Escape of Mycobacterium tuberculosis from the macrophage is regulated by eicosano

结核分枝杆菌从巨噬细胞中逃逸受二十碳烷调节

基本信息

批准号：
7849877
负责人：
SAMUEL M BEHAR
金额：
$ 56.16万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
2009-07-22 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7849877
关键词：
Acquired Immunodeficiency Syndrome Adenylate Cyclase Adoptive Transfer Aerosols Affect Alveolar Macrophages Antigens Apoptosis Apoptotic Bacillus (bacterium)Bacteria Bacterial Translocation Biological Assay Cell Death Cell membrane Cells Cessation of life Cyclic AMP-Dependent Protein Kinases Cytolysis Cytosol Defense Mechanisms Dendritic Cells Dinoprostone Dose Eicosanoids Environment Epidemic Equilibrium Event Exocytosis Fostering Genes Genetic Transcription Golgi Apparatus Host Defense Human Immune Immune response Immune system Impairment In Vitro Induction of Apoptosis Infection Integration Host Factors Kinetics Lesion Link Lung Lysosomes Mediating Membrane Mitochondria Modeling Multi-Drug Resistance Mus Mycobacterium tuberculosis Necrosis PTGS2 gene Pathogenesis Pathway interactions Persons Phagocytes Phagolysosome Phagosomes Phase Play Population Prevention Process Production Prostaglandins Relative (related person)Research Resistance Role Route Signal Transduction Staging System T-Lymphocyte Testing Tissues Tuberculosis United States Vesicle Virulence Virulent extracellular human WFDC2 protein in vivo insight killings lipid mediator lipoxin A4 macrophage microbial host novel pathogen prevent prostaglandin EP2 receptor protective effect repaired sensor success synaptotagmin VII

项目摘要

Mycobacterium tuberculosis (Mtb) alters the intracellular environment of the alveolar macrophage (M¿), the primary host cell, allowing bacterial replication within the cell. However virulent Mtb eventually induces necrosis characterized by M¿ lysis facilitating escape of the bacteria and dissemination. To induce necrosis virulent Mtb inhibits apoptosis, which is beneficial to the host leading to death of the pathogens. We showed that following Mtb infection, the balance of the host lipid mediators prostaglandin E2 and lipoxin A4 determines whether infected M¿ undergo necrosis or apoptosis. Virulent Mtb induce production of lipoxin A4, which suppresses prostaglandin E2 production leading to necrosis. In contrast, M¿ infected with avirulent Mtb produce mainly prostaglandin E2 leading to apoptosis. This is accomplished by rapid resealing of Mtb-induced plasma membrane microdisruptions triggered by a lysosome and Golgi vesicle dependent repair mechanism. In contrast, infection with virulent Mtb inhibits membrane repair leading to necrosis. We hypothesize that impairment of membrane repair leads to phagosomal membrane damage, cytosol entry of the bacteria, and necrosis. Following necrosis of the host M¿ Mtb infect other cells to initiate another cycle of replication. We propose to investigate how the lipid mediators regulate membrane repair, how Mtb escapes from the phagosome and whether membrane repair is important to prevent escape and spreading of the bacteria. Better understanding of the events leading to M¿ apoptosis and necrosis of Mtb-infected M¿ will foster our understanding of tuberculosis pathogenesis and will guide research into new therapies.

结核分枝杆菌（MTB）改变了主要宿主细胞肺泡巨噬细胞的细胞内环境，从而允许细胞内细菌复制。然而，有毒的MTB有时会诱导以裂解为特征的坏死，以支持细菌的逃脱和传播。诱导坏死性有毒MTB抑制细胞凋亡，这对导致病原体死亡的宿主有益。我们表明，MTB感染后，宿主脂质介质的平衡前列腺素E2和Lipoxin A4决定了感染的M€是否经历了坏死还是凋亡。有毒的MTB诱导脂氧蛋白A4的产生，从而抑制前列腺素E2的产生，导致坏死。相比之下，感染的MTB感染的m主要产生前列腺素E2，导致细胞凋亡。这是通过快速重新密封由MTB诱导的质膜微切中断的，这些质膜微区由溶酶体和高尔基囊泡依赖性修复机制触发。相反，用毒性MTB感染抑制膜修复，导致坏死。我们假设膜修复受损会导致吞噬膜损伤，细菌的细胞质进入和坏死。宿主MTB坏死后，感染了其他细胞，以引发另一个复制周期。我们建议研究脂质介质如何调节膜修复，MTB如何从吞噬体中逃脱，以及膜修复是否对于防止细菌的逃生和扩散很重要。更好地了解导致MTB感染的M凋亡和坏死的事件将促进我们对结核病发病机理的理解，并将指导对新疗法的研究。