Bacterial amyloids: interactions with DNA and pathogenicity

细菌淀粉样蛋白：与 DNA 的相互作用和致病性

• 批准号: 9551789
• 负责人: Cagla Tukel
• 金额: $ 55.73万
• 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: 2017-09-07 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9551789
• 关键词: Alzheimer' s Disease; Amyloid; Amyloid Proteins; Amyloid fibers; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Bacteria; Bacterial DNA; Bacterial Infections; Caspase; Cell Death; Chromatin; Clinical; Communities; Complement; Complex; Cytosol; DNA; DNA Binding; DNA receptor; Detection; Disease; Endosomes; Enteral; Enterobacteriaceae; Escherichia coli; Exposure to; Extracellular Matrix; Fiber; Generations; Goals; Human; IL17 gene; Immune response; Immune system; Immunologic Receptors; In Vitro; Infection; Inflammasome; Inflammation; Inflammatory; Innate Immune System; Interferon Type I; Interferons; Lead; Link; Lipopolysaccharides; Microbial Biofilms; Molecular; Mus; Pathogenesis; Pathogenicity; Patients; Pattern; Pattern recognition receptor; Periodontal Diseases; Prion Diseases; Role; Salmonella typhimurium; Septic Shock; Structure; Syndrome; Systemic Lupus Erythematosus; TLR4 gene; Techniques; Testing; Toll-like receptors; Urinary tract infection; Work; beta pleated sheet; ds-DNA; expectation; extracellular; human disease; in vivo; innovation; microbial; multidisciplinary; novel; novel therapeutics; pathogen; protein complex; public health relevance; receptor; response; rhinosinusitis

Summary Amyloids are complex proteins with a conserved beta sheet structure. Bacteria use amyloids to decorate the extracellular matrix of their biofilms, highly structured multicellular communities. Curli are amyloids expressed by enteric bacteria, including Salmonella Typhimurium and Escherichia coli. Our group has shown that curli amyloid fibers are recognized by TLR2/1 as well as the NLRP3 inflammasome. This finding is of broad relevance, because detection of amyloids by the innate immune system drives the pathogenesis of Alzheimer's disease and prion diseases. A recent study demonstrated that an artificially formed amyloid protein can bind DNA in vitro and this complex elicits an autoimmune response in mice. Since the biofilm extracellular matrix naturally harbors amyloids and DNA, we explored the interactions between these two molecules and determined that bacterial DNA released during biofilm formation was irreversibly incorporated into curli fibers. Bacteria expressing curli or purified curli/DNA complex triggered autoimmune responses in vivo. The primary objective of this application is to elucidate the mechanism by which bacterial amyloids are recognized by the immune system, leading to their pathogenic effects in the host. Our central hypothesis is that bacterial amyloid/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 triggers not only for SLE but also for several other complex human diseases.

摘要 淀粉样蛋白是一种复杂的蛋白质，具有保守的β-折叠结构。细菌利用淀粉样蛋白 装饰它们生物膜的细胞外基质，高度结构的多细胞群落。 卷曲是由肠道细菌表达的淀粉样蛋白，包括鼠伤寒沙门氏菌和 大肠埃希菌。我们的团队已经证明TLR2/1也能识别卷曲的淀粉样纤维 作为NLRP3炎症体。这一发现具有广泛的相关性，因为淀粉样蛋白的检测 由先天免疫系统驱动阿尔茨海默氏病和普里恩病的发病机制。 最近的一项研究表明，人工形成的淀粉样蛋白在体外可以与DNA结合 这种复合体在小鼠身上引发了一种自身免疫反应。由于生物膜细胞外基质 天然含有淀粉样蛋白和DNA，我们探索了这两个分子之间的相互作用 并确定在生物膜形成过程中释放的细菌DNA被不可逆转地结合 变成卷曲纤维。表达Curli或纯化Curli/DNA复合体的细菌触发自身免疫 活体内的反应。 这一应用的主要目的是阐明细菌通过 淀粉样蛋白被免疫系统识别，导致其在宿主中的致病作用。 我们的中心假设是细菌淀粉样蛋白/DNA复合体是致病分子 通过访问多个蜂窝隔间并使用几个模式识别来操作 受体，包括TLR2、TLR9和NLRP3，导致炎症和自身免疫 回应。我们期望建议的研究能顺利完成，以确定 细菌淀粉样蛋白作为一种新的强大的病原体相关分子模式(PAMP)，即 通过多个受体被免疫系统识别，并建立一种新的范式， 感染表达淀粉样蛋白的细菌不仅是系统性红斑狼疮的主要环境诱因，而且 对其他几种复杂的人类疾病也是如此。