Cellular Response to Infectious Triggers

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DESCRIPTION (provided by applicant): The long time goal of our studies is to delineate the molecular mechanism that regulates the immune defense against invading pathogens. The study proposed is focused on the role of the family transcription factors of interferon regulatory factors (IRF) in the innate and acquired responses to viral infection. These factors were shown to participate not only in the induction of Type I IFN genes but also in the induction of other cytokines, chemokines and genes directly involved in the antiviral and anti-inflammatory responses. Over the past years we have sequentially isolated IRF-3, IRF-7 and IRF-5 and have shown that these factors serve as direct transporters of virus induced signaling. The function of these factors is not redundant since these factors are expressed in different cell types and stimulate a profile of distinct genes. Among these three factors IRF-7 plays a limiting role in the induction of IFNa that was shown to be important both for the innate and adaptive immune responses. It is our hypothesis that these three IRFs, especially then IRF-7, are regulating both of these immune responses. The key objective of this application is to validate this hypothesis and to determine the molecular mechanism by which IRFs activates the targeted genes in response to pathogens. The study has three aims. In Aim#1 we shall examine the molecular mechanism involved in the IRF-7 mediated activation of antiviral genes. In Aim#2 we shall determine whether Toll 3 and Toll 9 responses to dsRNA and CpG DNA respectively results in the activation of IRF-3, IRF-5 and IRF-7. In Aim #3 we shall determine whether the stimulation of macrophages and dendritic cells by virus, dsRNA and CpG DNA targets similar or distinct set of antiviral genes. We believe that the basic understanding of the role of IRF factors in pathogen induced cellular responses will provide a new therapeutic platform for the treatment of the immune and inflammatory disease.