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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

概括淀粉样蛋白是具有保守β片结构的复杂蛋白质。细菌使用淀粉样蛋白为了装饰其生物膜的细胞外基质，高度结构化的多细胞群落。 curli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杆菌。我们的小组表明，卷淀粉样蛋白纤维也被TLR2/1识别作为NLRP3炎症体。这一发现具有广泛的相关性，因为检测淀粉样蛋白通过先天的免疫系统驱动了阿尔茨海默氏病和prion病的发病机理。最近的一项研究表明，人为形成的淀粉样蛋白可以在体外结合DNA 这种复合物引起了小鼠的自身免疫反应。由于生物膜外基质自然地武器淀粉样蛋白和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是不可逆转的进入卷纤维。表达卷曲或纯化的卷/DNA复合物触发自身免疫的细菌体内反应。该应用的主要目的是阐明细菌的机制淀粉样蛋白被免疫系统识别，从而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复合物是致病分子通过访问多个蜂窝室并参与几种模式识别来行动受体，包括TLR2，TLR9和NLRP3，导致炎症和自身免疫性回答。我们期望成功完成拟议的研究将确定细菌淀粉样蛋白作为一种新型强大的病原体相关分子模式（PAMP）通过多个受体识别免疫系统，并建立一个新的范式表达淀粉样蛋白细菌的感染不仅是SLE的主要环境触发因素，而且是也适用于其他几种复杂的人类疾病。