小鼠、原代细胞和KP临床分离株(1)通过以下方式确定其机制 哪个CD36和BATF2增强下游巨噬细胞效应细胞因子反应，(2)评估 定位CD36的上游分子事件，以利用多药最佳吞噬和杀伤KP 来自ICU的耐药临床分离株，以及(3)检测BATF2和干扰素调节因子的作用 体内急性肺内感染时的相互作用。这些目标的成功完成将阐明 新的宿主控制和辅助机制在了解肺炎克雷伯菌感染的长期目标中的作用 合理、有针对性的治疗设计的易感宿主。