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Home / Equine Research Bank / Pathogens / Equine Herpesvirus Type 1 ORF76 Encoding US9 as a Neurovirul...
Pathogens (Basel, Switzerland)2024; 13(10); 865; doi: 10.3390/pathogens13100865

Equine Herpesvirus Type 1 ORF76 Encoding US9 as a Neurovirulence Factor in the Mouse Infection Model.

Abstract: Equine herpesvirus type 1 (EHV-1) causes rhinopneumonitis, abortion, and neurological outbreaks (equine herpesvirus myeloencephalopathy, EHM) in horses. EHV-1 also causes lethal encephalitis in small laboratory animals such as mice and hamsters experimentally. EHV-1 ORF76 is a homolog of HSV-1 US9, which is a herpesvirus kinase. Starting with an EHV-1 bacterial artificial chromosome clone of neuropathogenic strain Ab4p (pAb4p BAC), we constructed an ORF76 deletion mutant (Ab4p∆ORF76) by replacing ORF76 with the rpsLneo gene. Deletion of ORF76 had no influence on replication, cell-to-cell spread in cultured cells, or replication in primary neuronal cells. In Western blots of EHV-1-infected cell lysates, an EHV-1 US9-specific polyclonal antibody detected multiple bands ranging from 35 to 42 kDa. In a CBA/N1 mouse infection model following intranasal inoculation, the parent and Ab4p∆ORF76 revertant caused the same histopathology in the brain and olfactory bulbs. The parent, Ab4p∆ORF76, and revertant mutant replicated similarly in the olfactory mucosa, although Ab4p∆ORF76 was not transported to the olfactory bulbs and was unable to infect the CNS. These results indicated that ORF76 (US9) plays an essential role in the anterograde spread of EHV-1.
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Publication Date: 2024-10-02 PubMed ID: 39452736PubMed Central: PMC11510313DOI: 10.3390/pathogens13100865Google Scholar: Lookup
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  • Journal Article

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 research investigates the role of the Equine Herpesvirus Type 1 (EHV-1) gene ORF76, which encodes the US9 protein, in viral neurovirulence using a mouse infection model.
  • The study demonstrates that ORF76 is crucial for the virus’s ability to spread to the central nervous system (CNS), impacting its neurovirulence.

Introduction and Background

  • Equine Herpesvirus Type 1 (EHV-1): A virus causing respiratory illness (rhinopneumonitis), abortions, and neurological disease (equine herpesvirus myeloencephalopathy – EHM) in horses.
  • Neurovirulence: The virus’s ability to infect and cause damage to the nervous system, leading to conditions such as encephalitis (brain inflammation).
  • Animal Models: Mice and hamsters are used experimentally to study EHV-1 infection and its mechanisms due to their susceptibility to lethal encephalitis caused by the virus.
  • US9 Homolog: EHV-1 ORF76 gene encodes a protein homologous to US9 in Herpes Simplex Virus 1 (HSV-1), which is associated with viral transport and kinase activity.

Objectives

  • To determine the function of the ORF76 gene in EHV-1 replication, spread, and neurovirulence.
  • To investigate how the deletion of ORF76 affects viral propagation in cultured cells, neuronal cells, and in vivo within mice.
  • To examine the role of ORF76 in viral transport from the olfactory mucosa to the brain and central nervous system (CNS).

Methods

  • Genetic Engineering: Created an ORF76 deletion mutant virus (Ab4p∆ORF76) from a neuropathogenic strain clone (pAb4p BAC) by replacing ORF76 with the rpsLneo gene for selection.
  • In Vitro Experiments: Measured viral replication and cell-to-cell spread in cultured cells and primary neuronal cells to assess the effect of ORF76 deletion.
  • Protein Detection: Used Western blotting with an EHV-1 US9-specific polyclonal antibody to detect the presence and characterize the size of the US9 protein bands in infected cells.
  • In Vivo Mouse Model: Inoculated CBA/N1 mice intranasally with either the parent virus, the ORF76 deletion mutant, or a revertant virus to analyze viral replication, brain pathology, and viral transport to the CNS.

Key Findings

  • Replication and Cell Spread: Deletion of ORF76 did not affect virus replication or spread in cultured and primary neuronal cells, indicating ORF76 is not essential for these processes.
  • Protein Expression: The US9 protein was detected as multiple bands of 35 to 42 kDa in infected cell lysates, confirming its expression during infection.
  • Neuroinvasion: The parent and revertant viruses caused similar brain and olfactory bulb pathology, whereas the ORF76 deletion mutant was unable to infect the CNS despite similar replication in the olfactory mucosa.
  • Viral Transport: ORF76 deletion mutant was deficient in anterograde transport from the olfactory mucosa to the olfactory bulbs and CNS, highlighting ORF76’s critical role in viral spread within the nervous system.

Conclusions

  • ORF76 (US9) protein is not necessary for viral replication or cell-to-cell spread in vitro but is essential for anterograde neuronal transport in vivo.
  • The inability of the ORF76 deletion mutant to reach the olfactory bulbs and CNS demonstrates the gene’s crucial role in EHV-1 neurovirulence.
  • This finding advances understanding of how EHV-1 spreads within the host nervous system and may inform strategies to mitigate or prevent neurological disease caused by EHV-1 in animals.

Implications for Future Research

  • Further studies could explore the molecular mechanisms by which ORF76 facilitates viral transport in neurons.
  • Investigating the potential of targeting ORF76 or its pathway for therapeutic intervention to block neurological infection by EHV-1.
  • Expanding research to other animal models and EHV-1 strains for broader understanding of neurovirulence factors.

Cite This Article

APA
Nayel M, Kasem S, Fukushi N, El-Habashi N, Elsify A, Salama A, Hassan H, Yanai T, Ohya K, Fukushi H. (2024). Equine Herpesvirus Type 1 ORF76 Encoding US9 as a Neurovirulence Factor in the Mouse Infection Model. Pathogens, 13(10), 865. https://doi.org/10.3390/pathogens13100865

Publication

Pathogens (Basel, Switzerland)
ISSN: 2076-0817
NlmUniqueID: 101596317
Country: Switzerland
Language: English
Volume: 13
Issue: 10
PII: 865

Researcher Affiliations

Nayel, Mohamed
  • Department of Applied Veterinary Sciences, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
  • Department of Animal Medicine and Infectious Diseases, Faculty of Veterinary Medicine, University of Sadat City, Sadat City 32897, Egypt.
Kasem, Samy
  • Department of Applied Veterinary Sciences, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
  • Department of Virology, Faculty of Veterinary Medicine, Kafr Elsheikh University, Kafr Elsheikh 33516, Egypt.
Fukushi, Noriko
  • Department of Applied Veterinary Sciences, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
El-Habashi, Nagwan
  • Department of Pathology, Faculty of Veterinary Medicine, Kafr Elsheikh University, Kafr Elsheikh 33516, Egypt.
  • Department of Veterinary Pathology, Faculty of Applied Biological Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
Elsify, Ahmed
  • Department of Animal Medicine and Infectious Diseases, Faculty of Veterinary Medicine, University of Sadat City, Sadat City 32897, Egypt.
Salama, Akram
  • Department of Animal Medicine and Infectious Diseases, Faculty of Veterinary Medicine, University of Sadat City, Sadat City 32897, Egypt.
Hassan, Hany
  • Department of Animal Medicine and Infectious Diseases, Faculty of Veterinary Medicine, University of Sadat City, Sadat City 32897, Egypt.
Yanai, Tokuma
  • Department of Veterinary Pathology, Faculty of Applied Biological Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
Ohya, Kenji
  • Department of Applied Veterinary Sciences, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
Fukushi, Hideto
  • Department of Applied Veterinary Sciences, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
  • Department of Veterinary Pathology, Faculty of Applied Biological Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.

MeSH Terms

  • Animals
  • Herpesvirus 1, Equid / pathogenicity
  • Herpesvirus 1, Equid / genetics
  • Mice
  • Disease Models, Animal
  • Viral Proteins / genetics
  • Viral Proteins / metabolism
  • Herpesviridae Infections / virology
  • Herpesviridae Infections / veterinary
  • Virulence Factors / genetics
  • Virulence Factors / metabolism
  • Virus Replication
  • Brain / virology
  • Brain / pathology
  • Brain / metabolism
  • Mice, Inbred CBA
  • Gene Deletion
  • Neurons / virology
  • Neurons / pathology
  • Neurons / metabolism
  • Horses
  • Olfactory Bulb / virology
  • Olfactory Bulb / metabolism
  • Olfactory Bulb / pathology

Grant Funding

  • 17380181, 21380179 and 18H02343 / Japan Society for the Promotion of Science

Conflict of Interest Statement

The authors declare no conflicts of interest.

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Citations

This article has been cited 1 times.
  1. Kasem S, Abdel-Moneim AS, Fukushi H. Effect of thymidine kinase-deficiency (∆ORF38) on neuropathogenicity of equine herpesvirus-1 in the mouse model and expression of neighboring genes.. Virus Genes 2025 Apr;61(2):179-192.
    doi: 10.1007/s11262-024-02128-wpubmed: 39681760google scholar: lookup
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