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BMC veterinary research2018; 14(1); 245; doi: 10.1186/s12917-018-1563-4

Deletion of the ORF2 gene of the neuropathogenic equine herpesvirus type 1 strain Ab4 reduces virulence while maintaining strong immunogenicity.

Abstract: Equine herpesvirus type 1 (EHV-1) induces respiratory infection, abortion, and neurologic disease with significant impact. Virulence factors contributing to infection and immune evasion are of particular interest. A potential virulence factor of the neuropathogenic EHV-1 strain Ab4 is ORF2. This study on 24 Icelandic horses, 2 to 4 years of age, describes the infection with EHV-1 Ab4, or its deletion mutant devoid of ORF2 (Ab4ΔORF2) compared to non-infected controls (each group n = 8). The horses' clinical presentation, virus shedding, viremia, antibody and cellular immune responses were monitored over 260 days after experimental infection. Results: Infection with Ab4ΔORF2 reduced fever and minimized nasal virus shedding after infection compared to the parent virus strain Ab4, while Ab4ΔORF2 established viremia similar to Ab4. Concurrently with virus shedding, intranasal cytokine and interferon α (IFN-α) production increased in the Ab4 group, while horses infected with Ab4ΔORF2 expressed less IFN-α. The antibody response to EHV-1 was evaluated by a bead-based multiplex assay and was similar in both infected groups, Ab4 and Ab4ΔORF2. EHV-1 specific immunoglobulin (Ig) G1 was induced 8 days after infection (d8 pi) with a peak on d10-12 pi. EHV-1 specific IgG4/7 increased starting on d10 pi, and remained elevated in serum until the end of the study. The intranasal antibody response to EHV-1 was dominated by the same IgG isotypes and remained elevated in both infected groups until d130 pi. In contrast to the distinct antibody response, no induction of EHV-1 specific T-cells was detectable by flow cytometry after ex vivo re-stimulation of peripheral blood mononuclear cells (PBMC) with EHV-1 in any group. The cellular immune response was characterized by increased secretion of IFN-γ and interleukin10 in response to ex vivo re-stimulation of PBMC with EHV-1. This response was present during the time of viremia (d5-10 pi) and was similar in both infected groups, Ab4 and Ab4ΔORF2. Conclusions: ORF2 is a virulence factor of EHV-1 Ab4 with impact on pyrexia and virus shedding from the nasal mucosa. In contrast, ORF2 does not influence viremia. The immunogenicity of the Ab4ΔORF2 and parent Ab4 viruses are identical. Graphical abstract - Deletion of ORF2 reduces virulence of EHV-1 Ab4. Graphical summary of the main findings of this study: ORF2 is a virulence factor of EHV-1 Ab4 with impact on pyrexia and virus shedding from the nasal mucosa.
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Publication Date: 2018-08-22 PubMed ID: 30134896PubMed Central: PMC6106926DOI: 10.1186/s12917-018-1563-4Google 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.

The study investigates the impact of the ORF2 gene in EHV-1, a horse herpesvirus, showing that removing this gene in the neuropathogenic strain, Ab4, decreases the virus’s virulence but doesn’t affect its ability to provoke an immune response.

About EHV-1 and the ORF2 Gene

  • Equine herpesvirus type 1 (EHV-1) is responsible for causing respiratory infections, abortions, and neurological conditions in horses. It is crucial to study the factors that lead to the infection and evasion of the immune system to better understand this virus. The study puts a particular focus on ORF2, a gene which is considered a potential virulence factor of the neuropathogenic EHV-1 strain called Ab4.
  • Virulence factors are molecules produced by a virus that enable it to achieve its harmful effects on a host. They can increase the microbe’s ability to establish itself in the host’s body, evade the body’s defence mechanisms, and/or damage the host. In this case, the ORF2 gene is suspected to enhance the virulence of the EHV-1 strain Ab4.

Research Design and Methodology

  • The researchers conducted a study involving 24 Icelandic horses aged between 2 and 4 years. They divided these horses into three groups: the control group which was not infected, one group infected with the full EHV-1 Ab4 virus, and another group infected with a version of the EHV-1 Ab4 virus that had the ORF2 gene removed (named Ab4ΔORF2).
  • They monitored the clinical presentation of the horses, the virus shedding (virus replication and release), viremia (presence of the virus in the bloodstream), and the immune responses of the horses for a period of 260 days after infection.

Research Findings

  • The infection with Ab4ΔORF2 caused less fever and led to less nasal virus shedding compared to the parent strain Ab4. However, both strains resulted in similar levels of viremia.
  • The horses infected with Ab4 showed an increase in cytokine and interferon α (IFN-α) production with virus shedding. However, the Ab4ΔORF2 infected horses expressed less IFN-α.
  • Despite these differences, the antibody response to the virus was similar in both infected groups (Ab4 and Ab4ΔORF2), as assessed by a bead-based multiplex assay. There was no induction of EHV-1 specific T-cells. However, secretion of IFN-γ and interleukin10 increased in response to ex vivo re-stimulation of peripheral blood mononuclear cells (PBMC) with the virus.
  • The research concludes that the ORF2 gene affects the virulence of the virus and influences the occurrence of fever and nasal virus shedding. However, it does not have an impact on viremia. Overall, the immunogenicity of the altered Ab4ΔORF2 virus and the parent Ab4 viruses remained identical.

Implications and Relevance

  • The study provides valuable knowledge about the role the ORF2 gene plays in the virulence of the EHV-1 virus strain Ab4. This understanding could have implications for developing treatments or vaccines for EHV-1 infections.
  • Understanding that the ORF2 gene does not influence the virus’s immunogenicity could open up new ways of creating a weakened version of the virus (like Ab4ΔORF2) for use in a potential vaccine, given that it causes less severe symptoms but still triggers an immune response similar to the full-virulence virus.

Cite This Article

APA
Schnabel CL, Wimer CL, Perkins G, Babasyan S, Freer H, Watts C, Rollins A, Osterrieder N, Wagner B. (2018). Deletion of the ORF2 gene of the neuropathogenic equine herpesvirus type 1 strain Ab4 reduces virulence while maintaining strong immunogenicity. BMC Vet Res, 14(1), 245. https://doi.org/10.1186/s12917-018-1563-4

Publication

BMC veterinary research
ISSN: 1746-6148
NlmUniqueID: 101249759
Country: England
Language: English
Volume: 14
Issue: 1
Pages: 245

Researcher Affiliations

Schnabel, Christiane L
  • Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
Wimer, Christine L
  • Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
Perkins, Gillian
  • Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
Babasyan, Susanna
  • Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
Freer, Heather
  • Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
Watts, Christina
  • Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
Rollins, Alicia
  • Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
Osterrieder, Nikolaus
  • Institut für Virologie, Freie Universität Berlin, Philippstrasse 13, 10115, Berlin, Germany.
Wagner, Bettina
  • Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA. bw73@cornell.edu.

MeSH Terms

  • Animals
  • Cytokines / metabolism
  • Female
  • Herpesviridae Infections / veterinary
  • Herpesvirus 1, Equid / genetics
  • Herpesvirus 1, Equid / immunology
  • Herpesvirus 1, Equid / pathogenicity
  • Horse Diseases / immunology
  • Horse Diseases / virology
  • Horses
  • Leukocytes, Mononuclear / virology
  • Male
  • Nasal Mucosa / virology
  • Sequence Deletion
  • Viral Proteins / genetics
  • Viremia / veterinary
  • Virulence / genetics
  • Virulence Factors / genetics
  • Virus Shedding / genetics

Grant Funding

  • 2015-67015-23091 / National Institute of Food and Agriculture
  • 2005-01812 / National Institute of Food and Agriculture
  • 2015-67015-23072 / National Institute of Food and Agriculture

Conflict of Interest Statement

ETHICS APPROVAL: The experimental EHV-1 infection and all sample collections for this study were carried out in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institute of Health. The Institutional Animal Care and Use Committee at Cornell University approved the animal protocol (protocol #2011–0011). Since the study was performed in horses the work also followed the Guide for Care and Use of Animals in Agricultural Research and Teaching. All efforts were made to minimize suffering of the animals, for example by sedation of nervous or excited horses before sampling. At the end of this experimental study, all horses were kept at the facility at Cornell University as research horses. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that they have no competing interests with the content of this article. PUBLISHER’S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Citations

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