Phenol-Soluble Modulins From <i>Staphylococcus aureus</i> Biofilms Form Complexes With DNA to Drive Autoimmunity.

Abstract

The bacterial amyloid curli, produced by Enterobacteriales including <i>Salmonella</i> species and <i>Escherichia coli</i>, is implicated in the pathogenesis of several complex autoimmune diseases. Curli binds to extracellular DNA, and these complexes drive autoimmunity <i>via</i> production of anti-double-stranded DNA autoantibodies. Here, we investigated immune activation by phenol-soluble modulins (PSMs), the amyloid proteins expressed by <i>Staphylococcus</i> species. We confirmed the amyloid nature of PSMs expressed by <i>S. aureus</i> using a novel specific amyloid stain, (<i>E</i>,<i>E)</i>-1-fluoro-2,5-bis(3-hydroxycarbonyl-4-hydroxy) styrylbenzene (FSB). Direct interaction of one of the <i>S. aureus</i> PSMs, PSMα3, with oligonucleotides promotes fibrillization of PSM amyloids and complex formation with bacterial DNA. Finally, utilizing a mouse model with an implanted mesh-associated <i>S. aureus</i> biofilm, we demonstrated that exposure to <i>S. aureus</i> biofilms for six weeks caused anti-double-stranded DNA autoantibody production in a PSM-dependent manner. Taken together, these results highlight how the presence of PSM-DNA complexes in <i>S. aureus</i> biofilms can induce autoimmune responses, and suggest an explanation for how bacterial infections trigger autoimmunity.