Viruses alter cellular pathways to create an environment conducive for their replication cycles as well as to inactivate or escape cellular antiviral responses. Viruses also utilize cell proteins to facilitate or enhance virus-specific molecular processes essential for their life cycles. Little is currently known about the mechanisms used by flaviviruses, such as West Nile virus, to regulate or facilitate their synthetic processes, to remodel host cell or to suppress cell stress/defense responses. Recent data obtained by the investigator's lab show that the highly conserved cell stress granule proteins, TIAR and TIA-1, facilitate flavivirus plus strand RNA synthesis by interacting with the 3'terminal stem loop of the viral complementary RNA. The interaction between these cell proteins and the viral 3'(-) SL RNA is also involved in suppressing the cell stress granule response. TIAR and TIA-1 are multifunctional RNA binding, nucleo-cytoplasmic shuttling proteins that mediate alternative RNA splicing, translational silencing and stress granule formation. To more fully understand flavivirus-mediated suppression of a host stress response, more information must first be obtained. The cell and viral components and domains involved in colocalization of TIAR and TIA-1 with flavivirus viral replication complexes and the functional consequences of this colocalization will be analyzed. In addition to the relocation of TIAR and TIA-1 to viral replication complexes in infected cells, suppression of eIF21 phosphorylation is observed even though PRK is up-regulated suggesting that additional mechanisms are involved in virus suppression of the cell SG response. Experiments are proposed to obtain insights about how the phosphorylation of eIF21 is suppressed in infected cells. Structural studies of the interaction between the 3'(-) SL RNA and TIAR/TIA-1 will provide insights about how the viral 3'(-) SL RNA out competes AU-rich sequences in cell mRNAs for TIAR/TIA-1 binding. This information will be relevant to the future development of novel antivirals.

Public Health Relevance

The long term goal of this research is to delineate the mechanisms involved in the use by flaviviruses, such as West Nile virus, of cell proteins to positively regulate steps in their replication cycles and to remodel or suppress cellular pathways to create an environment that is conducive for efficient virus replication. These studies will lead to the discovery of new targets for the future development of novel antiviral therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
4R01AI048088-08
Application #
8224055
Study Section
Special Emphasis Panel (ZRG1-IDM-R (03))
Program Officer
Repik, Patricia M
Project Start
2000-07-01
Project End
2013-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
8
Fiscal Year
2011
Total Cost
$286,110
Indirect Cost
Name
Georgia State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302
Zhang, Jin; Pearson, Joseph Z; Gorbet, Gary E et al. (2017) Spectral and Hydrodynamic Analysis of West Nile Virus RNA-Protein Interactions by Multiwavelength Sedimentation Velocity in the Analytical Ultracentrifuge. Anal Chem 89:862-870
Basu, Mausumi; Brinton, Margo A (2017) How do flavivirus-infected cells resist arsenite-induced stress granule formation? Future Virol 12:247-249
Basu, Mausumi; Courtney, Sean C; Brinton, Margo A (2017) Arsenite-induced stress granule formation is inhibited by elevated levels of reduced glutathione in West Nile virus-infected cells. PLoS Pathog 13:e1006240
Brinton, Margo A; Basu, Mausumi (2015) Functions of the 3' and 5' genome RNA regions of members of the genus Flavivirus. Virus Res 206:108-19
Wu, Xianfang; Lee, Emily M; Hammack, Christy et al. (2014) Cell death-inducing DFFA-like effector b is required for hepatitis C virus entry into hepatocytes. J Virol 88:8433-44
Brinton, Margo A (2014) Replication cycle and molecular biology of the West Nile virus. Viruses 6:13-53
Davis, William G; Basu, Mausumi; Elrod, Elizabeth J et al. (2013) Identification of cis-acting nucleotides and a structural feature in West Nile virus 3'-terminus RNA that facilitate viral minus strand RNA synthesis. J Virol 87:7622-36
Scherbik, S V; Pulit-Penaloza, J A; Basu, M et al. (2013) Increased early RNA replication by chimeric West Nile virus W956IC leads to IPS-1-mediated activation of NF-?B and insufficient virus-mediated counteraction of the resulting canonical type I interferon signaling. J Virol 87:7952-65
Courtney, S C; Scherbik, S V; Stockman, B M et al. (2012) West nile virus infections suppress early viral RNA synthesis and avoid inducing the cell stress granule response. J Virol 86:3647-57
Basu, Mausumi; Brinton, Margo A (2011) West Nile virus (WNV) genome RNAs with up to three adjacent mutations that disrupt long distance 5'-3' cyclization sequence basepairs are viable. Virology 412:220-32

Showing the most recent 10 out of 18 publications