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

基本信息

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
项目类别：
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

项目摘要

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，以及重症监护病房最常见的感染全球范围内出现多重耐药、产生碳青霉烯酶的克雷伯菌菌株。肺炎杆菌 (KP) 是一种细胞外革兰氏阴性细菌，与显着的发病率和死亡率相关这对老年患者、癌症患者、免疫功能低下者和重症 KP 患者影响尤为严重。感染也是亚洲和非洲部分地区社区获得性侵袭综合症的根源。关于巨噬细胞、前哨免疫细胞如何在组织内战略性定位的知识肺部等环境，增强宿主对 KP 等入侵病原体的防御能力。通过模式识别受体（例如 TLR4）进行初始识别，宿主巨噬细胞必须协调细菌发出大量外部触发信号并执行有效的吞噬程序，我们最近证明了 CD36，一种结合的清道夫受体。内源性 DAMP，例如 oxLDL 的氧化磷脂酰胆碱或淀粉样蛋白 β 肽，为宿主提供通过增强 LPS 反应性和巨噬细胞来预防 KP 肺内感染吞噬作用，是宿主生存、肺细菌负荷、肺外细菌负担的关键决定因素尽管CD36功能突变是传播、吞噬和炎症细胞因子反应的关键。在社区获得性侵袭性 KP 综合征盛行的某些人群中广泛发现对于在分子水平上防御这种病原体的宿主控制机制知之甚少，这广泛的长期目标是确定不同的宿主决定因素。我们的主要假设是 CD36 在近端至关重要。控制巨噬细胞效应细胞因子反应和吞噬作用，以增强宿主对K. 我们的初步研究结果表明 CD36 会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) 来促进反应根据这些发现，我们提出以下建议。旨在利用遗传缺陷小鼠、原代细胞和 KP 临床分离株来 (1) 通过以下方式确定机制：其中 CD36 和 BATF2 增强下游巨噬细胞效应细胞因子反应，(2) 评估使用多种药物定位 CD36 以获得最佳吞噬作用和杀死 KP 的上游分子事件来自 ICU 的耐药临床分离株，以及 (3) 检查 BATF2 和干扰素调节因子的作用体内急性肺内感染期间的相互作用将阐明成功完成的目标。宿主控制的新机制和有助于理解 KP 感染的长期目标易感宿主进行合理的、有针对性的治疗设计。