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2025-12
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Microbiology and Immunology
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Autoimmune diseases are complex: caused by combinations of genetics and environmental factors, one of the most potent being bacterial dysbiosis and/or infection. We have previously observed that the functional amyloid, curli, found in biofilms of Salmonella and E. coli, among other enterics, induced an autoimmune response in mice characterized by inflammation in knee joints and antinuclear autoantibodies, analogous to Reactive Arthritis (ReA) and Systemic Lupus Erythematosus (SLE), respectively. We aimed to determine if and how curli interacts with genetic predisposition to exacerbate pro-inflammatory responses and autoimmunity. ReA is associated strongly with the HLA-B27 genotype. We showed that curli induced a stronger unfolded protein response (UPR) in HLA-B27tg macrophages than in C57BL/6, and in cecal tissue of HLA-B27tg mice infected with curli-producing Salmonella Typhimurium (STm). Inhibitors of IRE1α, an upstream UPR sensor, significantly reduced the IL-6 response to curli treatment in macrophages. GRP78, a UPR protein, colocalized with curli in the cytoplasm of macrophages and in the ceca of infected mice, where curli appeared to be taken up by primarily F4/80+ macrophages in the lamina propria. These findings suggest a novel mechanistic link through the UPR connecting HLA-B27 and curli in ReA pathogenesis.
The genetics of SLE are complex, but we can use NZBxW/F1 and MRL/lpr mice as genetics-driven models that recapitulate human sequalae, including autoantibody production, proteinuria, and progressive immune complex glomerulonephritis. Previous work showed that NZBxW/F1 mice treated with curli before normal onset of disease, developed higher levels of anti-dsDNA autoantibodies than curli-treated wild-type mice. Meanwhile, we found that levels of anti-dsDNA in NZBxW/F1 mice several weeks after disease onset were all high, compared to pre-onset, and indistinguishable between curli-treated and untreated. In contrast, anti-C1q autoantibodies, a biomarker associated with nephritis, were significantly higher in curli-treated NZBxW/F1 mice than untreated, regardless of age group (pre-disease, early-disease, and late-disease), though the baseline anti-C1q level in untreated mice increased with age, consistent with previous studies. Curli treatment, extracted from either STm or E. coli biofilms, or STm infection, also induced anti-C1q autoantibodies in wild-type mice. The curli-treated late-disease NZBxW/F1 mice lost significantly more weight than untreated mice and a greater number failed to survive the full 7-week experiment, though this difference was not statistically significant. Early-disease curli-treated MRL/lpr mice, which have a faster disease progression than NZBxW/F1 mice, developed significantly higher levels of anti-C1q antibodies than untreated mice, more drastically different than was seen in NZBxW/F1 mice. While neither curli-treated NZBxW/F1 nor MRL/lpr developed significant differences in proteinuria, a marker of kidney damage, curli-treated MRL/lpr mice had significantly higher deposition of C1q in the glomeruli of the kidneys. These results suggest that the higher anti-C1q level is associated with greater recruitment of C1q into immune complex deposits, and that curli, from infection or dysbiosis, can break tolerance to C1q in addition to DNA, as previously demonstrated. This provides a novel link between bacterial biofilms and nephritis development in SLE patients. Together, these findings provide new understanding of the mechanisms involved in autoimmunity, and how genetics and bacteria synergize to promote disease. Once we understand dysregulated mechanisms, treatments can be developed to address or prevent infection-associated autoimmune diseases.
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