The long-term objective of our studies is to understand the molecular mechanism of the innate immune defense against pathogen. The present application is focused on an examination of the in vivo role of IRF-5 in innate antiviral response and in tumorigenesis. Interferon regulatory factors (IRF) are transcriptional mediators of virus and IFN-induced signaling pathways, involved in the antiviral defense, immune response, cell growth and apoptosis. IRF-3, IRF-5 and IRF-7 function as direct transducers of virus mediated signaling and play crucial role in the expression of type I IFN genes. In addition IRF-5 is a downstream target of tumor suppressor, p53. While the functions of IRF-3 and IRF-7 in response to infection are well characterized, the role of IRF-5 in vivo is unknown. To investigate the function of IRF-5 in vivo, we have generated mice with the null allele of the IRF-5 gene. Mice homozygous for the mutated IRF-5 are viable and developmentally normal.
Aim 1 will analyze the role of IRF-5 in the innate antiviral response, characterize the lymphoid cells subsets, and determine the antiviral response to viral infections;
Aim 2 will examine the role of IRF-5 in the in Toll receptor like 7 (TLR7) mediated signaling and the molecular mechanism of the TLR7 mediated induction of the antiviral and inflammatory responses. The question whether IRF-5 plays a critical role in the TLR7 mediated recognition of siRNA in PDC will be addressed.
Aim 3 will asses the susceptibility of IRF5 null mice to spontaneous tumorigenesis; the phenotype of these tumors will be compared with the phenotype of tumors formed in p53 null mice. The susceptibility of the IRF-5 null mice to the retroviral induced B cell lymphogenesis will be examined. Results from these studies should clearly define the role of IRF-5 in the antiviral immune response, and its role in the TLR7 mediated antiviral pathways. It will also contribute to our understanding of the possible role of IRF-5 in the growth regulatory pathway of p53 and its contribution to virus induced lymphomagenesis. Understanding the mechanism by which IRF-5 participates in the innate antiviral response and inflammation will provide a new rational base for the therapeutic control of harmful immune responses. Furthermore, uncovering the possible role of IRF-5 in tumor surveillance and p53 mediated growth regulatory pathways may provide a new approach for the control and therapy of tumors with functionally inactive p53. ? ? ?
