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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.

总结