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Iron Acquisition by Mycobacterium tuberculosis Within Phagocytes

吞噬细胞内结核分枝杆菌对铁的获取

基本信息

批准号：
8601148
负责人：
BRADLEY E BRITIGAN
金额：
--
依托单位：
OMAHA VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8601148
关键词：
Acute Anemia due to Chronic Disorder Antibiotics Antitubercular Agents Bacteria Bone Marrow Cell membrane Cells Cellular biology Chronic Citrates Clinical Confocal Microscopy Culture Media Cytoplasm Data Defensins Dendritic Cells Development Disease Drug resistance in tuberculosis Enzyme-Linked Immunosorbent Assay FDA approved Family Francisella tularensis Functional disorder Gallium Gene Mutation Genetic Growth Health Heme Hepatocyte Hereditary hemochromatosis Homeostasis Host Defense Human Hypercalcemia of Malignancy Immunoblot Analysis In Vitro Individual Infection Interferons Interleukin-6 Iron Kinetics Lactoferrin Lead Life Link Liver Locales Lung Measures Mediating Metabolic Pathway Metabolism Methods Microbe Microbial Biofilms Minority Mission Modeling Movement Multi-Drug Resistance Mus Mycobacterium tuberculosis Myelogenous Nature Organism Pathogenesis Patients Peptides Phagocytes Phagosomes Pharmaceutical Preparations Physiological Platelet Factor 4 Play Predisposition Prevalence Prevention strategy Process Production Protein Export Pathway Proteins Pseudomonas aeruginosa Pulmonary Tuberculosis Research Support Resistance Reverse Transcriptase Polymerase Chain Reaction Role Route Serum Severity of illness Siderophores Site Small Interfering RNA Source Spleen Testing Therapeutic Agents Transferrin Transition Elements Tuberculosis Veterans Virulent Work base cell type cytokine extracellular heme oxygenase-1 hepcidin high risk in vivo insight macrophage metal transporting protein 1 microbial microbicide novel novel strategies pathogen public health relevance response trafficking treatment strategy tuberculosis drugs tuberculosis treatment uptake

项目摘要

DESCRIPTION (provided by applicant): The pathophysiology of tuberculosis (TB) is linked to the ability of the causative organism, Mycobacterium tuberculosis (M.tb), to grow within human macrophages. Lung myeloid dendritic cells are a newly recognized reservoir of M.tb during lung infection. M.tb metabolism in macrophages and dendritic cells may differ. Iron (Fe) acquisition is critical for M.tb growth. In vivo, most extracellular Fe is chelated to transferrin (TF) and lactoferrin (LF), decreasing microbial access to Fe. We find that M.tb in human macrophages can acquire Fe from TF and LF, as well as the macrophage cytoplasm. Fe uptake from extracellular TF and LF may involve Fe moving into the cytoplasm. Some (e.g. hereditary hemochromatosis) conditions that lower intracellular Fe in macrophages, decrease M.tb Fe uptake. Whether other factors that regulate macrophage Fe metabolism (e.g. ferroportin, heme oxygenase 1 (HO-1), hepcidin) impact M.tb Fe acquisition is unknown. Similarly unknown is whether Fe acquisition by M.tb growing in dendritic cells is different from that occurring in macrophages. We hypothesize that: 1) M.tb acquires Fe from an intracellular Fe pool(s) in macrophages and dendritic cells; 2) acquisition of extracellular Fe by M.tb involves initial Fe movement into this pool; 3) the kinetics/route of M.tb Fe uptake varies with the extracellular Fe chelate and host cell type (macrophage vs. dendritic cell) involved; 4) genetic or physiological factors that modulate macrophage and/or dendritic cell cytoplasmic Fe alter Fe available for use by M.tb; and 4) administration of Ga, which disrupts M.tb Fe-dependent metabolism could prove to be a novel therapy for TB. In order to test these hypotheses we will pursue the following specific aims: 1. Delineate and compare the ability of M.tb residing within human macrophages and myeloid dendritic cells to: A) acquire Fe from physiologic extracellular chelates (e.g. TF and LF) and from cytoplasmic sites in the macrophage and dendritic cell; and B) to what extent Fe acquisition from extracellular chelates involves initial Fe movement into these same cytoplasmic sites. 2. Determine: A) if M.tb modulates macrophage Fe metabolism, which in turn alters Fe acquisition and growth by the bacteria; and B) the role of key components of macrophage Fe metabolism (e.g. ferroportin, HFE, HO-1, hepcidin) on M.tb Fe acquisition and growth. 3. Determine the efficacy of Ga as a therapeutic agent against M.tb using a murine model of M.tb infection. If positive results are seen, further ascertain the mechanism(s) of Ga's anti-tuberculous activity. The proposed studies use human macrophages and dendritic cells along with fully virulent M.tb strains to accomplish these aims. Experimental methods employed include: measuring uptake of 59Fe, siRNA, confocal microscopy, immunoblot analysis, RT-PCR, and ELISA and use of a murine model of pulmonary TB. Insight into M.tb Fe metabolism could lead to novel treatments that would benefit veterans.

描述（由申请人提供）：