Immune recognition of amyloid/extracellular DNA complexes

淀粉样蛋白/细胞外 DNA 复合物的免疫识别

• 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
• 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' 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

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以下途径暴露于细菌配体： 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质是 与DNA形成高度免疫原性复合物的淀粉样卷曲。感染卷曲- 表达细菌或全身暴露于沙门氏菌的纯化卷曲-DNA复合物 生物膜通过第一代干扰素和抗双链抗体触发自身免疫 双链DNA（ds DNA）然而，参与促自身免疫作用的机制 curli/DNA复合物仍然未知。 本申请的主要目的是阐明 细菌淀粉样蛋白被免疫系统识别，导致其致病性 在主机上的影响。我们的中心假设是curli/DNA复合物是致病的 这些分子通过进入多个细胞区室并与几个 模式识别受体，包括TLR 2、TLR 9和NLRP 3，导致 炎症和自身免疫反应。我们期望， 拟议研究的完成将确定细菌淀粉样蛋白是一种新型的强效药物 病原体相关分子模式（PAMP），由免疫系统识别 系统通过多种受体，并建立了一个新的范例，感染淀粉样蛋白- 表达细菌是引发复杂人类疾病的主要环境因素。