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Intrapulmonary itaconate as a host-protective metabolite during ER Stress and Klebsiella pneumoniae infection

肺内衣康酸作为内质网应激和肺炎克雷伯菌感染期间宿主保护性代谢物

基本信息

批准号：
10426735
负责人：
Tomeka L Suber
金额：
$ 16.07万
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：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10426735
关键词：
Aconitic Acid Acute Acute Lung Injury Address Affect Alveolar Macrophages Antibiotic Resistance Bacteria Basic Science Biology Bleomycin Bone Marrow Carboxy-Lyases Cell Death Cell Line Cell Survival Cells Cellular Stress Response Cellular biology Chimera organism Citric Acid Cycle Clinical Critical Care Critical Illness Development Plans Elderly Enzymes Epithelial Cells Equilibrium Exhibits Experimental Models Exposure to Fibroblasts Focal Infection Foundations Goals Gram-Negative Bacteria Host Defense Host Defense Mechanism Human Immune Immunocompromised Host Immunophenotyping In Vitro Infection Inflammation Inflammatory Response Injury Intensive Care Units Interferon Type I K-Series Research Career Programs Klebsiella pneumoniae Knockout Mice Knowledge Lipopolysaccharides Lower Respiratory Tract Infection Lung Lung infections Mediator of activation protein Medicine Mentors Mentorship Metabolic Metabolism Mitochondria Modeling Multi-Drug Resistance Mus Myelogenous Myeloid Cells Nosocomial pneumonia Outcome Pathway interactions Patients Physicians Pneumonia Population Predisposition Prevalence Production Proteins Publishing Pulmonary Fibrosis Regulation Research Research Personnel Resolution Role Scientist Sepsis Single Nucleotide Polymorphism Slice Small Interfering RNA Source Specificity Structure of parenchyma of lung Syndrome Systemic disease Techniques Testing Tissues Training Translational Research Work alveolar epithelium biological adaptation to stress career development cell injury conditional knockout cytokine defense response effective therapy endoplasmic reticulum stress epithelial injury improved improved outcome in vivo in vivo Model interest knock-down macrophage metabolomics monocyte mortality mouse model multidisciplinary novel pathogen patient population pneumonia model programs resilience resistant Klebsiella pneumoniae response skills stressor success targeted treatment therapy design therapy development tissue injury tool transcriptomics wound healing

项目摘要

PROJECT ABSTRACT Gram negative bacteria are the most common pathogens implicated in nosocomial pneumonia in critically ill patients. Klebsiella pneumoniae (KP) in particular has grown in prominence worldwide with increasing prevalence of antibiotic resistance, hypervirulent strains, and invasive clinical syndromes. Mechanisms of host defense responsible for effective clearance of KP infection from the lung in susceptible hosts are still unclear. Cis-aconitate decarboxylase 1 (Acod1) is a mitochondrial enzyme robustly induced in murine and human alveolar macrophages that catalyzes the production of itaconate. Itaconate suppresses inflammatory responses through a proposed Nrf2-dependent mechanism. The goal of this proposal is to define the role of myeloid-derived itaconate in pulmonary host defense during KP infection and to determine how it confers protection from local tissue injury. In a murine model of pneumonia using KP as the pathogen, we have shown that Acod1 deficiency is associated with decreased survival and increased bacterial dissemination. We have also shown that itaconate depletion reduces expression of key proteins of the cellular integrated stress response (ISR) pathway during ER stress, suggesting that it may regulate this pathway. Our proposal will address the following specific aims: 1) To determine if myeloid cell-derived itaconate limits local KP infection and protects against extrapulmonary sepsis; and 2) To determine whether itaconate is host-protective through the ISR and decreases cellular injury during KP infection. We hypothesize that Acod1, and thus itaconate production, is protective against sepsis and associated tissue injury in this model and increases host resilience. We also anticipate that macrophage-derived itaconate increases protection from ER stress both in macrophages and lung epithelial cells in vitro and in vivo. These studies will utilize in vitro and translational tools including an in vivo intrapulmonary KP infection model using wild-type and Acod1-/- mice, bone marrow chimeras, RAW 264.7 macrophage cell lines (wild-type and Acod1-/-), human and mouse precision-cut lung tissue slices, and human alveolar macrophages to address our research questions. In addition, we will perform transcriptomic and metabolomic profiling across affected tissues during disseminated KP infection, immunophenotype myeloid subsets, and execute complementary cell biology studies to examine key targets of the integrated stress response pathway in the presence or absence of itaconate in myeloid and epithelial cells. This work will elucidate novel immune mechanisms that may be exploited to reduce mortality associated with this pathogen. The proposal incorporates a strong mentorship team led by Dr. Janet Lee as Director of the Acute Lung Injury Center of Excellence and a robust career development plan. Support of this proposal with a K08 Career Development Award will establish a foundation for success and independence for the candidate as a physician-scientist in pulmonary and critical care medicine.

项目摘要