Bacterial biofilm product Curli/eDNA induces NETs and serum anti-Curli/eDNA levels correlate with bacteriuria and lupus activity.

Abstract

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/eDNA antibodies and curli/eDNA complexes can stimulate the innate immune system. We investigated 98 lupus patients who met at least 4 SLICC criteria. Results were compared to 54 age, sex and race matched healthy controls. We tested the production of anti-curli/DNA complex of both IgG and IgA subclasses. We than correlated the levels of anti-curli/DNA antibodies with clinical parameters. Finally, we stimulated human neutrophils with curli/eDNA complexes. We found that anti-curli/eDNA IgG levels were detected in both lupus and controls plasma. In lupus patients, anti-curli/eDNA levels correlated with persistent bacteriuria and disease flares (p<0.05). In addition, anti-curli/eDNA antibodies recognized dsDNA suggesting a potential molecular mimicry mechanism for curli/eDNA with self-antigens such as dsDNA. We also found that IgA anti-curli/eDNA levels were higher (p<0.01) in lupus donors compared to controls. Finally we found that curli/eDNA induced neutrophil extracellular traps (NETs) and the induction was ROS-dependent. We conclude that curli/eDNA complexes from UTIs can activate the innate immune system and IgG and IgA anti-curli/eDNA are strong biomarkers for disease activity and severity.