Immune recognition of amyloid/extracellular DNA complexes

人类免疫系统经常通过以下途径暴露于细菌配体 与微生物群的相互作用和感染。细菌生物膜与 大量的人类感染。在肠道生物膜中表达的主要蛋白质是 淀粉样卷曲，与DNA形成高度免疫原性的复合体。感染卷曲- 表达细菌或全身暴露于纯化的沙门氏菌卷曲DNA复合体 生物被膜通过第一代干扰素和抗双链抗体触发自身免疫 搁浅(DS)DNA。然而，促自身免疫效应所涉及的机制 Curli/DNA复合体仍不清楚。 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 对宿主的影响。我们的中心假设是Curli/DNA复合体是致病的 分子通过进入多个细胞隔间并与几个 模式识别受体，包括TLR2，TLR9和NLRP3，导致 炎症和自身免疫反应。我们的期望是，成功 拟议研究的完成将确定细菌淀粉样蛋白是一种新的强大的 免疫识别的病原体相关分子模式(PAMP) 系统通过多个受体，并建立一个新的范例，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。

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.