Molecular mechanisms of Salmonella mediated autoimmunity

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Summary Chronic autoimmune diseases occur when the immune system recognizes self- antigens as foreign, leading to inflammation and destruction of specific tissues and organs. Although the etiology of many chronic autoimmune diseases is generally unknown, there are many examples of diseases in which bacterial infections initiate or exacerbate autoimmune responses. One of the well-described autoimmune conditions that develop in response to an infection is reactive arthritis (ReA), also known as post-infectious arthritis or ankylosing spondylitis. Following gastrointestinal infections with enteric pathogens such as Salmonella, Shigella, or Yersinia, 5-10% of patients develop ReA, a painful form of inflammatory arthritis. By using Salmonella enterica serovar Typhimurium (STm) as a model organism, we discovered that a STm amyloid surface structure involved in biofilm formation, curli fibrils, form stable complexes with DNA, and that the curli/DNA complexes are potent stimulators of autoimmunity. Systemic exposure to these complexes triggers an autoimmune response characterized by the production of type I interferons (IFNs) and anti-double stranded DNA (anti-dsDNA) autoantibodies. The primary objective of this application is to investigate the mechanisms by which curli/DNA complexes are recognized by the immune system and trigger autoimmunity following gastrointestinal infection. Here, we hypothesize that that the production of curli in the gut by the invasive STm leads to autoimmune sequelae by triggering epithelial damage and activating TLR2 and TLR9, which in turn results in the upregulation of type-I IFN and of type-17 immunity. In aim 1, we will determine the role of curli-expressing bacteria and of curli/DNA complexes in the development of autoimmunity. In aim 2, we will identify the immune pathways that contribute to the autoimmunity induced by STm infection. In aim 3, we will determine whether genetic susceptibility to autoimmunity enhances the immune activation by curli/DNA complexes.