Exposure to bacterial Curli triggers antibody production and type I interferon activation in lupus patients

Abstract

Infections are a major contributor to lupus disease. We have previously demonstrated that bacterial amyloid curli, produced by E.coli, can accelerate disease in mouse models of lupus. Interestingly curli incorporates extracellular DNA, which in turn can be both adjuvant and a self-antigen in lupus. Finally, uropathogenic E. coli (UPEC) is responsible for the majority of urinary tract infections in SLE. Based on our previous results, we hypothesize that exposure to UPEC triggers anti-curli antibodies, and that curli can also trigger the innate immune system. We investigated 34 lupus patients who met at least 4 SLICC criteria. Results were compared to 17 age, sex and race matched healthy controls. We tested the production of anti-curli/DNA complex for both IgG and IgA subclasses. We than correlated the levels of anti-curli/DNA antibodies with clinical parameters, including anti-dsDNA antibodies and bacteriuria. Finally, we used curli/DNA complexes to stimulate PBMCs from lupus patients and controls and determined the levels by rt-PCR of IL-6 (bacterial response) and MX-1 (type I interferon (IFN I) activation). We found that lupus patients and healthy controls generated anti-curli antibodies of IgG and IgA subclasses. The levels of anti-curli antibodies significantly correlated with the levels of anti-dsDNA antibodies (p=0.029) and persistent bacteriuria (p=0.035) in lupus patients. Finally we found that curli/DNA complexes triggered production of IL-6 and MX-1 in both healthy and lupus PBMCs. Nevertheless, the expression of MX-1 was significantly higher in PBMCs from lupus patients (p=0.012). Our results show that bacterial curli/DNA is a trigger of systemic autoimmunity via activation of IFN I and production of autoantibodies.