Molecular mechanisms of Salmonella mediated autoimmunity

沙门氏菌介导的自身免疫的分子机制

• 批准号: 10031214
• 负责人: Cagla Tukel
• 金额: $ 38.46万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 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/10031214
• 关键词: Alleles; Amyloid; Animal Model; Ankylosing spondylitis; Antibiotic Therapy; Arthritis; Autoantibodies; Autoantigens; Autoimmune Process; Autoimmune Responses; Autoimmunity; Bacteria; Bacterial Infections; Campylobacter; Collagen Arthritis; Complex; DNA; DNA receptor; Data; Development; Disease; Dose; Endosomes; Enterobacteriaceae; Epithelial; Epithelium; Escherichia coli; Etiology; Exposure to; Generations; Genetic Predisposition to Disease; Goals; HLA Antigens; Histocompatibility; Human; Immune; Immune system; Immunity; Individual; Infection; Inflammation; Inflammatory Arthritis; Interferon Type I; Interferons; Interleukin-17; Intestines; Leaky Gut; Link; Lupus; Measures; Mediating; Microbial Biofilms; Modeling; Molecular; Morbidity - disease rate; Mus; Oral; Organ; Pain; Pathogenesis; Pathway interactions; Patients; 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; mortality; mutant; prevent; public health relevance; response

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 当免疫系统识别出自身免疫性疾病时，就会发生慢性自身免疫性疾病。 抗原作为外来物，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，有许多由细菌感染引起的疾病的例子 或加剧自身免疫反应。一种被充分描述的自身免疫性疾病 因感染而出现的病症是反应性关节炎 (ReA)，也称为反应性关节炎 (ReA) 称为感染后关节炎或强直性脊柱炎。下列的 肠道病原体引起的胃肠道感染，例如沙门氏菌、志贺氏菌或 耶尔森菌感染后，5-10% 的患者会出现 ReA，这是一种痛苦的炎症性关节炎。经过 使用肠沙门氏菌鼠伤寒血清型（STm）作为模式生物，我们 发现 STm 淀粉样蛋白表面结构参与生物膜形成，curli 原纤维，与 DNA 形成稳定的复合物，并且 Curli/DNA 复合物是 自身免疫的有效刺激剂。全身暴露于这些复合物会触发 以产生 I 型干扰素为特征的自身免疫反应 (IFN) 和抗双链 DNA (抗 dsDNA) 自身抗体。 该应用程序的主要目的是通过以下方式研究其机制 哪些 curli/DNA 复合物被免疫系统识别并触发 胃肠道感染后的自身免疫。在这里，我们假设 侵入性 STm 在肠道中产生卷曲会导致自身免疫性后遗症 通过触发上皮损伤并激活 TLR2 和 TLR9，从而导致 I 型干扰素和 17 型免疫的上调。在目标 1 中，我们将 确定 Curli 表达细菌和 Curli/DNA 复合物在 自身免疫的发展。在目标 2 中，我们将确定免疫途径 有助于 STm 感染诱导的自身免疫。在目标 3 中，我们将 确定对自身免疫的遗传易感性是否会增强免疫 由curli/DNA复合物激活。