A single amino acid change in the Marburg virus glycoprotein arises during serial cell culture passages and attenuates the virus in a macaque model of disease

Kendra J. Alfson, Laura E. Avena, Jenny Delgado, Michael W. Beadles, Jean L. Patterson, Ricardo Carrion, Anthony Griffiths

    Research output: Contribution to journalArticle

    3 Citations (Scopus)

    Abstract

    Marburg virus (MARV) causes disease with high case fatality rates, and there are no approved vaccines or therapies. Licensing of MARV countermeasures will likely require approval via the FDA's Animal Efficacy Rule, which requires wellcharacterized animal models that recapitulate human disease. This includes selection of the virus used for exposure and ensuring that it retains the properties of the original isolate. The consequences of amplification of MARV for challenge studies are unknown. Here, we serially passaged and characterized MARV through 13 passes from the original isolate. Surprisingly, the viral genome was very stable, except for a single nucleotide change that resulted in an amino acid substitution in the hydrophobic region of the signal peptide of the glycoprotein (GP). The particle/PFU ratio also decreased following passages, suggesting a role for the amino acid in viral infectivity. To determine if amplification introduces a phenotype in an animal model, cynomolgus macaques were exposed to either 100 or 0.01 PFU of low- and highpassage- number MARV. All animals succumbed when exposed to 100 PFU of either passage 3 or 13 viruses, although animals exposed to the high-passage-number virus survived longer. However, none of the passage 13 MARV-exposed animals succumbed to 0.01-PFU exposure compared to 75% of passage 3-exposed animals. This is consistent with other filovirus studies that show some particles that are unable to yield a plaque in cell culture can cause lethal disease in vivo. These results have important consequences for the design of experiments that investigate MARV pathogenesis and that test the efficacy of MARV countermeasures.

    Original languageEnglish (US)
    Article numbere00401-17
    JournalmSphere
    Volume3
    Issue number1
    DOIs
    StatePublished - Jan 1 2018

    Fingerprint

    Marburgvirus
    Macaca
    Glycoproteins
    Cell Culture Techniques
    Viruses
    Amino Acids
    Marburg Virus Disease
    Animal Models
    Active Immunotherapy
    Viral Genome
    Amino Acid Substitution
    Licensure
    Protein Sorting Signals
    Nucleotides
    Phenotype
    Mortality

    Keywords

    • Adaptation
    • Attenuation
    • Glycoprotein
    • Marburg virus
    • Monkey model
    • Pathogenesis
    • Signal peptide

    ASJC Scopus subject areas

    • Microbiology
    • Molecular Biology

    Cite this

    A single amino acid change in the Marburg virus glycoprotein arises during serial cell culture passages and attenuates the virus in a macaque model of disease. / Alfson, Kendra J.; Avena, Laura E.; Delgado, Jenny; Beadles, Michael W.; Patterson, Jean L.; Carrion, Ricardo; Griffiths, Anthony.

    In: mSphere, Vol. 3, No. 1, e00401-17, 01.01.2018.

    Research output: Contribution to journalArticle

    Alfson, Kendra J. ; Avena, Laura E. ; Delgado, Jenny ; Beadles, Michael W. ; Patterson, Jean L. ; Carrion, Ricardo ; Griffiths, Anthony. / A single amino acid change in the Marburg virus glycoprotein arises during serial cell culture passages and attenuates the virus in a macaque model of disease. In: mSphere. 2018 ; Vol. 3, No. 1.
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