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Updated: Jun 17, 2025
siRNA Electroporation to Modulate Autophagy in Herpes Simplex Virus Type 1-Infected Monocyte-Derived Dendritic Cells
Published on: October 28, 2019
Inhibition of mitophagy via the EIF2S1-ATF4-PRKN pathway contributes to viral encephalitis
Xiaowei Song1, Yiliang Wang2, Weixiangmin Zou3
1Institute of Biomedicine, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Key Laboratory of Innovative Technology Research on Natural Products and Cosmetics Raw Materials, Jinan University, Guangzhou 510632, China; Center for Mitochondrial Genetics and Health, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou 511400, China.
Introduction:
Mitophagy, a selective form of autophagy responsible for maintaining mitochondrial homeostasis, regulates the antiviral immune response and acts as viral replication platforms to facilitate infection with various viruses. However, its precise role in herpes simplex virus 1 (HSV-1) infection and herpes simplex encephalitis (HSE) remains largely unknown.
Objectives:
We aimed to investigate the regulation of mitophagy by HSV-1 neurotropic infection and its role in viral encephalitis, and to identify small compounds that regulate mitophagy to affect HSV-1 infection.
Methods:
The antiviral effects of compounds were investigated by Western blot, RT-PCR and plaque assay. The changes of Parkin (PRKN)-mediated mitophagy and Nuclear Factor kappa B (NFKB)-mediated neuroinflammation were examined by TEM, RT-qPCR, Western blot and ELISA. The therapeutic effect of taurine or PRKN-overexpression was confirmed in the HSE mouse model by evaluating survival rate, eye damage, neurodegenerative symptoms, immunohistochemistry analysis and histopathology.
Results:
HSV-1 infection caused the accumulation of damaged mitochondria in neuronal cells and in the brain tissue of HSE mice. Early HSV-1 infection led to mitophagy activation, followed by inhibition in the later viral infection. The HSV-1 proteins ICP34.5 or US11 deregulated the EIF2S1-ATF4 axis to suppress PRKN/Parkin mRNA expression, thereby impeding PRKN-dependent mitophagy. Consequently, inhibition of mitophagy by specific inhibitor midiv-1 promoted HSV-1 infection, whereas mitophagy activation by PRKN overexpression or agonists (CCCP and rotenone) attenuated HSV-1 infection and reduced the NF-κB-mediated neuroinflammation. Moreover, PRKN-overexpressing mice showed enhanced resistance to HSV-1 infection and ameliorated HSE pathogenesis. Furthermore, taurine, a differentially regulated gut microbial metabolite upon HSV-1 infection, acted as a mitophagy activator that transcriptionally promotes PRKN expression to stimulate mitophagy and to limit HSV-1 infection both in vitro and in vivo.
Conclusion:
These results reveal the protective function of mitophagy in HSE pathogenesis and highlight mitophagy activation as a potential antiviral therapeutic strategy for HSV-1-related diseases.
Insights
Mitophagy, a process for clearing damaged mitochondria, is impaired by herpes simplex virus 1 (HSV-1) infection, worsening herpes simplex encephalitis (HSE). Activating mitophagy protects against HSV-1 and may be a new antiviral therapy.
Area of Science:
- Neurovirology
- Mitochondrial Biology
- Immunology
Background:
- Mitophagy maintains mitochondrial health and influences antiviral immunity.
- Herpes simplex virus 1 (HSV-1) infection and encephalitis (HSE) involve complex interactions with cellular processes.
- The role of mitophagy in HSV-1 infection and HSE is not well understood.
Purpose of the Study:
- Investigate mitophagy regulation during HSV-1 neurotropic infection.
- Determine mitophagy's role in the pathogenesis of viral encephalitis.
- Identify compounds that modulate mitophagy to impact HSV-1 infection.
Main Methods:
- Utilized Western blot, RT-PCR, plaque assays, and transmission electron microscopy (TEM).
- Assessed Parkin (PRKN)-mediated mitophagy and Nuclear Factor kappa B (NFKB)-mediated neuroinflammation.
- Employed in vitro and in vivo models, including an HSE mouse model treated with taurine or PRKN overexpression.
Main Results:
- HSV-1 infection initially activates mitophagy but later inhibits it by suppressing PRKN expression via viral proteins ICP34.5/US11.
- Inhibiting mitophagy enhances HSV-1 infection, while activating mitophagy (via PRKN overexpression or agonists) reduces viral load and neuroinflammation.
- Taurine, a gut metabolite, activates mitophagy by promoting PRKN expression, thus limiting HSV-1 infection in vitro and in vivo.
Conclusions:
- Mitophagy plays a protective role in herpes simplex encephalitis (HSE) pathogenesis.
- Activating mitophagy represents a promising antiviral therapeutic strategy for HSV-1-related diseases.
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