权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Regulation of Apoptotic Envelope Formation by MTB in the Host Macrophage

MTB 对宿主巨噬细胞中凋亡包膜形成的调节

基本信息

批准号：
7523349
负责人：
HEINZ Gernot REMOLD
金额：
$ 44.29万
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：
2009-05-22 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7523349
关键词：
Alanine Amino Acids Annexin A1 Annexins Apoptosis Apoptotic Attenuated Bacillus (bacterium)Binding Biochemical Biological Assay Cell Membrane Permeability Cell membrane Cell surface Cells Cleaved cell Collaborations Confocal Microscopy Containment Cytolysis Data Development Dinoprostone Excision Exocytosis Extracellular Space Fortune Fostering Generations Genes Genetic Glutamine Habitats Human Immunology Individual Induction of Apoptosis Infection Inner mitochondrial membrane Knowledge LAMP-1 Length Ligands Lysine Lysosomes Maintenance Membrane Mitochondria Molecular Weight Mutate Mycobacterium tuberculosis N-terminal Nature Necrosis Necrosis Induction Pathway interactions Peptide Hydrolases Peptides Phagocytes Pharmaceutical Preparations Phosphatidylserines Plasminogen Activator Plasminogen Activator Inhibitor 2 Prevention Production Property Protease Inhibitor Proteins Proteolysis Publishing Pump Regulation Role Serine Serpins Staging Structure Surface System Testing Thapsigargin Thick Tissues Toxic effect Transglutaminases Tuberculosis Vesicle Virulence Factors Virulent crosslink extracellular inhibitor/antagonist keratinocyte link protein macrophage mitochondrial membrane mutant mycobacterial novel strategies pathogen peptide A polyglutamine prevent repaired research study response scaffold seal synaptotagmin VII uptake

项目摘要

Mycobacterium tuberculosis (Mtb) grows in human macrophages, the principal host cell, where it occupies a niche allowing it to replicate without being recognized by the host. Attenuated Mtb induce apoptosis of the host macrophages resulting in containment of the bacilli and their elimination by phagocytes. An essential property of virulent Mtb and a virulence factor is the induction of necrosis characterized by plasma membrane lysis and release of the bacilli into the intercellular space that leads to spread of the infection. In contrast, attenuated Mtb induce predominantly apoptosis in the host macrophage. A hallmark of apoptosis is the presence of a 15 nm thick cell surface envelope scaffold consisting of cross-linked proteins including (annexin-1 and the protease inhibitor serpin plasminogen activator type 2 (PAI-2) as first described from the lkornified envelope of keratinocytes. Annexin-1, a 37 kDa protein with a phosphatidyl serine (PS) binding domain and a poly-gln region required for cross-linking is transported to the macrophage surface during apoptosis and binds to the PS lattice on the surface of the apoptotic Mcp. We found that annexin-1 is not only a common constituent of the apoptotic envelope of the macrophage infected with attenuated Mtb, but also an lorganizing principle required for cross-linking of the envelope by transglutaminases. In the presence of [protease inhibitors such as PAI-2 proteolytic degradation of annexin-1 resulting in an inactive product lacking lthe poly-gln region is blocked and formation of the apoptotic envelope is enabled. In this application we lpropose to investigate the capacity of virulent Mtb to interfere with the formation of the apoptotic envelope on host macrophages by modulating proteolytic degradation of annexin-1 and its transport to the cell surface. We will further study the role of membrane repair mechanisms in Mtb infection of the macrophage in the formation of the apoptotic envelope. These studies will enhance our knowledge about critical host-pathogen interactions in tuberculosis that could foster development of novel approaches to treatment and prevention.

结核分枝杆菌（Mtb）在人类巨噬细胞中生长，巨噬细胞是主要的宿主细胞，它占据了一个生态位，允许它在不被宿主识别的情况下复制。减毒的结核分枝杆菌诱导宿主巨噬细胞凋亡，从而抑制芽孢杆菌并使其被吞噬细胞消灭。毒力结核分枝杆菌和毒力因子的一个基本特性是诱导坏死，其特征是质膜裂解和杆菌释放到细胞间隙，从而导致感染的传播。相反，减毒Mtb主要诱导宿主巨噬细胞凋亡。凋亡的一个标志是存在一个15nm厚的细胞表面包膜支架，由交联蛋白组成，包括膜联蛋白-1和蛋白酶抑制剂丝氨酸酶原激活剂2型（PAI-2）