Heme-mediated STAT1 Dysfunction in Macrophages During Klebsiella pneumoniae Lung Infection

肺炎克雷伯菌肺部感染期间巨噬细胞中血红素介导的 STAT1 功能障碍

基本信息

批准号：
10534918
负责人：
Shekina Gonzalez-Ferrer
金额：
$ 4.68万
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：
2022
资助国家：
美国
起止时间：
2022-08-05 至 2025-08-04
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10534918
关键词：
Acute Acute Respiratory Distress Syndrome Address Anemia due to Chronic Disorder Antioxidants Autophagocytosis Bacteremia Bacterial Infections Bacterial Pneumonia Biochemical Genetics Biological Models Biological Process Biomedical Research Blood Transfusion Bone Marrow Cells Development Dysmyelopoietic Syndromes Effector Cell Erythrocytes Erythrophagocytosis Excision Exhibits Exposure to Functional disorder Gene Expression Profile Healthcare Hematological Disease Heme Heme Iron Hemeproteins Hemin Hemoglobin Hemolytic Anemia Hemorrhage Host Defense IRF1 gene Immune Immune response Immunosuppression Impairment In Vitro Infection Inflammation Inflammatory Injury Interferons Invaded Iron Iron Overload Kidney Kinetics Klebsiella pneumoniae Leukocyte Elastase Life Liver Lung Lung infections Macrophage Activation Mediating Metabolism Modeling Mus Oxidative Stress Pathogenesis Pathogenicity Pathologic Patients Phenotype Physiological Prevention strategy Process Production Proteins Recycling Respiratory Tract Infections Risk STAT1 protein Sepsis Sickle Cell Anemia Signal Transduction Stress Structure System Testing Tissues Transfusion Wild Type Mouse antimicrobial peptide base chemokine combat confocal imaging cytokine genetic approach high risk in vivo in vivo Model macrophage mortality neutrophil novel opportunistic pathogen pathogen protein expression resilience response senescence transcription factor treatment strategy uptake

项目摘要

PROJECT SUMMARY/ABSTRACT Macrophages are key effector immune cells in host defense against pathogen invasion, and understanding factors that cause macrophage dysfunction during severe infection remains a high priority in biomedical research. An acute rise in red blood cell engulfment by macrophages, called stressed erythrophagocytosis, occurs in pathologic conditions such as transfusion heme-iron overload, anemia of inflammation, certain hemolytic anemias, or severe sepsis, and involves the uptake of excess senescent red cells (sRBCs). Using a two-hit model of red cell transfusion and acute pulmonary infection, we recently uncovered a mechanism whereby stressed erythrophagocytosis led to a state of immunosuppression following Klebsiella pneumoniae (KP) infection in mice. This state of immunosuppression arose from a disruption in interferon signaling in the liver during infection, was caused by excess heme handling by macrophages, and led to a deficiency of STAT1, a master regulator of interferon responses. We previously established an experimental system in which macrophages are exposed to KP infection and concomitant sRBC delivery or excess hemin in vitro. In addition, we have developed a well-established bacterial pneumonia model system using KP that will be combined with direct delivery of sRBC or heme to the lung in order to examine alterations in macrophage phenotype and the immune cell repertoire in vivo. This proposal will test the hypothesis that excess heme in the lung, such as in conditions of local tissue damage during severe infection, can induce a state of STAT1-deficiency in macrophages, in part, by impairing STAT1 protein stability with deleterious consequences on host defense. Utilizing in vitro and in vivo model systems, I propose to investigate this hypothesis by pursuing the following aims: Aim 1. Determine whether excess heme induces a state of STAT1 deficiency in macrophages during KP infection by impairing STAT1 protein stability in vitro. Aim 2. Examine whether excess heme alters macrophage phenotype in the lung and impairs effective host defense during KP infection in vivo. Successful completion of this project will provide novel information regarding host-pathogen interactions during pathologic conditions of excess heme, and will address a gap in understanding of dysregulated host response in the lung during severe respiratory infection.

项目摘要/摘要巨噬细胞是宿主防御病原体侵袭的关键效应免疫细胞，并且理解在严重感染期间引起巨噬细胞功能障碍的因素仍然是很高的优先事项生物医学研究。巨噬细胞吞噬红细胞的急性上升，称为应力红细胞增多症，发生在病理状况（例如输血性血红素过载），贫血等病理状况炎症，某些溶血性贫血或严重的败血症，涉及多余的衰老红色细胞（SRBC）。使用红细胞输血和急性肺部感染的两次打击模型，我们最近发现了强调红细胞增多的一种机制导致克雷伯氏病后的免疫抑制状态小鼠肺炎（KP）感染。这种免疫抑制的状态来自干扰素的破坏感染过程中肝脏中的信号传导是由巨噬细胞过多的血红素处理引起的，并导致了 STAT1的缺陷，干扰素响应的主要调节剂。我们以前建立了一个实验巨噬细胞暴露于KP感染和伴随SRBC递送或过量的hemin的系统体外。此外，我们使用KP开发了一个公认的细菌肺炎模型系统结合直接递送SRBC或血红素到肺部，以检查巨噬细胞的改变表型和体内免疫细胞库。该提议将检验以下假设。肺部，例如在严重感染期间局部组织损伤的条件下，肺部可能引起STAT1缺乏症状在巨噬细胞中，部分原因是损害STAT1蛋白质稳定性，对宿主防御产生有害后果。利用体外和体内模型系统，我建议通过追求以下来研究这一假设目的：目标1。确定过量血红素是否在KP期间诱导巨噬细胞中的STAT1缺乏状态通过在体外损害STAT1蛋白质稳定性来感染。瞄准2。检查多余的血红素是否改变巨噬细胞在体内KP感染期间，肺中的表型会损害有效的宿主防御。成功完成该项目将在病理条件下提供有关宿主病原体相互作用的新信息过多的血红素，并将解决严重期间肺部失调宿主反应的差距呼吸道感染。