Src Family Kinase Inhibitors Block Translation of Alphavirus Subgenomic mRNAs

Authors

Rebecca Broeckel, Oregon Health and Science University
Sanjay Sarkar, University of North Carolina at Chapel Hill
Nicholas A. May, University of North Carolina at Chapel Hill
Jennifer Totonchy, Chapman UniversityFollow
Craig N. Kreklywich, Oregon Health and Science University
Patricia Smith, Oregon Health and Science University
Lee Graves, University of North Carolina at Chapel Hill
Victor R. DeFilippis, Oregon Health and Science University
Mark T. Heise, University of North Carolina at Chapel Hill
Thomas E. Morrison, University of Colorado
Nathaniel Moorman, University of North Carolina at Chapel Hill
Daniel N. Streblow, Oregon Health and Science University

Document Type

Article

Publication Date

1-28-2019

Abstract

Alphaviruses are arthropod-transmitted RNA viruses that can cause arthralgia, myalgia, and encephalitis in humans. Since the role of cellular kinases in alphavirus replication is unknown, we profiled kinetic changes in host kinase abundance and phosphorylation following chikungunya virus (CHIKV) infection of fibroblasts. Based upon the results of this study, we treated CHIKV-infected cells with kinase inhibitors targeting the Src family kinase (SFK)–phosphatidylinositol 3-kinase (PI3K)–AKT–mTORC signaling pathways. Treatment of cells with SFK inhibitors blocked the replication of CHIKV as well as multiple other alphaviruses, including Mayaro virus, O’nyong-nyong virus, Ross River virus, and Venezuelan equine encephalitis virus. Dissecting the effect of SFK inhibition on alphavirus replication, we found that viral structural protein levels were significantly reduced, but synthesis of viral genomic and subgenomic RNAs was unaffected. By measuring the association of viral RNA with polyribosomes, we found that the SFK inhibitor dasatinib blocks alphavirus subgenomic RNA translation. Our results demonstrate a role for SFK signaling in alphavirus subgenomic RNA translation and replication. Targeting host factors involved in alphavirus replication represents an innovative, perhaps paradigmshifting, strategy for exploring the replication of CHIKV and other alphaviruses while promoting antiviral therapeutic development.

Comments

This article was originally published in Antimicrobial Agents and Chemotherapy, volume 63, issue 4, in 2019. DOI: 10.1128/AAC.02325-18

Recommended Citation

Broeckel R, Sarkar S, May NA, Totonchy J, Kreklywich CN, Smith P, Graves L, DeFilippis VR, Heise MT, Morrison TE, Moorman N, Streblow DN. 2019. Src family kinase inhibitors block translation of alphavirus subgenomic mRNAs. 63:e02325-18. https://doi.org/10.1128/AAC.02325-18.

Copyright

The authors

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.