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: 10402395
• 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
• 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/10402395
• 关键词: Alleles; Amyloid; Animal Model; 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; Epithelial; 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.

摘要 慢性自身免疫性疾病发生时，免疫系统识别自身 抗原是外来的，会导致炎症和特定组织的破坏 器官。尽管许多慢性自身免疫性疾病的病因通常是 未知的是，有许多疾病是由细菌感染引发的 或加剧自身免疫反应。一种被广泛描述的自身免疫性疾病 对感染作出反应的情况是反应性关节炎(ReA)，也 称为感染后关节炎或强直性脊柱炎。跟随 肠道病原体如沙门氏菌、志贺氏菌或 耶尔西尼亚，5%-10%的患者会患上REA，这是一种痛苦的炎症性关节炎。通过 以鼠伤寒沙门氏菌(STM)为模式生物，我们 发现一种STM淀粉样蛋白表面结构参与生物膜的形成，Curli 纤维与DNA形成稳定的络合物，卷曲/DNA络合物是 强大的自身免疫力刺激剂。全身暴露在这些复合体中会触发 一种自身免疫反应，特征是产生I型干扰素 (IFN)和抗双链DNA(抗dsDNA)自身抗体。 这个应用程序的主要目标是通过以下方式研究机制 哪些卷曲/DNA复合体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 侵袭性STM在肠道中产生卷曲导致自身免疫后遗症 通过触发上皮损伤并激活TLR2和TLR9，进而导致 在I型干扰素和17型免疫的上调中。在目标1中，我们将 确定表达Curli的细菌和Curli/DNA复合体在 自身免疫的发展。在目标2中，我们将确定 在STM感染诱导自身免疫中起重要作用。在《目标3》中，我们将 确定自身免疫的遗传易感性是否能增强免疫力 由Curli/DNA复合体激活。