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Interaction of microvesicles and bacterial toxins with immune cells

微泡和细菌毒素与免疫细胞的相互作用

基本信息

批准号：
8091345
负责人：
RUSSELL D. SALTER
金额：
$ 35.16万
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：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8091345
关键词：
Affect Anthrax disease Antigen Presentation Antigens Apoptosis Bacillus anthracis Bacteria Bacterial Toxins Binding Biological Assay Biology CD4 Positive T Lymphocytes CD8B1 gene Calcium Cell Maturation Cell membrane Cell physiology Cells Cholesterol Cytolysins Cytolysis Dendritic Cells Family Family member Filopodia Gram-Positive Bacteria Histocompatibility Antigens Class II Human Immune Immune response Immunosuppressive Agents In Vitro Infection Lead Ligands MHC Class II Genes Mediating Methods Phagocytes Phenotype Physiologic pulse Production Property Protein Secretion Proteins Proteomics Reporting Research Personnel Site Stimulus Structure Surface T cell response T-Lymphocyte TLR4 gene Tetanus Time Toxin Up-Regulation Vesicle base cell type cytokine immune function induced pluripotent stem cell macrophage monocyte pathogen perforin programs response streptolysin O tetanolysin trafficking uptake

项目摘要

Description (provided by applicant): Avoidance of the immune response is an important aspect of the biology of many pathogens, and a wide variety of mechanisms have been defined. For Gram-positive bacteria, secretion of proteins belonging to the family of cholesterol dependent cytolysins (CDC) may lead to lysis of some cell types at high concentrations, but at lower concentrations may also sensitize cells such as macrophages to apoptosis-inducing stimuli by engagement of TLR4. This was recently reported for anthrolysin O, a CDC produced by B. anthracis, and for a number of other CDC family members. Stimulation of TLR however could be considered a double edged sword, since this might also stimulate the immune response, particularly when involving potent ARC such as dendritic cells (DC). We have investigated the effects of three CDC proteins, anthrolysin O, tetanolysin O and streptolysin O, and observed that human DC rapidly respond to treatment with non-toxic levels of these proteins by fluxing calcium and then secreting or shedding microvesicles (MV) that have on their surface class II MHC proteins. At the same time, DC lose the ability to up-regulate class II MHC in response to IPS. Based on these results, we hypothesize that CDC act to impair antigen presentation by DC by inducing secretion of MV containing class II MHC and other proteins important to antigen presenting function precisely at the time of pathogen encounter. Furthermore, we suggest that released MV may themselves have immunosuppressive properties, based on similarities to vesicles called exosomes, and that CDC toxins might be disseminated throughout the body and taken up by phagocytes, in this way impacting antigen presentation more widely than at the site of infection. We propose to further characterize these effects of a representative CDC protein, TLO, on the function of human monocyte-derived DC and to investigate the impact of TLO-induced MV on immune reponses in the following aims: 1. how TLO affects class II localization in moDC will be determined; 2. the protein contents of TLO-induced MV will be characterized; 3. the mechanism of MV production and uptake by cells will be probed; 4. the effect of TLO-induced and constitutively produced MV on CD4 and CDS T cell function will be determined. Lay statement; Understanding how toxins from bacteria affect the immune response could help devise new treatments for tetanus, streptococcal disease, and anthrax.

描述（由申请人提供）：避免免疫反应是许多病原体生物学的一个重要方面，并且已经定义了各种各样的机制。对于革兰氏阳性菌，胆固醇依赖性细胞溶解素（CDC）家族蛋白的分泌在高浓度下可能导致某些细胞类型的溶解，但在较低浓度下也可能使细胞（如巨噬细胞）对TLR4参与诱导凋亡的刺激敏感。这是最近报道的一种由炭疽杆菌产生的CDC溶血素O，以及其他一些CDC家族成员。然而，刺激TLR可能被认为是一把双刃剑，因为这也可能刺激免疫反应，特别是当涉及强效ARC（如树突状细胞）时。我们研究了三种CDC蛋白，溶血素O、破伤风溶血素O和溶血素O的作用，并观察到人类DC对无毒水平的这些蛋白的治疗迅速反应，通过钙的流动，然后分泌或脱落微泡（MV），微泡表面有II类MHC蛋白。同时，DC在IPS作用下失去了上调II类MHC的能力。基于这些结果，我们假设CDC通过诱导含有II类MHC的MV和其他对抗原呈递功能重要的蛋白质的分泌，从而损害DC的抗原呈递。此外，我们认为释放的MV本身可能具有免疫抑制特性，基于与称为外泌体的囊泡的相似性，并且CDC毒素可能散布在全身并被吞噬细胞吸收，以这种方式比感染部位更广泛地影响抗原呈递。我们建议进一步表征具有代表性的CDC蛋白TLO对人单核细胞源性DC功能的影响，并研究TLO诱导的MV对免疫反应的影响，目的如下：将确定TLO如何影响moDC中的II类定位；2. 对tlo诱导的MV蛋白含量进行表征；3. 探讨细胞产生和摄取MV的机制；4. tlo诱导的和组成性产生的MV对CD4和CDS T细胞功能的影响将被确定。声明;了解细菌毒素是如何影响免疫反应的，可以帮助设计出治疗破伤风、链球菌病和炭疽的新方法。