The long-term goal of this project is to understand how bacterial pathogens evade host innate immune responses with the view that this will provide insight into host-pathogen interactions and facilitate development of antimicrobial therapeutics. Salmonella infection of the intestine induces rapid recruitment of immune cells and intestinal inflammation. Salmonella is able to survive and even takes advantage of this inflammatory response to spread systemically. In contrast, systemic infection, particularly during the chronic stage, is not associated with overtly high levels of host inflammation. A key underlying hypothesis of this proposal is that Salmonella promotes persistent infection by modulating host inflammatory responses. Innate immune recognition of bacterial infection involves pattern recognition receptors that sense conserved microbial structures as well as virulence activities. Members of the cytosolic Nod-like Receptor (NLR) protein family direct assembly of multiprotein complexes termed 'inflammasomes'in response to detection of microbial products in the cytosol or disruption of cellular membranes by microbial virulence factors. Inflammasome assembly induces activation of caspase-1, and caspase-1 dependent cleavage and secretion of IL-1 family cytokines and a caspase-1 dependent pro-inflammatory cell death (pyroptosis). Inflammasome activation plays a key role in host defense against diverse pathogens, but a number of bacterial and viral pathogens have recently been found to interfere with inflammasome activation. Activation of inflammasomes by Salmonella involves sensing of bacterial flagellin by NLRC4, and sensing of an unknown bacterial signal by NLRP3. Salmonella downregulates flagellin expression to evade the NLRC4 inflammasome, but how Salmonella might prevent NLRP3 inflammasome activation is not known. We have used a novel screening approach to identify Salmonella genes that modulate NLRP3 inflammasome activation. As a number of genes identified in this screen contribute to Salmonella persistence, our central hypothesis is that evading inflammasome activation promotes Salmonella persistence.
Aim 1 of this project will define the mechanisms of NLRP3 inflammasome evasion by the Salmonella genes we have identified.
Aim 2 of this project will test the role of inflammasome evasion in establishing and maintaining Salmonella persistent infection. These studies will provide novel insight into a critical aspect of Salmonella-host interactions, and are likely to provide novel therapeutic targets.
Salmonella infection is the largest single foodborne bacterial cause of morbidity and mortality in the United States. Increasing resistance among Gram-negatives including Salmonella to front-line antibiotics requires new approaches for antimicrobial development. We have identified Salmonella factors that modulate innate immune responses and will define the mechanism and role of these factors in Salmonella pathogenesis. These studies will aid in identifying novel therapeutic targets.
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