Research Project
10485414
Summary Type I Interferon (IFN-I) is the name of a family of anti-viral cytokines. In humans and mice, the predominant IFN-I subtypes are a single IFN-? and multiple IFN-?s (14 in mice and 13 in humans) which are encoded by a set of short intron-less genes clustered in a ~300 kb locus (chromosome 9 in humans, 4 in mice). IFN-? has ~25- 30% of homology with the different IFN-?s and the IFN-?s of a given species have ~85% homology among them. Notably, the multiplicity of the IFN-?s emerged independently through gene duplication and conversion in most eutherian mammals suggesting a strong evolutionary pressure to increase the number of IFN-? genes. In this project we will use novel mouse models produced in the lab and three different viruses -ectromelia virus (ECTV), West Nile Virus (WNV) and Zika Virus (ZIKV)- to fill three major gaps in our understanding of the IFN-I field. The first knowledge gap is that we do not know what is the role of the so called ?early? IFN-? and IFN-?4 in resistance to viruses that disseminate lymphohematogenously. When fibroblasts are infected with RNA viruses in vitro, IFN- ? and IFN-?4 are produced immediately after infection and are required for the expression of IFN-? non4 (all the IFN-? except IFN-?4). The reason for this is that to be transcribed, the promoters of IFN-? and IFN-?4 can use the transcription factors IRF7, IRF3 and/or NF?B while IFN-? non4 can only use IRF7. While IRF3 and NF?B are constitutively expressed in most cells, IRF7 is an interferon inducible gene (ISG). Thus, the transcription of IFN- ? non4 depends on a positive feedback loop or ?priming? by IFN-? and/or IFN-?4. Yet, whether IFN-? and IFN- ?4 regulate IFN-I transcription in vivo and are required alone or together for resistance to viral diseases is unknown. Thus, in Aim 1 we will use novel mouse models infected with ECTV, WNV or ZIKV to determine the roles of IFN-? and IFN-?4 in the regulation of the IFN-I response and resistance to acute viral diseases in vivo. The second knowledge gap is that we do not know why there is a need for so many IFN-Is. It is possible that they have additive and/or differential biological effects. Thus, in Aim 2 we will investigate the need for multiple IFN-Is in resistance to viral diseases using novel mouse models infected with each of these three viruses and supplement Ifna-/- mice with different IFN-?s. The third knowledge gap is that we do not know whether there are specific cell types that must obligatory produce IFN-? for resistance to viral infections. Preliminary results with ECTV suggest that cells of hematopoietic origin are obligatory IFN-I producers, at least for ECTV infection. Therefore, in Aim 3 we will use bone marrow chimeras and mice with conditional deletions in IFN-? in different cell types to identify cells that are necessary producers of IFN-I for each of the different viruses. Thus, using novel mice, we will fill three knowledge gaps in our understanding of how IFN-I protects from viral diseases. By using multiple viruses, we will be able to draw general conclusions and to identify virus-specific differences. Our work should inform development of new therapeutics for improving resistance to acute viral diseases.
