Host cells have evolved elaborate intrinsic mechanisms to detect and restrict invading viruses, a better understanding of which is crucial for the development of safe and effective antiviral therapies. Influenza viruses are medically important viral pathogens that cause significant morbidity and mortality worldwide. The limited options for anti-influenza drugs, along with the constant emergence of drug-resistant influenza virus strains and new subtypes to which no vaccines are available, highlight the urgent need of designing new and broad-spectrum antiviral therapies to combat future influenza outbreaks. In preliminary studies we have demonstrated that TRIM56, a tripartite motif protein abundantly expressed in the lung, possesses antiviral activity against influenza A virus. We have also found that TRIM56 positively regulates innate immune signaling to interferon induction via the Toll-like receptor 3 (TLR3) pathway, although these two activities of TRIM56 seem to be uncoupled. We hypothesize that TRIM56 is a novel antiviral host factor that acts to restrict influenza virus propagation and to promote innate immune signaling through distinct mechanisms. We propose two specific aims to explore the novel roles of TRIM56 in innate antiviral defense through the combined use of virus-cell culture system, mutagenesis studies, biochemical and cell biological approaches.
In Aim 1, we will characterize the molecular determinants and antiviral action(s) of TRIM56 that mediate the restriction of influenza virus.
In Aim 2, we will investigate the mechanism by which TRIM56 promotes TLR3 antiviral signaling. Completion of the proposed studies will yield important new knowledge about the role of TRIM56 in innate antiviral immunity and shed new light on the development of novel antiviral strategies against influenza and possibly other emerging viral infections.

Public Health Relevance

Our studies will provide new knowledge on how TRIM56 regulates host cell intrinsic antiviral defense pathways and how TRIM56 mediates the restriction of influenza virus propagation, which may lead to new ways of treating infections by influenza viruses and other viruses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI101526-02
Application #
8604677
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Hauguel, Teresa M
Project Start
2013-01-15
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$168,750
Indirect Cost
$56,250
Name
University of Tennessee Health Science Center
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Liu, Baoming; Li, Nan L; Wang, Jie et al. (2014) Overlapping and distinct molecular determinants dictating the antiviral activities of TRIM56 against flaviviruses and coronavirus. J Virol 88:13821-35
Lester, Sandra N; Li, Kui (2014) Toll-like receptors in antiviral innate immunity. J Mol Biol 426:1246-64