Contribution of local Salmonella infection to autoreactivity: divergent roles of type I interferons in colonization and autoantibody production

Salmonella biofilm-associated amyloid protein curli is a potent inducer of systemic inflammation and autoimmunity, promoting anti-double-stranded DNA (dsDNA) autoantibodies and pro-inflammatory cytokines, including type I interferons (IFNs). Although type I IFNs are key drivers of autoantibody production in systemic lupus erythematosus (SLE), their role in bacterial biofilm-induced autoimmunity remains unclear. To address this, we utilized type I IFN receptor-deficient ( Ifnar ^{−/ −} ) mice. Repeated curli administration induced anti-dsDNA autoantibodies independently of IFNAR signaling. We next orally infected C57BL/6 and Ifnar ^{−/ −} mice with a Salmonella enterica serovar Typhimurium (STm) Δ spiB mutant, which permits long-term colonization without lethal disease. While IFNAR deficiency altered local immune responses and reduced bacterial persistence beginning at 7 days post-infection, it did not affect autoantibody generation. Because extrafollicular splenic responses contribute to both Salmonella immunity and antibody-mediated autoimmunity, we examined germinal center activity and splenic involvement. Δ spiB infection neither suppressed nor stimulated splenic germinal center formation. Nevertheless, both wild-type and Δ spiB infections induced anti-dsDNA autoantibodies, suggesting that autoreactive responses occur independently of germinal center activity. Consistent with this, splenectomized mice infected with Δ spiB produced anti-dsDNA autoantibodies at levels comparable to sham-surgery controls. Together, these findings demonstrate that curli- and Salmonella -induced autoimmunity can arise independently of both type I IFN signaling and the spleen. Our results further identify early gastrointestinal colonization by S. Typhimurium as sufficient to trigger systemic autoreactive responses through mechanisms distinct from classical lupus pathways.

IMPORTANCE

Persistent colonization of the gastrointestinal tract by bacterial pathogens can have long-term consequences for host immunity that extend beyond the site of infection. Here, we show that intestinal colonization by Salmonella enterica serovar Typhimurium is sufficient to trigger systemic anti-DNA autoantibody responses, even in the absence of type I interferon signaling or the spleen. While type I interferon signaling promoted bacterial persistence, it was dispensable for autoreactive antibody production, revealing that bacterial colonization and autoimmunity can be uncoupled. Unexpectedly, splenectomized mice generated anti-DNA autoantibodies at levels comparable to controls, demonstrating that the spleen is not required for infection-induced autoreactivity. These findings identify early host-microbe interactions in the gut as a key driver of systemic immune dysregulation and highlight how bacterial colonization can shape immune responses and disease outcomes far beyond the intestinal environment.