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.