Research Article: Therapeutic efficacy of favipiravir against Bourbon virus in mice

Date Published: June 13, 2019

Publisher: Public Library of Science

Author(s): 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, Sonja Best.


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.

Partial Text

Bourbon virus (BRBV) is an emerging tick-borne RNA virus and a member of the genus Thogotovirus in the family orthomyxoviridae. It was first discovered in 2014 in a clinical specimen obtained from a severely ill patient from Bourbon County, Kansas. This individual died two days later from complications of renal failure, acute respiratory distress syndrome, and ventricular tachycardia [1]. The genome of BRBV is composed of six gene-segments that are predicted to encode for PB2, PB1, and PA polymerase proteins, a nucleoprotein (NP), a surface glycoprotein (GP), and a matrix (M) protein. Following the initial discovery of this virus, one additional case of human BRBV infection was identified [2].

BRBV is a recently discovered tick-borne orthomyxovirus that was first identified in 2014 in a human patient who died due to complications from the disease. Currently, there is no approved therapy or vaccine against BRBV. Here we report the isolation and characterization of the second human isolate of BRBV (BRBV-STL) from a fatal case and demonstrate that BRBV replication is inhibited by the broad-spectrum antiviral drug favipiravir. Using a novel mouse model of BRBV pathogenesis, we also show that favipiravir has prophylactic and therapeutic activity against fatal BRBV disease. These findings support the possible evaluation of favipiravir as a therapeutic for future human BRBV cases.




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