Systems Analysis of Cross-regulation Between Immune Receptors

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Summary Innate immune cells lack the exquisite specificity of the adaptive immune system, yet in order to respond in a measured way, they must be able to tailor their activity to the specific pathogen. These cells have therefore evolved pattern recognition receptors (PRRs) that recognize conserved molecules characteristic of the microbe, which are not found within the host. Microorganisms contain multiple innate immune agonists and the macrophage response to live pathogens is shaped by the interaction of multiple signaling pathways. The aggregate response is complex and cannot be predicted from analysis of each pathway in isolation, however it is tractable using the tools of systems biology. In macrophages, this cross-regulation can arise from the simultaneous activation of multiple Toll-like receptors (TLRs). The group has demonstrated that the set of genes transcribed by simultaneous activation of the adaptor MyD88 (by TLR2, TLR4, TLR7, or TLR9) and the adaptor TICAM-1 (TRIF) (by TLR3 or TLR4) is not equivalent to the sum of the sets of genes that are activated by each adaptor alone. For example, a subset of genes whose induction is exclusive to a single adaptor is repressed by simultaneous activation of both adaptors. In their preliminary studies, the group determined that MyD88-dependent repression of TICAM-1-induced signaling is dependent on type I IFN. Multiple lines of evidence suggest that inflammatory and type I interferon pathways cross-regulate each other to shape the immune response although the precise mechanisms have yet to be fully defined. While the role of type I interferons has been extensively studied in viral infections, it has been increasingly appreciated that they also function in the response to bacteria. Understanding the cross- regulation between TLRs and type I interferon is particularly relevant to the pathogenesis of bacterial super- infection following viral infections. In this project, the Aderem laboratory will examine macrophages from mice with either targeted deletions or ENU-induced mutations in genes that our systems analysis has suggested as candidate regulators using a suite of tools that comprehensively characterize cross-regulation between TLR and IFNAR signaling in order to uncover molecules that regulate this phenomenon. They will define their mechanisms of action and impacts on their control of bacterial infections.