Session Title: Systemic Lupus Erythematosus - Animal Models
Session Type: Abstract Submissions (ACR)
Background/Purpose: Infection is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). This is largely due to the use of potent immunosuppressive therapy, but may also stem from inherent immune dysregulation. Curli is a bacterial amyloid that serves as a component of enteric bacterial biofilms including those of Escherichia coli and Salmonella enterica serovar Typhimurium. Patients are exposed to curli during urinary tract infections, gastrointestinal infections, and sepsis. Nucleic acids are also an integral part of curli biofilms as treatment with DNases leads to biofilm dissociation. Here we studied the immune response to nucleic acid-containing curli amyloids in the context of murine SLE.
Methods: Curli amyloid was isolated from Salmonella bacterial cultures. In vitro studies were performed using bone marrow-derived dendritic cells (BMDCs) from wild type and lupus-prone mice. BMDCs were activated with a dose titration of curli amyloid. Synthetic curli was used to study the role of nucleic acids in the immune response. In vivo studies were performed using lupus-prone NZBW-F1 mice. To simulate a chronic bacterial infection, eight 6-week-old mice were injected intraperitoneally (i.p.) with curli or PBS three times a week for 5 weeks and monitored for autoantibody production.
Results: We found that curli amyloids from bacterial cultures contain abundant nucleic acids and that exogenous DNA enhances amyloid fibrillization. BMDCs strongly respond to curli, producing large quantities of IL-12, IL-6, and IL-10. Curli also induces expression of IFN-β and IFN-simulated genes, with BMDCs from lupus-prone mice over-expressing these genes compared to wild type. Using both natural and synthetic curli, we found that curli and nucleic acids synergize to activate DCs. Lupus-prone NZBW-F1 mice injected i.p. with curli, compared to PBS, produce high quantities of anti-dsDNA and anti-chromatin autoantibodies within 2 weeks of the first injection.
Conclusion: The bacterial amyloid curli contains nucleic acids which are integral to the immune response to bacterial biofilms. Curli is a potent activator of dendritic cells and can rapidly accelerate autoimmunity in lupus-prone mice. This work suggests that nucleic acid-containing bacterial amyloids are an important environmental trigger for lupus and that curli injection may be useful as a novel method to accelerate murine lupus.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/bacterial-amyloids-promote-type-i-interferon-production-and-accelerate-autoimmunity/