[Source: PLoS One, full page: (LINK). Abstract, edited.]
OPEN ACCESS / PEER-REVIEWED / RESEARCH ARTICLE
Therapeutic efficacy of favipiravir against Bourbon virus in mice
Traci L. Bricker, Md. Shafiuddin, Anshu P. Gounder, Andrew B. Janowski, Guoyan Zhao, Graham D. Williams, Brett W. Jagger, Michael S. Diamond, Thomas Bailey, Jennie H. Kwon, David Wang, Adrianus C. M. Boon
Published: June 13, 2019 / DOI: https://doi.org/10.1371/journal.ppat.1007790
Bourbon virus (BRBV) is an emerging tick-borne RNA virus in the orthomyxoviridae family that was discovered in 2014. Although fatal human cases of BRBV have been described, little is known about its pathogenesis, and no antiviral therapies or vaccines exist. We obtained serum from a fatal case in 2017 and successfully recovered the second human infectious isolate of BRBV. Next-generation sequencing of the St. Louis isolate of BRBV (BRBV-STL) showed >99% nucleotide identity to the original reference isolate. Using BRBV-STL, we developed a small animal model to study BRBV-STL tropism in vivo and evaluated the prophylactic and therapeutic efficacy of the experimental antiviral drug favipiravir against BRBV-induced disease. Infection of Ifnar1-/- mice lacking the type I interferon receptor, but not congenic wild-type animals, resulted in uniformly fatal disease 6 to 10 days after infection. RNA in situ hybridization and viral yield assays demonstrated a broad tropism of BRBV-STL with highest levels detected in liver and spleen. In vitro replication and polymerase activity of BRBV-STL were inhibited by favipiravir. Moreover, administration of favipiravir as a prophylaxis or as post-exposure therapy three days after infection prevented BRBV-STL-induced mortality in immunocompromised Ifnar1-/- mice. These results suggest that favipiravir may be a candidate treatment for humans who become infected with BRBV.
Bourbon virus (BRBV) is a novel tick-borne RNA virus that can cause fatal disease in humans. No approved antiviral treatment is available. We have cultured the second human isolate of BRBV and with it developed a small animal disease model. In this mouse model, BRBV causes severe disease as measured by weight loss after infection and uniform death 6 to 10 days after infection. Virus replication occurred predominantly in the spleen and the liver of the infected animals, with additional organs infected at later time points after infection. This disease model was used to test the efficacy of favipiravir, a viral RNA polymerase inhibitor that was developed for the related Influenza A virus. Prophylactic and therapeutic treatment with favipiravir resulted in complete protection from a lethal BRBV infection. These data suggest that favipiravir and perhaps other RNA polymerase inhibitors could be used to treat BRBV infections in humans.
Citation: Bricker TL, Shafiuddin M, Gounder AP, Janowski AB, Zhao G, Williams GD, et al. (2019) Therapeutic efficacy of favipiravir against Bourbon virus in mice. PLoS Pathog 15(6): e1007790. https://doi.org/10.1371/journal.ppat.1007790
Editor: Sonja Best, National Institute of Allergy and Infectious Diseases, UNITED STATES
Received: February 6, 2019; Accepted: April 26, 2019; Published: June 13, 2019
Copyright: © 2019 Bricker et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The genome sequence of Bourbon virus: All sequence files are available from the GenBank database (accession number(s) MK453524-MK453529). All other relevant data are within the manuscript and its supporting information files.
Funding: The work was in part funded by R01-AI118938, and R21-AI137450 and the Children’s Discovery Institute grant PD-II-2018-702. APG and GDW were supported by the Infectious Disease Training Grant (T32 AI007172). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Keywords: Bourbon virus; Viral pathogenesis; Antivirals; Favipiravir; Animal models.