SummaryHuman intestinal tract is colonized by diverse microbial communities, termed the microbiota.Microbiota plays an important role in educating the immune system. However, the nature of themicrobe-host interactions that help maintain immune homeostasis is poorly understood. Onefeature of the gut microbiota is the formation of multicellular communities, termed biofilms, in themucus layer. The formation of biofilms is accompanied by the release of bacterial products thatform an extracellular matrix. Amyloid fibers are an important extracellular matrix component ofbiofilms formed by diverse groups of bacteria, including many members of the Proteobacteria,Bacteroidia and Firmicutes. Conserved beta sheet structure of amyloid fibers is recognized byreceptors of the innate immune system as a conserved molecular pattern (i.e. a so-calledpathogen-associated molecular pattern or PAMP). However, it is not known whether detection ofamyloid fibrils by the innate immune system represents one of the elusive microbe-hostinteractions that contribute to immune homeostasis at the mucosal surface. In addition toamyloids, extracellular bacterial DNA (eDNA) has been shown to be present in several bacterialbiofilms. The objective of this application is to determine the mechanisms by which bacterialamyloid curli/DNA complexes are recognized by the immune system in the gut. We hypothesizethat the immune system recognizes bacterial amyloid curli/DNA complexes as conservedmolecules common to bacterial biofilms. Curli/DNA complex acts by accessing multiple cellularcompartments and activates multiple PRRs including TLR2, TLR9 and NLRP3 leading to epithelialbarrier reinforcement in the gut by the generation of immunomodulatory cytokines, IL-10 and IL-18.