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Proceedings of the National Academy of Sciences of the United States of America2013; 110(15); E1407-E1415; doi: 10.1073/pnas.1219217110

Identification of a previously undescribed divergent virus from the Flaviviridae family in an outbreak of equine serum hepatitis.

Abstract: Theiler's disease is an acute hepatitis in horses that is associated with the administration of equine blood products; its etiologic agent has remained unknown for nearly a century. Here, we used massively parallel sequencing to explore samples from a recent Theiler's disease outbreak. Metatranscriptomic analysis of the short sequence reads identified a 10.5-kb sequence from a previously undescribed virus of the Flaviviridae family, which we designate "Theiler's disease-associated virus" (TDAV). Phylogenetic analysis clusters TDAV with GB viruses of the recently proposed Pegivirus genus, although it shares only 35.3% amino acid identity with its closest relative, GB virus D. An epidemiological survey of additional horses from three separate locations supports an association between TDAV infection and acute serum hepatitis. Experimental inoculation of horses with TDAV-positive plasma provides evidence that several weeks of viremia preceded liver injury and that liver disease may not be directly related to the level of viremia. Like hepatitis C virus, the best characterized Flaviviridae species known to cause hepatitis, we find TDAV is capable of efficient parenteral transmission, engendering acute and chronic infections associated with a diversity of clinical presentations ranging from subclinical infection to clinical hepatitis.
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Publication Date: 2013-03-18 PubMed ID: 23509292PubMed Central: PMC3625295DOI: 10.1073/pnas.1219217110Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • Non-U.S. Gov't
  • Research Support
  • U.S. Gov't
  • Non-P.H.S.

Summary

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This study identifies a new type of virus from the Flaviviridae family, named “Theiler’s disease-associated virus” (TDAV), that’s linked to Theiler’s disease outbreak which causes acute hepatitis in horses. The researchers found that TDAV infections occur several weeks before liver injury is observed, hinting towards a unique disease progression pattern.

Identification and Classification of TDAV

  • The research utilized advanced sequencing techniques on samples from a recent Theiler’s disease outbreak in horses. Analysis of these sequences revealed a 10.5-kb sequence from a previously unclassified virus, which the research team named “Theiler’s disease-associated virus” (TDAV).
  • Phylogenetic analysis showed that TDAV is clustered with GB viruses of the recently proposed Pegivirus genus. However, it shares a relatively low level of similarity (35.3% amino acid identity) with its closest relative, GB virus D.

Epidemiological Study and Inoculation Experiment

  • An epidemiological survey of additional horses from three different locations backed the link between TDAV infection and acute serum hepatitis, helping establish TDAV as a possible etiological agent of Theiler’s disease.
  • To further investigate the disease progression of TDAV, experimental inoculation was conducted. The researchers infected horses with TDAV-positive plasma and found that disease activity, measured by viremia, starts several weeks before any liver injury, implying a specific pathogenesis pattern of TDAV infection.

TDAV Transmission and Clinical Presentations

  • Similarly to hepatitis C virus (a well-studied member of the Flaviviridae family), TDAV showed efficient parenteral transmission, meaning it can spread effectively via direct body fluid contact.
  • The study shows that TDAV can lead to both acute and chronic infections with varying clinical presentations. These can range from subclinical infection (no visible symptoms) to clinical hepatitis, indicating a broad spectrum of disease severity associated with TDAV infection.

Cite This Article

APA
Chandriani S, Skewes-Cox P, Zhong W, Ganem DE, Divers TJ, Van Blaricum AJ, Tennant BC, Kistler AL. (2013). Identification of a previously undescribed divergent virus from the Flaviviridae family in an outbreak of equine serum hepatitis. Proc Natl Acad Sci U S A, 110(15), E1407-E1415. https://doi.org/10.1073/pnas.1219217110

Publication

Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
NlmUniqueID: 7505876
Country: United States
Language: English
Volume: 110
Issue: 15
Pages: E1407-E1415

Researcher Affiliations

Chandriani, Sanjay
  • Department of Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, CA 94608, USA.
Skewes-Cox, Peter
    Zhong, Weidong
      Ganem, Donald E
        Divers, Thomas J
          Van Blaricum, Anita J
            Tennant, Bud C
              Kistler, Amy L

                MeSH Terms

                • Animals
                • Botulinum Toxins / metabolism
                • Cluster Analysis
                • Disease Outbreaks
                • Flaviviridae / genetics
                • Flaviviridae Infections / veterinary
                • Flaviviridae Infections / virology
                • Gene Library
                • Genome, Viral
                • Hepatitis, Viral, Animal / virology
                • Horses / virology
                • Metagenomics
                • Molecular Sequence Data
                • Phylogeny
                • RNA, Viral / metabolism
                • Sequence Analysis, DNA

                Conflict of Interest Statement

                Conflict of interest statement: A.L.K., S.C., P.S.-C., T.J.D., and B.C.T. are coinventors on a patent application relating to the results herein. A.L.K., S.C., P.S.-C., D.E.G., and W.Z. are employees of the Novartis Institutes for BioMedical Research.

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