PI: TAYLOR, ROGER TRAVIS Project: 1K22AI099020-01 Title: Role of TRIM79 in innate immunity to tick-borne encephalitis virus Accession Number: 3398464 ================== NOTICE: THIS ABSTRACT WAS EXTRACTED FROM APPLICATION AND HAS NOT BEEN PROOFED BY AN SRA.WHEN THERE ARE PROBLEMS WITH THE APPLICATION SCANNING PROCESS, THE EXTRACTED TEXT MAY BE INCORRECT OR INCOMPLETE. ================== The flaviviruses represent a tremendous disease burden to humans, including dengue virus, West Nile virus (WNV) and tick-borne encephalitis virus (TBEV). These viruses are highly sensitive to the antiviral effects of type I interferon (IFN). However, the effectiveness of IFN asa therapeutic is limited by the ability of these viruses to inhibit IFN-dependent signal transduction and therefore dampen the expression of IFN-stimulated genes (ISGs). ISGs are responsible for the antiviral effects of IFN, although little is known regarding the function of individual gene products. A molecular understanding of virus-specific antiviral molecules is needed to define how host interferon (IFN) responses are effective against virus infections. Although many ISGs function as general inhibitors of virus infection, ISGs necessary for protection against specific viruses exist, evolved to selectively target unique viral protein sequences. Members of the TRIM family of proteins are emerging as potent but virus-specific detection and antiviral factors, in addition to regulators of innate immune signal pathways. Our work has identified a virus-specific TRIM protein, TRIM79, as an ISG that binds the NS5 protein from tick-borne encephalitis virus (TBEV) and targets it for degradation, resulting in virus restriction. TRIM79 was not able to bind to NS5 from the closely related West Nile virus (WNV), nor restrict WNV replication. Thus, the TRIM79/NS5 interaction represents a unique model to explore the molecular and cellular determinants required for protein recognition and degradation as well as restriction of viruses directly relevant to human health on a global scale. The overall goal of this work is to identify mechanisms of specific virus restriction by cellular antiviral molecules by dissecting apart the TRIM79/NS5 relationship, insight from which will enable identification of other antiviral molecules with similar mechanisms. We will accomplish this goal by identifying the structural and functional determinants for both TRIM79 and NS5 necessary for binding, protein degradation and subsequent virus restriction. Insight gained from initial studies will be used to rationally engineer mutations into the NS5 from flaviviruses either resistant (TBEV) or susceptible (WNV) to TRIM79- mediated restriction and measure effect of mutation on virus replication and interferon sensitivity. These studies will define the role of TRIM79 for TBEV restriction, as well as normal cellular functions. Flaviviruses, including TBEV, WNV and DENV, account for an overwhelming worldwide disease burden, with limited treatment options. A mechanistic understanding of how a single TBEV-specific antiviral gene that is central to the innate antiviral response will enable development of therapeutics effective against flaviviruses evolved to specifically disable IFN-dependent signal transduction.

Public Health Relevance

Flaviviruses, including TBEV, WNV and DENV, account for an overwhelming worldwide disease burden, with limited treatment options. A mechanistic understanding of how a single TBEV-specific antiviral gene that is central to the innate antiviral response will enable development of therapeutics effective against flaviviruses evolved to specifically disable IFN-dependent signal transduction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Career Transition Award (K22)
Project #
5K22AI099020-02
Application #
8611898
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Repik, Patricia M
Project Start
2013-02-05
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$108,000
Indirect Cost
$8,000
Name
University of Toledo
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614