Molecular mechanisms of Salmonella mediated autoimmunity

沙门氏菌介导的自身免疫的分子机制

基本信息

批准号：
10624790
负责人：
Cagla Tukel
金额：
$ 39.63万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624790
关键词：
Acceleration Alleles Amyloid Ankylosing spondylitis Antibiotic Therapy Arthritis Autoantibodies Autoantigens Autoimmune Autoimmune Diseases Autoimmune Responses Autoimmunity Bacteria Bacterial Infections Campylobacter Collagen Arthritis Complex DNA DNA receptor Data Development Disease Dose Endosomes Enterobacteriaceae Epithelium Escherichia coli Etiology Exposure to Generations Genetic Predisposition to Disease Goals HLA Antigens Histocompatibility Human IL17 gene Immune Immune system Immunity Individual Infection Inflammation Inflammatory Arthritis Interferon Type I Intestines Leaky Gut Link Lupus Measures Mediating Microbial Biofilms Modeling Molecular Morbidity - disease rate Mus Oral Organ Pain Pathogenesis Pathway interactions Patients Predisposition Preventive Process Production Reiter Disease Research Role Salmonella Salmonella typhimurium Shigella Sodium Dextran Sulfate Structure Surface TLR2 gene TLR9 gene Testing Therapeutic Tissues Transgenic Mice Up-Regulation Wild Type Mouse Yersinia chronic autoimmune disease chronic infection cytokine ds-DNA enteric infection enteric pathogen gastrointestinal infection immune activation joint inflammation model organism mortality mutant prevent public health relevance response

项目摘要

Summary Chronic autoimmune diseases occur when the immune system recognizes self- antigens as foreign, leading to inflammation and destruction of specific tissues and organs. Although the etiology of many chronic autoimmune diseases is generally unknown, there are many examples of diseases in which bacterial infections initiate or exacerbate autoimmune responses. One of the well-described autoimmune conditions that develop in response to an infection is reactive arthritis (ReA), also known as post-infectious arthritis or ankylosing spondylitis. Following gastrointestinal infections with enteric pathogens such as Salmonella, Shigella, or Yersinia, 5-10% of patients develop ReA, a painful form of inflammatory arthritis. By using Salmonella enterica serovar Typhimurium (STm) as a model organism, we discovered that a STm amyloid surface structure involved in biofilm formation, curli fibrils, form stable complexes with DNA, and that the curli/DNA complexes are potent stimulators of autoimmunity. Systemic exposure to these complexes triggers an autoimmune response characterized by the production of type I interferons (IFNs) and anti-double stranded DNA (anti-dsDNA) autoantibodies. The primary objective of this application is to investigate the mechanisms by which curli/DNA complexes are recognized by the immune system and trigger autoimmunity following gastrointestinal infection. Here, we hypothesize that that the production of curli in the gut by the invasive STm leads to autoimmune sequelae by triggering epithelial damage and activating TLR2 and TLR9, which in turn results in the upregulation of type-I IFN and of type-17 immunity. In aim 1, we will determine the role of curli-expressing bacteria and of curli/DNA complexes in the development of autoimmunity. In aim 2, we will identify the immune pathways that contribute to the autoimmunity induced by STm infection. In aim 3, we will determine whether genetic susceptibility to autoimmunity enhances the immune activation by curli/DNA complexes.

概括当免疫系统识别自身时，会发生慢性自身免疫性疾病抗原作为外国，导致特定组织的炎症和破坏器官。尽管许多慢性自身免疫性疾病的病因通常是未知，有许多疾病的例子，其中细菌感染引发了或加剧自身免疫反应。描述良好的自身免疫性之一因感染而发展的疾病是反应性关节炎（REA），也是被称为感染后关节炎或强直性脊柱炎。下列的胃肠道感染，肠道病原体，例如沙门氏菌，志贺氏菌或耶尔森氏菌，5-10％的患者发展为炎症性关节炎的一种痛苦形式。经过使用沙门氏菌血清鼠伤寒（STM）作为模型有机体，我们发现与生物膜形成有关的STM淀粉样蛋白表面结构卷原纤维，与DNA形成稳定的复合物，并且卷/DNA复合物为自身免疫的有效刺激器。这些复合物的系统性暴露触发以I型干扰素产生为特征的自身免疫反应（IFN）和抗双链DNA（抗DSDNA）自身抗体。该应用的主要目的是通过免疫系统和触发识别哪种卷/DNA复合物胃肠道感染后的自身免疫性。在这里，我们假设侵入性STM在肠道中的卷曲产生导致自身免疫后遗症通过触发上皮损伤并激活TLR2和TLR9，这反过来导致在IFN型和17型免疫的上调中。在AIM 1中，我们将确定表达卷卷菌的细菌和卷/DNA复合物在自身免疫的发展。在AIM 2中，我们将确定免疫道路有助于由STM感染引起的自身免疫。在AIM 3中，我们将确定自身免疫性的遗传敏感性是否增强了免疫卷/DNA复合物激活。