Bacterial amyloids promote type I interferon production and accelerate autoimmunity (BA6P.124)

Abstract

Abstract Infections can be pathogenic in systemic lupus erythematosus (SLE). Curli is a bacterial amyloid part of enteric bacterial biofilms, like those of E. coli and Salmonella. We have recently found that curli fibers form highly immunogenic composites with DNA within the biofilm. Here we studied the immune response to curli-DNA complexes in the context of murine SLE. For in vitro studies, we stimulated bone marrow-derived dendritic cells (cDCs) from WT and lupus-prone mice with curli amyloid from S. Typhimurium biofilms. A dose titration of curli amyloid induced robust proinflammatory cytokine and type I-IFN responsive gene expression in cDCs. Using synthetic curli peptide, we found that curli and nucleic acids synergize to activate cDCs. We injected in vivo pre-diseased lupus-prone NZB/W-F1 mice i.p. with curli-DNA complexes and found that they accelerate disease, inducing high titers of anti-dsDNA and anti-chromatin autoantibodies. Curli-DNA complexes induced autoantibodies also in non-autoimmune C57BL/6 mice. Finally, we infected NZB/W-F1 mice i.p. with curli-expressing or curli mutant E. coli or Salmonella. Curli-competent bacteria triggered far higher autoantibody titers than curli mutant strains. In conclusion, biofilm-derived curli-DNA complexes are potent activators of DCs and can rapidly break tolerance and accelerate autoimmunity in mice, suggesting that bacterial amyloids and biofilm-based bacterial infections are important environmental triggers in lupus.