In vivo synthesis of bacterial amyloid curli contributes to joint inflammation during S. Typhimurium infection

Reactive arthritis, an autoimmune disorder, occurs following gastrointestinal infection with invasive enteric pathogens, such asSalmonella enterica. Curli, an extracellular, bacterial amyloid with cross beta-sheet structure can trigger inflammatory responses by stimulating pattern recognition receptors. Here we show thatS. Typhimurium produces curli amyloids in the cecum and colon of mice after natural oral infection, in both acute and chronic infection models. Production of curli was associated with an increase in anti-dsDNA autoantibodies and joint inflammation in infected mice. The negative impacts on the host appeared to be dependent on invasive systemic exposure of curli to immune cells. We hypothesize thatin vivosynthesis of curli contributes to known complications of enteric infections and suggest that cross-seeding interactions can occur between pathogen-produced amyloids and amyloidogenic proteins of the host. Author summary Our manuscript focuses on curli, a 'functional amyloid' produced by Salmonella as well as other enteric bacteria. We present the first biochemical evidence that these fibers are produced in the gastrointestinal tract of mice after oral infection, the natural route for Salmonella infections. This finding is significant because of the immune impacts on the host; we show that curli cause an increase in autoimmunity and inflammation in the knee joints of infected mice. Reactive arthritis is a known autoimmune complication after enteric infections and our results indicate that presence of curli in the gut provides a novel linchpin of pathogenesis. As curli or curli-like amyloids are also produced by the commensal bacteria, it is possible that the unintended release of amyloids produced by the microbiota could trigger similar autoimmune reactions. Finally, our work provides conceptual evidence for the possibility of cross-seeding between bacterial amyloids like curli and human amyloids involved in amyloid-associated diseases such as Alzheimer's Disease via the gut microbiome or infections.