Src Family Kinase Inhibitors Block Translation of Alphavirus Subgenomic mRNAs

Area of Science:

• Virology
• Molecular Biology
• Immunology

Background:

• Alphaviruses are arthropod-borne RNA viruses causing significant human diseases like encephalitis.
• The role of host cellular kinases in alphavirus replication remains largely unexplored.
• Understanding host-pathogen interactions is key to developing antiviral therapies.

Purpose of the Study:

• To investigate the role of host cellular kinases in alphavirus replication.
• To identify potential therapeutic targets for alphavirus infections.
• To explore the impact of kinase inhibition on viral RNA translation and replication.

Main Methods:

• Profiling host kinase abundance and phosphorylation after chikungunya virus (CHIKV) infection.
• Treating infected cells with kinase inhibitors targeting SFK-PI3K-AKT-mTORC pathways.
• Assessing viral replication, protein levels, RNA synthesis, and RNA-polyribosome association.

Main Results:

• SFK inhibition blocked replication of CHIKV and other alphaviruses (Mayaro, O'nyong-nyong, Ross River, Venezuelan equine encephalitis).
• SFK inhibition reduced viral structural protein levels but did not affect viral RNA synthesis.
• Dasatinib, an SFK inhibitor, was found to block alphavirus subgenomic RNA translation.

Conclusions:

• SFK signaling plays a critical role in alphavirus subgenomic RNA translation and overall replication.
• Targeting host SFK signaling presents a promising antiviral therapeutic strategy for alphavirus infections.
• This study highlights a paradigm shift towards host-directed therapies for alphaviruses.