The host response to a viral infection initiates with the synthesis of interferons (IFNs) and antiviral factors that combat infection. The ability to resolve these responses and return to homeostasis is important, as unrestrained production of IFNs results in tissue damage. The post-transcriptional regulation of immune genes has been implicated in the resolution of IFN responses. Proteomic screens and RNA immunoprecipitation (IP) experiments revealed that zinc-finger antiviral protein short isoform (ZAP-S) negatively regulates IFNL3 mRNA. The long isoform of ZAP, ZAP-L (long), has been characterized previously as a viral restriction factor. Since ZAP is expressed as a long and a short isoform and there is currently no known function of ZAP-S, this raises the possibility that ZAP isoforms have distinct cellular functions. We hypothesize that ZAP-L functions as a viral restriction factor by degrading viral RNA, while ZAP-S binds to host interferon mRNA to resolve host antiviral responses. To test this, we will characterize the unique cellular roles of long and short isoforms of ZAP in antiviral immunity and interferon regulation. Describe the distinct subcellular localizations of ZAP isoforms and if this dictates their distinct functions. This proposal has the potential to identify a novel regulatory mechanism of IFN resolution that could have important implications for antiviral immunity and IFN mediated autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI135437-02
Application #
9614269
Study Section
Immunity and Host Defense (IHD)
Program Officer
Jiang, Chao
Project Start
2017-12-14
Project End
2019-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195