Distinct Roles of NF-[kappa]B p50 Homodimer in the Genomic Innate Immune Response

Two signaling systems play major roles in the innate immune response to pathogens. The NF-[kappa]B signaling network is primarily associated with the innate immune response to bacterial pathogens, while the network of interferon response factors (IRFs) is primarily associated with the response to viral pathogens. Some pathogen associated molecular pattern (PAMP) receptors coordinate signaling between both the NF-[kappa]B and IRF signaling networks. Although these networks can classically act in a synergistic manner and are capable of crosstalk, I propose that some scenarios provoke antagonistic interactions between the two systems. I hypothesize that while there is a core innate immune response that is activated in response to disparate pathogens, there is also specificity demonstrated by subsets of innate immune effector genes. Furthermore, I hypothesize that the NF-[kappa]B p50 homodimer is binding to and regulating a subset of Interferon Response Elements (IRE) and repressing both IFN -responsive genes and IFN-independent genes. To investigate the above hypotheses I undertook experiments to address four primary aims : (1) Determine the role of the NF-[kappa]B and IFN signaling systems during macrophage responses to PAMPs and infection by viral and bacterial pathogens; (2) Characterize the aberrant p50ko response to TLR agonists and pathogens by exploring the effect of p50ko in the context of ablated type I IFN signaling; (3) Examine the innate immune specificity in the macrophage expression response to TLR agonists and pathogens using next generation sequencing; (4) Investigate the differences in innate immune activity between acute and relapsing brucellosis in a patient cohort in Lima, Peru by comparing cytokine gene expression and protein secretion in peripheral blood mononuclear cells in response to TLR ligands and heat-killed Brucella melitensis. Taken together, these studies define the role of p50 during macrophage host defense and examine the overall specificity of the innate immune response to pathogen