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RNA Interference Screening Reveals Requirement for Platelet-Derived Growth Factor Receptor Beta in Japanese
Minmin Zhou1,2, Shaobo Wang1,2, Jiao Guo1,2
1State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
Abstract:
Mosquito-borne Japanese encephalitis virus (JEV) causes serious illness worldwide and is associated with high morbidity and mortality. To identify potential host therapeutic targets, a high-throughput receptor tyrosine kinase small interfering RNA library screening was performed with recombinant JEV particles. Platelet-derived growth factor receptor beta (PDGFRβ) was identified as a hit after two rounds of screening. Knockdown of PDGFRβ blocked JEV infection and transcomplementation of PDGFRβ could partly restore its infectivity. The PDGFRβ inhibitor imatinib, which has been approved for the treatment of malignant metastatic cancer, protected mice against JEV-induced lethality by decreasing the viral load in the brain while abrogating the histopathological changes associated with JEV infection. These findings demonstrated that PDGFRβ is important in viral infection and provided evidence for the potential to develop imatinib as a therapeutic intervention against JEV infection.
Insights
Japanese encephalitis virus (JEV) infection can be blocked by targeting platelet-derived growth factor receptor beta (PDGFRβ). The drug imatinib, targeting PDGFRβ, protected mice against JEV, suggesting a new therapeutic strategy.
Area of Science:
- Virology
- Molecular Biology
- Pharmacology
Background:
- Japanese encephalitis virus (JEV) is a significant mosquito-borne pathogen causing severe neurological disease globally.
- High morbidity and mortality rates underscore the urgent need for effective therapeutic interventions against JEV.
Purpose of the Study:
- To identify novel host cellular targets for therapeutic intervention against JEV infection.
- To investigate the role of receptor tyrosine kinases in JEV pathogenesis.
Main Methods:
- A high-throughput small interfering RNA (siRNA) screen targeting receptor tyrosine kinases was conducted using recombinant JEV particles.
- Platelet-derived growth factor receptor beta (PDGFRβ) was identified as a key host factor.
- The effect of PDGFRβ knockdown and inhibition by imatinib on JEV infection was assessed in vitro and in vivo.
Main Results:
- Knockdown of PDGFRβ significantly inhibited JEV infection, while its complementation partially restored infectivity.
- The PDGFRβ inhibitor imatinib demonstrated protective effects in a mouse model of JEV infection.
- Imatinib treatment reduced viral load in the brain and mitigated JEV-induced histopathological damage.
Conclusions:
- PDGFRβ is a critical host factor supporting JEV replication and pathogenesis.
- Imatinib, an FDA-approved drug, shows therapeutic potential for treating Japanese encephalitis.
- Targeting PDGFRβ represents a promising strategy for developing new anti-JEV therapies.
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