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Home / Equine Research Bank / Viruses / Breaking Latent Infection: How ORF37/38-Deletion Mutants Off...
Viruses2024; 16(9); 1472; doi: 10.3390/v16091472

Breaking Latent Infection: How ORF37/38-Deletion Mutants Offer New Hope against EHV-1 Neuropathogenicity.

Abstract: Equid alphaherpesvirus 1 (EHV-1) has been linked to the emergence of neurological disorders, with the horse racing industry experiencing significant impacts from outbreaks of equine herpesvirus myeloencephalopathy (EHM). Building robust immune memory before pathogen exposure enables rapid recognition and elimination, preventing infection. This is crucial for effectively managing EHV-1. Removing neuropathogenic factors and immune evasion genes to develop live attenuated vaccines appears to be a successful strategy for EHV-1 vaccines. We created mutant viruses without ORF38 and ORF37/38 and validated their neuropathogenicity and immunogenicity in hamsters. The ∆ORF38 strain caused brain tissue damage at high doses, whereas the ∆ORF37/38 strain did not. Dexamethasone was used to confirm latent herpesvirus infection and reactivation. Dexamethasone injection increased viral DNA load in the brains of hamsters infected with the parental and ∆ORF38 strains, but not in those infected with the ∆ORF37/38 strain. Immunizing hamsters intranasally with the ∆ORF37/38 strain as a live vaccine produced a stronger immune response compared to the ∆ORF38 strain at the same dose. The hamsters demonstrated effective protection against a lethal challenge with the parental strain. This suggests that the deletion of ORF37/38 may effectively inhibit latent viral infection, reduce the neuropathogenicity of EHV-1, and induce a protective immune response.
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Publication Date: 2024-09-16 PubMed ID: 39339948PubMed Central: PMC11437417DOI: 10.3390/v16091472Google 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 effects of deleting specific genes (ORF37 and ORF38) in Equid alphaherpesvirus 1 (EHV-1) to reduce its neurological damage and improve vaccine effectiveness.
  • Researchers developed mutant viruses lacking these genes and tested their ability to cause disease and stimulate immunity in hamsters, finding promising results for a live attenuated vaccine against EHV-1.

Background

  • Equid alphaherpesvirus 1 (EHV-1): A virus affecting horses that can cause severe neurological diseases, notably equine herpesvirus myeloencephalopathy (EHM), which impacts horse health and the racing industry.
  • Neuropathogenicity: The virus has genes that contribute to brain damage and immune system evasion, making infections difficult to manage.
  • Latency: EHV-1 can remain dormant (latent) in the host and reactivate later, which complicates disease control.
  • Vaccination challenge: Effective vaccines should prevent both infection and the establishment of latency while avoiding damage to the host.

Research Objectives

  • To create mutant strains of EHV-1 with deletions in the ORF38 gene alone and both ORF37 and ORF38 genes.
  • To evaluate whether these mutants reduce neuropathogenic effects in animal models (hamsters).
  • To test if these mutations affect the virus’s ability to establish latent infection and reactivate.
  • To assess the immune response and protective efficacy provided by these mutant strains as potential live attenuated vaccines.

Methodology

  • Creation of Mutants: Developed two mutant virus strains—one lacking ORF38 (∆ORF38) and another lacking both ORF37 and ORF38 (∆ORF37/38).
  • Animal Model: Used hamsters to test neuropathogenicity, immune response, and latent infection/reactivation.
  • Neuropathogenicity Assays: Infected hamsters at high doses and examined brain tissue damage.
  • Latency and Reactivation Testing: Administered dexamethasone, a drug known to induce herpesvirus reactivation, to see if latent virus would reactivate by measuring viral DNA in brain tissues.
  • Immunization and Challenge Experiments: Intranasally vaccinated hamsters with mutant strains and then challenged with the parental (wild-type) virus to evaluate protection.

Key Findings

  • The ∆ORF38 strain caused brain tissue damage at high doses, indicating it retained some neuropathogenicity.
  • The ∆ORF37/38 strain did not cause brain damage, suggesting the combined deletion reduced neuropathogenicity effectively.
  • When dexamethasone was administered:
    • Viral DNA load increased in hamsters infected with the parental and ∆ORF38 strains, indicating reactivation of latent infection.
    • No increase in viral DNA was observed in ∆ORF37/38-infected hamsters, implying this strain did not establish or reactivate latent infection effectively.
  • Vaccination with ∆ORF37/38 induced a stronger immune response than vaccination with ∆ORF38 at the same dosage.
  • Hamsters immunized with ∆ORF37/38 were effectively protected against a lethal challenge from the parental virus, demonstrating its potential as a vaccine candidate.

Implications and Conclusions

  • Deleting ORF37 along with ORF38 in EHV-1 significantly reduces the virus’s ability to cause neurological damage and establish latency.
  • This double-deletion mutant (∆ORF37/38) elicits a strong immune response and provides protective immunity against wild-type virus challenges.
  • The ∆ORF37/38 strain shows promise as a live attenuated vaccine candidate, addressing critical issues of neuropathogenicity and viral latency.
  • By preventing latent infection and reactivation, this approach could improve long-term control of EHV-1 outbreaks in horse populations.

Cite This Article

APA
Hu Y, Zhang SY, Sun WC, Feng YR, Gong HR, Ran DL, Zhang BZ, Liu JH. (2024). Breaking Latent Infection: How ORF37/38-Deletion Mutants Offer New Hope against EHV-1 Neuropathogenicity. Viruses, 16(9), 1472. https://doi.org/10.3390/v16091472

Publication

Viruses
ISSN: 1999-4915
NlmUniqueID: 101509722
Country: Switzerland
Language: English
Volume: 16
Issue: 9
PII: 1472

Researcher Affiliations

Hu, Yue
  • Laboratory of Animal Infectious Disease, College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi 830052, China.
  • CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, China.
Zhang, Si-Yu
  • Laboratory of Animal Infectious Disease, College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi 830052, China.
Sun, Wen-Cheng
  • Laboratory of Animal Infectious Disease, College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi 830052, China.
Feng, Ya-Ru
  • Laboratory of Animal Infectious Disease, College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi 830052, China.
Gong, Hua-Rui
  • CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, China.
Ran, Duo-Liang
  • Laboratory of Animal Infectious Disease, College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi 830052, China.
Zhang, Bao-Zhong
  • CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, China.
Liu, Jian-Hua
  • Laboratory of Animal Infectious Disease, College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi 830052, China.

MeSH Terms

  • Animals
  • Cricetinae
  • Female
  • Brain / virology
  • Brain / pathology
  • Herpesviridae Infections / prevention & control
  • Herpesviridae Infections / virology
  • Herpesviridae Infections / immunology
  • Herpesvirus 1, Equid / genetics
  • Herpesvirus 1, Equid / immunology
  • Herpesvirus 1, Equid / pathogenicity
  • Horse Diseases / virology
  • Horse Diseases / prevention & control
  • Horse Diseases / immunology
  • Horses
  • Latent Infection / immunology
  • Latent Infection / virology
  • Mesocricetus
  • Open Reading Frames
  • Sequence Deletion
  • Vaccines, Attenuated / immunology
  • Vaccines, Attenuated / genetics
  • Vaccines, Attenuated / administration & dosage
  • Viral Load
  • Viral Proteins / genetics
  • Viral Proteins / immunology
  • Virus Latency
  • Rabbits

Grant Funding

  • Grant No. ZYYD2023C03 / the Special Projects of the Central Government in Guidance of Local Science and Technology Development
  • (Grant No. 2022A02013-2-5) / he Major Scientific and Technology Special Project of Xinjiang Uygur Autonomous Region

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.

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Citations

This article has been cited 1 times.
  1. Liu D, Zhao X, Wang X. The Genomic Characterization of Equid Alphaherpesviruses: Structure, Function, and Genetic Similarity.. Vet Sci 2025 Mar 3;12(3).
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