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：
10133128
负责人：
Kong Chen
金额：
$ 60.39万
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10133128
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：革兰氏阴性细菌引起的急性下呼吸道感染是一种常见影响住院患者的问题，以及重症监护病房中最常见的感染全世界。抗多药的碳青霉酶产生的克雷伯氏菌菌株的全球出现肺炎（KP）是一种细胞外革兰氏阴性细菌，与明显的发病率和死亡率有关这对老年患者，癌症患者，免疫功能低下的患者和重病患者的影响不成比例。 KP 感染也是亚洲和非洲部分地区社区侵入性综合征的根源。一个关键的差距知识存在于巨噬细胞，哨兵免疫细胞如何在组织中策略性位置的知识诸如肺部，增强宿主防御侵入病原体（例如KP）的环境。超越通过图案识别受体（例如TLR4）的初始识别，宿主巨噬细胞必须协调A 细菌的大量外部触发信号并执行有效的吞噬计划，细胞因子反应和病原体进化。我们最近表明，CD36是一种绑定的清道夫接收器内源性潮湿，例如OXLDL的氧化磷脂酰胆碱或淀粉样蛋白β肽，提供宿主通过增强LPS反应性和巨噬细胞来防止KP肺内感染吞噬作用，是宿主存活，肺细菌燃烧，肺外对的关键决定剂传播，吞噬作用和炎性细胞因子反应。尽管CD36功能突变是在某些人类人群中发现，社区获得的侵入性KP综合症占上风，非常明显关于宿主控制机制几乎知之甚少提出了进步的关键障碍。广泛的长期目标是定义不同的主机决定者控制K.肺炎（KP）感染。我们的主要假设是CD36在近端是关键控制巨噬细胞效应子细胞因子反应和吞噬作用，以扩大宿主对K的防御。肺中的肺炎。我们的初步发现表明CD36放大器巨噬细胞干扰素通过诱导基本亮氨酸拉链转录因子ATF样2（BATF2）的响应以促进有效的细胞因子反应和吞噬程序。根据这些发现，我们提出以下内容旨在利用一般不足的小鼠，原代细胞和KP临床分离株来确定通过哪种CD36和BATF2增强了下游巨噬细胞效应子细胞因子反应，（2）评估上游分子事件将CD36定位为最佳吞噬作用和使用多药物杀死KP 来自ICU的抗性临床分离株，（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。成功完成目标将阐明宿主控制的新机制和帮助理解KP感染的长期目标易感宿主进行有理，有针对性的治疗设计。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

SCUBE1 Controls BMPR2-Relevant Pulmonary Endothelial Function: Implications for Diagnostic Marker Development in Pulmonary Arterial Hypertension.

DOI：
10.1016/j.jacbts.2020.08.010
发表时间：
2020-11
期刊：
JACC. Basic to translational science
影响因子：
0
作者：
Sun W;Tang Y;Tai YY;Handen A;Zhao J;Speyer G;Al Aaraj Y;Watson A;Romanelli ME;Sembrat J;Rojas M;Simon MA;Zhang Y;Lee J;Xiong Z;Dutta P;Vasamsetti SB;McNamara D;McVerry B;McTiernan CF;Sciurba FC;Kim S;Smith KA;Mazurek JA;Han Y;Vaidya A;Nouraie SM;Kelly NJ;Chan SY
通讯作者：
Chan SY

Practical Guidelines for Collection, Manipulation and Inactivation of SARS-CoV-2 and COVID-19 Clinical Specimens.

DOI：
10.1002/cpcy.77
发表时间：
2020-06-01
期刊：
Current protocols in cytometry
影响因子：
0
作者：
Bain, William;Lee, Janet S;Stitt-Fischer, Molly S
通讯作者：
Stitt-Fischer, Molly S

BATF2 enhances proinflammatory cytokine responses in macrophages and improves early host defense against pulmonary Klebsiella pneumoniae infection.

BATF2 增强巨噬细胞中的促炎细胞因子反应，并改善宿主对肺部肺炎克雷伯菌感染的早期防御。

DOI：
10.1152/ajplung.00441.2022
发表时间：
2023
期刊：
American journal of physiology. Lung cellular and molecular physiology
影响因子：
0
作者：
vanderGeest,Rick;Peñaloza,HernánF;Xiong,Zeyu;Gonzalez-Ferrer,Shekina;An,Xiaojing;Li,Huihua;Fan,Hongye;Tabary,Mohammadreza;Nouraie,SMehdi;Zhao,Yanwu;Zhang,Yingze;Chen,Kong;Alder,JonathanK;Bain,WilliamG;Lee,JanetS
通讯作者：
Lee,JanetS

Translational Sepsis Research: Spanning the Divide.