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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：
9532512
负责人：
Janet Sojung Lee
金额：
$ 39.06万
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/9532512
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 pneumonia bacterium 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：急性下呼吸道感染是一种常见的革兰氏阴性菌感染