# IFN-I production in vivo for resistance to acute disseminating viral Infections > **NIH NIH R56** · THOMAS JEFFERSON UNIVERSITY · 2021 · $437,417 ## Abstract 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-β and multiple IFN-αs (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-β has ~25- 30% of homology with the different IFN-αs and the IFN-αs of a given species have ~85% homology among them. Notably, the multiplicity of the IFN-αs emerged independently through gene duplication and conversion in most eutherian mammals suggesting a strong evolutionary pressure to increase the number of IFN-α 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-β and IFN-α4 in resistance to viruses that disseminate lymphohematogenously. When fibroblasts are infected with RNA viruses in vitro, IFN- β and IFN-α4 are produced immediately after infection and are required for the expression of IFN-α non4 (all the IFN-α except IFN-α4). The reason for this is that to be transcribed, the promoters of IFN-β and IFN-α4 can use the transcription factors IRF7, IRF3 and/or NFκB while IFN-α non4 can only use IRF7. While IRF3 and NFκB are constitutively expressed in most cells, IRF7 is an interferon inducible gene (ISG). Thus, the transcription of IFN- α non4 depends on a positive feedback loop or “priming” by IFN-β and/or IFN-α4. Yet, whether IFN-β and IFN- α4 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-β and IFN-α4 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-αs. The third knowledge gap is that we do not know whether there are specific cell types that must obligatory produce IFN-α 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-α 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... ## Key facts - **NIH application ID:** 10485414 - **Project number:** 2R56AI110457-06A1 - **Recipient organization:** THOMAS JEFFERSON UNIVERSITY - **Principal Investigator:** Luis J Sigal - **Activity code:** R56 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $437,417 - **Award type:** 2 - **Project period:** 2014-12-01 → 2022-08-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10485414 ## Citation > US National Institutes of Health, RePORTER application 10485414, IFN-I production in vivo for resistance to acute disseminating viral Infections (2R56AI110457-06A1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10485414. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*