Activation of cytosolic activation of Nod like receptors (NLRs) induces the assembly of inflammasomes, which are cytosolic multiprotein complexes that activate inflammatory caspases (caspase-1 and -11). These caspases promote the cleavage of pro-IL-1? and pro- IL-18 to active IL-1? and IL-18, triggering also pyroptosis, an inflammatory cell death that kills the infected cell. IL-1? is a key cytokine that has been implicated in the pathogenesis of several inflammatory diseases as well as bacterial infections including Salmonella enterica serovar Typhimurium (S. Typhimurium) infection. NLRP3 is the best-characterized inflammasome, which can be activated with a wide range of danger signals and uses apoptosis-associated speck-like protein containing a CARD (ASC) as an adaptor molecule. Nonetheless, the molecule that trigger NLRP3 assembly during S. Typhimurium infection is not known. Amyloid proteins, produced both by bacteria and humans, are characterized by their conserved cross-?-sheet quaternary structure. Amyloid fibers are an important extracellular matrix component of biofilms formed by diverse groups of bacteria. Intriguingly, human amyloid-?, islet amyloid polypeptide and serum amyloid A (SAA) have all been demonstrated to activate the NLRP3 inflammasome resulting in the production of IL-1? . Our long-range goal is to elucidate the role of bacterial amyloids in microbe-host interactions. Amyloid fibers produced in the biofilms of S. Typhimurium are termed curli and have been shown to be expressed during infection. The objective of this application is to determine whether bacterial amyloid curli would trigger IL-1? and IL-18 production through NLRP3 activation during S. Typhimurium infection.
Foodborne Salmonella infections are the most common cause of morbidity and mortality in the United States. Biofilm formation help Salmonella survive the hostile conditions. We have identified Salmonella biofilm components that modulate innate immune responses. This application will further unravel the role of biofilms in Salmonella pathogenesis and expand our basic novel knowledge on how immune responses are generated in response to biofilms, which will facilitate the development of new therapeutic approaches.
