Immune recognition of amyloid/extracellular DNA complexes

淀粉样蛋白/细胞外 DNA 复合物的免疫识别

基本信息

批准号：
9373285
负责人：
Cagla Tukel
金额：
$ 23.4万
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：
2017
资助国家：
美国
起止时间：
2017-06-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9373285
关键词：
Alzheimer&apos s Disease Amino Acid Sequence Amyloid Amyloid fibers Antibodies Autoantibodies Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity Bacteria Bacterial Infections Chromatin Communities Complex Cytosol DNA DNA receptor Data Disease Endosomes Enteral Enterobacteriaceae Escherichia coli Exposure to Extracellular Matrix Fiber Generations Goals Human Immune Immune system Infection Inflammasome Inflammation Innate Immune System Interferon Type I Interferons Interleukin-17 Lead Ligands Link Microbial Biofilms Molecular Non-Insulin-Dependent Diabetes Mellitus Pathogenesis Pathogenicity Patients Pattern Pattern recognition receptor Prion Diseases Production Proteins Role Salmonella Salmonella enterica Structure Systemic Lupus Erythematosus TLR1 gene TLR2 gene Techniques Testing antimicrobial drug beta pleated sheet ds-DNA expectation extracellular human disease immunogenic in vivo innovation microbiome multidisciplinary novel pathogen physical property protein complex public health relevance receptor response

项目摘要

The human immune system is often exposed to bacterial ligands through interactions with the microbiome and infections. Bacterial biofilms are associated with numerous human infections. The predominant protein expressed in enteric biofilms is amyloid curli that forms highly immunogenic complexes with DNA. Infection with curli- expressing bacteria or systemic exposure to purified curli-DNA complexes of Salmonella biofilms trigger autoimmunity via the generation type I interferons and anti-double stranded (ds)DNA. However, the mechanisms involved in the pro-autoimmune effects of curli/DNA complexes remain unknown. The primary objective of this application is to elucidate the mechanisms by which bacterial amyloids are recognized by the immune system, leading to their pathogenic effects in the host. Our central hypothesis is that curli/DNA complexes are pathogenic molecules that act by accessing multiple cellular compartments and engaging several Pattern Recognition Receptors, including, TLR2, TLR9 and NLRP3 resulting in inflammation and autoimmune responses. It is our expectation that successful completion of the proposed studies will identify bacterial amyloids as a novel powerful Pathogen-Associated Molecular Pattern (PAMP) that is recognized by the immune system via multiple receptors and establish a new paradigm that infections with amyloid- expressing bacteria are major environmental trigger fir complex human diseases.

人类免疫系统通常通过细菌配体暴露于与微生物组和感染的相互作用。细菌生物膜与许多人类感染。在肠生物膜中表达的主要蛋白是与DNA形成高度免疫原性复合物的淀粉样蛋白卷。卷曲感染表达细菌或全身暴露于沙门氏菌的纯化的卷curli-DNA复合物生物膜通过I型干扰素和抗双触发自身免疫性触发自身免疫性滞留（DS）DNA。但是，涉及的自动免疫作用的机制卷/DNA复合物仍然未知。该应用的主要目的是阐明细菌淀粉样蛋白被免疫系统识别，导致其致病性主机的效果。我们的中心假设是卷/DNA复合物是致病性的通过访问多个蜂窝室并参与几个来起作用的分子模式识别受体，包括TLR2，TLR9和NLRP3，导致炎症和自身免疫反应。我们期望成功拟议的研究的完成将识别细菌淀粉样蛋白是一种新颖的功能病原体相关的分子模式（PAMP），由免疫识别通过多个受体进行系统，并建立一个新的范式，该范式感染了淀粉样蛋白表达细菌是主要的环境触发FIR复杂的人类疾病。