Innate immune detection of pathogens relies upon recognition of conserved pathogen associated molecular patterns (PAMPs). Toll-like receptor (TLR) mediated recognition of IPS, lipopeptides, flagellin and other molecules has provided us with a model of recognition of PAMPs by the innate immune system. There are 24 Nod/Nalp proteins that are involved in similar processes and follow the TLR paradigm, but recognize cytoplasmic rather than extracellular PAMPs. Nodi and Nod2 respond to bacterial peptidoglycan within the cytoplasmic compartment, likely responding to intracellular infections by bacteria such as Shigella and Listeria. Mutations in Nod/Nalp family members are associated with diseases of inflammatory dysregulation: Nod2 polymorphisms increase the risk of Crohn's disease while NalpS mutations cause a spectrum of syndromes characterized by hyperactivation of inflammatory responses. In this proposal we will focus on Ipaf, a Nod/Nalp family member. Ipaf activates NF-KappaB and Caspase 1 in immune cells. It is required for Caspase 1 activation and subsequent macrophage cell death caused by infection with Salmonella typhimurium. We will define the poorly understood Ipaf signaling pathway through Rip2 and ASC. The molecular protein-protein interactions between Ipaf and its signaling partners will be determined, and the contribution of Rip2 and ASC to the two outputs (NF-KappaB and Caspase 1) will be determined. We will characterize Salmonella mediated Ipaf activation and determine if this acts as predicted to promote inflammatory responses, or if the bacteria have subverted this innate response to their own benefit. These studies will define the function of macrophage PAMP recognition through Ipaf and determine if Salmonella has evolved strategies to corrupt the very mechanism designed to destroy them. Knowledge gained from the study of Ipaf signaling will be broadly applicable to other Nod/Nalp proteins and their regulation of immune defenses. These insights will apply to a broad range of inflammatory and infectious disease.
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