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Home / Equine Research Bank / J Virol / Hyperoside inhibits EHV-8 infection via alleviating oxidativ...
Journal of virology2024; 98(4); e0015924; doi: 10.1128/jvi.00159-24

Hyperoside inhibits EHV-8 infection via alleviating oxidative stress and IFN production through activating JNK/Keap1/Nrf2/HO-1 signaling pathways.

Abstract: Equine herpesvirus type 8 (EHV-8) causes abortion and respiratory disease in horses and donkeys, leading to serious economic losses in the global equine industry. Currently, there is no effective vaccine or drug against EHV-8 infection, underscoring the need for a novel antiviral drug to prevent EHV-8-induced latent infection and decrease the pathogenicity of this virus. The present study demonstrated that hyperoside can exert antiviral effects against EHV-8 infection in RK-13 (rabbit kidney cells), MDBK (Madin-Darby bovine kidney), and NBL-6 cells (E. Derm cells). Mechanistic investigations revealed that hyperoside induces heme oxygenase-1 expression by activating the c-Jun N-terminal kinase/nuclear factor erythroid-2-related factor 2/Kelch-like ECH-associated protein 1 axis, alleviating oxidative stress and triggering a downstream antiviral interferon response. Accordingly, hyperoside inhibits EHV-8 infection. Meanwhile, hyperoside can also mitigate EHV-8-induced injury in the lungs of infected mice. These results indicate that hyperoside may serve as a novel antiviral agent against EHV-8 infection.IMPORTANCEHyperoside has been reported to suppress viral infections, including herpesvirus, hepatitis B virus, infectious bronchitis virus, and severe acute respiratory syndrome coronavirus 2 infection. However, its mechanism of action against equine herpesvirus type 8 (EHV-8) is currently unknown. Here, we demonstrated that hyperoside significantly inhibits EHV-8 adsorption and internalization in susceptible cells. This process induces HO-1 expression via c-Jun N-terminal kinase/nuclear factor erythroid-2-related factor 2/Kelch-like ECH-associated protein 1 axis activation, alleviating oxidative stress and triggering an antiviral interferon response. These findings indicate that hyperoside could be very effective as a drug against EHV-8.
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Publication Date: 2024-03-19 PubMed ID: 38499512PubMed Central: PMC11019850DOI: 10.1128/jvi.00159-24Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

Overview

  • This study investigates the antiviral effects of hyperoside against equine herpesvirus type 8 (EHV-8) infection and elucidates the molecular mechanisms involved in its protective action.

Background and Significance

  • EHV-8 is a virus that causes abortion and respiratory disease in horses and donkeys, leading to significant economic losses worldwide.
  • Currently, there are no effective vaccines or treatments available to prevent or control EHV-8 infection.
  • This gap in treatment options highlights the need to identify novel antiviral agents to lower EHV-8’s impact on equine health and the industry.

Research Objectives

  • To evaluate whether hyperoside, a natural compound previously shown to inhibit other viral infections, can suppress EHV-8 infection.
  • To clarify the underlying molecular mechanisms by which hyperoside exerts its antiviral effects.
  • To determine if hyperoside can reduce tissue damage caused by EHV-8 infection in vivo.

Methodology

  • Cell Culture Models: The antiviral effects of hyperoside were tested in three cell lines susceptible to EHV-8 infection — RK-13 (rabbit kidney cells), MDBK (bovine kidney cells), and NBL-6 (E. Derm equine cells).
  • Viral Infection Assays: The study measured hyperoside’s ability to inhibit viral adsorption (attachment to host cells) and internalization (entry into cells).
  • Signaling Pathway Analysis: Investigations focused on the activation of the JNK (c-Jun N-terminal kinase)/Keap1/Nrf2 (nuclear factor erythroid-2-related factor 2)/HO-1 (heme oxygenase-1) signaling axis.
  • Oxidative Stress and Immune Response: The effect of hyperoside on oxidative stress reduction and induction of antiviral interferon production was assessed.
  • In Vivo Experimentation: Lung tissue from EHV-8 infected mice treated with hyperoside was examined to observe protective effects against viral injury.

Key Findings

  • Hyperoside effectively inhibited EHV-8 infection across all tested cell types by significantly reducing viral adsorption and entry.
  • Mechanistically, hyperoside activated the JNK/Keap1/Nrf2/HO-1 pathway, which led to increased expression of HO-1, a protein known for its antioxidant and cytoprotective properties.
  • Activation of this pathway reduced oxidative stress in infected cells, which is critical because viral infections often induce harmful oxidative damage.
  • Reduced oxidative stress subsequently enhanced the production of antiviral interferons, key components of the innate immune response against viruses.
  • In mouse models, hyperoside treatment minimized lung injury caused by EHV-8 infection, indicating its potential for protecting tissue from virus-induced damage in living organisms.

Mechanistic Insights

  • The JNK (c-Jun N-terminal kinase) pathway is a stress-activated protein kinase pathway that can regulate cellular responses to stress, including viral infections.
  • Keap1 serves as a negative regulator of Nrf2, which controls the expression of antioxidant proteins like HO-1.
  • When JNK is activated, it promotes Nrf2 to dissociate from Keap1 and translocate to the nucleus, where it upregulates HO-1 expression.
  • HO-1 has antioxidative and anti-inflammatory roles; its induction helps to reduce oxidative cellular damage during viral infection.
  • By alleviating oxidative stress, hyperoside indirectly supports the host’s antiviral defense by promoting interferon production, which inhibits viral replication.

Implications and Potential Applications

  • The identification of hyperoside as a potent inhibitor of EHV-8 offers a promising lead compound for developing antiviral therapies in equine veterinary medicine.
  • By targeting host cellular pathways to boost antiviral defenses rather than solely attacking the virus, hyperoside may reduce the risk of viral resistance development.
  • Given hyperoside’s broad antiviral activity against other viruses, this study supports further exploration of its clinical applications for multiple viral infections.
  • Future research could involve clinical trials in equines, dosage optimization, and assessment of hyperoside’s safety profile in animals.

Cite This Article

APA
Wang T, Hu L, Li R, Ren H, Li S, Sun Q, Ding X, Li Y, Wang C, Li L. (2024). Hyperoside inhibits EHV-8 infection via alleviating oxidative stress and IFN production through activating JNK/Keap1/Nrf2/HO-1 signaling pathways. J Virol, 98(4), e0015924. https://doi.org/10.1128/jvi.00159-24

Publication

Journal of virology
ISSN: 1098-5514
NlmUniqueID: 0113724
Country: United States
Language: English
Volume: 98
Issue: 4
Pages: e0015924
PII: e00159-24

Researcher Affiliations

Wang, Tongtong
  • College of Agronomy, Liaocheng University, Liaocheng, China.
Hu, Leyu
  • College of Agronomy, Liaocheng University, Liaocheng, China.
  • College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, China.
Li, Ruibo
  • College of Agronomy, Liaocheng University, Liaocheng, China.
Ren, Huiying
  • College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, China.
Li, Shuwen
  • College of Agronomy, Liaocheng University, Liaocheng, China.
Sun, Qi
  • College of Agronomy, Liaocheng University, Liaocheng, China.
Ding, Xiangdan
  • College of Agronomy, Liaocheng University, Liaocheng, China.
Li, Yubao
  • College of Agronomy, Liaocheng University, Liaocheng, China.
Wang, Changfa
  • College of Agronomy, Liaocheng University, Liaocheng, China.
Li, Liangliang
  • College of Agronomy, Liaocheng University, Liaocheng, China.

MeSH Terms

  • Animals
  • Cattle
  • Mice
  • Rabbits
  • Antiviral Agents / pharmacology
  • Herpesviridae Infections
  • Herpesvirus 1, Equid
  • Horses
  • Interferons / metabolism
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • MAP Kinase Signaling System
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress / drug effects
  • Quercetin / analogs & derivatives
  • Quercetin / pharmacology
  • Cell Line

Grant Funding

  • 32002248 / MOST | National Natural Science Foundation of China (NSFC)
  • ZR2020QC016 / | Natural Science Foundation of Shandong Province ()
  • ZR2020QC017 / | Natural Science Foundation of Shandong Province ()

Conflict of Interest Statement

The authors declare no conflict of interest.

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Citations

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