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Janus effects of ADAR1 on CVB3-induced viral myocarditis at different infection stages
Ning Dong1, Chunsheng Dong1, Sidong Xiong1
1Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China.
Insights
Adenosine deaminase acting on RNA 1 (ADAR1) plays a dual role in Coxsackievirus B3 (CVB3)-induced viral myocarditis (VMC). Modulating ADAR1 impacts viral replication and inflammation, offering potential therapeutic strategies for VMC.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Coxsackievirus B3 (CVB3) infection is a primary cause of viral myocarditis (VMC), marked by myocardial inflammation.
- Adenosine deaminase acting on RNA 1 (ADAR1), an interferon-inducible enzyme, exhibits varied roles in viral infections, acting as either antiviral or pro-viral depending on the virus.
Purpose of the Study:
- To investigate the role of ADAR1 in the pathogenesis of CVB3-induced viral myocarditis (VMC).
Main Methods:
- An acute VMC mouse model was established via CVB3 infection.
- ADAR1 expression was modulated in vivo using polyethyleneimine-mediated plasmid delivery for up-regulation and down-regulation.
Main Results:
- ADAR1 expression increased following CVB3 infection.
- Early-stage ADAR1 down-regulation ameliorated VMC by reducing viral replication and increasing IFN-β.
- Middle-late stage ADAR1 down-regulation aggravated VMC, suggesting a role in regulating PKR and NF-κB signaling pathways.
Conclusions:
- ADAR1 exhibits stage-dependent, double-edged effects in CVB3-induced VMC.
- Findings provide novel insights for therapeutic interventions targeting VMC.
Background:
Coxsackievirus (CVB3) infection is the most common cause of viral myocarditis (VMC) characterized by viral infection and myocardial inflammation. ADAR1, the interferon (IFN)-inducible adenosine deaminase acting on RNA, has been reported to be functional in various viruses. Recent studies have demonstrated that ADAR1 holds an antiviral role or promotes viral replication depending on virus type.
Objectives:
This study aims to investigate whether or not ADAR1 affects CVB3-induced VMC.
Methods:
We generated an acute VMC mouse model by CVB3 infection. ADAR1 expression was manipulated by in vivo polyethyleneimine-mediated ADAR1 up/down-regulation plasmid delivery.
Results:
Our study indicated that ADAR1 was up-regulated after CVB3 infection. ADAR1 down-regulation in the early stage of viral infection ameliorated CVB3-induced VMC. In this stage, viral replication was a key point to initiate inflammatory response. ADAR1 may affect inflammation mainly through viral replication as shown by the elevated IFN-β and decreased viral load with ADAR1 down-regulation. However, when the inflammatory response was established in the middle-late stage of viral infection, ADAR1 down-regulation aggravated disease progression. In this stage, Western blot analysis indicated that ADAR1 may directly influence inflammatory response through PKR and NF-κB signaling.
Conclusion:
We demonstrated that ADAR1 exhibited double-edged effects during the early or middle-late stage of CVB3-induced VMC. Our findings may provide new insights into the therapeutic treatments of VMC.
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