Therapeutic efficacy of #favipiravir against #Bourbon virus in mice (PLoS One, abstract)

[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

 

Abstract

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.

 

Author summary

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.

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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.

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Essential Role of #Interferon Response in Containing #Human #Pathogenic #Bourbon Virus (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 25, Number 7—July 2019 / Research

Essential Role of Interferon Response in Containing Human Pathogenic Bourbon Virus

Jonas Fuchs, Tobias Straub, Maximilian Seidl, and Georg Kochs

Author affiliations: University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

 

Abstract

Bourbon virus (BRBV) is a recently discovered tick-transmitted viral pathogen that is prevalent in the Midwest and southern United States. Since 2014, zoonotic BRBV infections have been verified in several human cases of severe febrile illness, occasionally with fatal outcomes, indicating a possible public health threat. We analyzed the pathology of BRBV infection in mice and found a high sensitivity of the virus to the host interferon system. Infected standard laboratory mice did not show clinical signs or virus replication. However, in mice carrying defects in the type I and type II interferon system, the virus grew to high titers and caused severe pathology. In cell culture, BRBV was blocked by antiviral agents like ribavirin and favipiravir (T705). Our data suggest that persons having severe BRBV infection might have a deficiency in their innate immunity and could benefit from an already approved antiviral treatment.

Keywords: Arbovirus; Bourbon virus; Tick-borne infections; Viral pathogenesis; Antivirals; Interferons; Ribavirin; Favipiravir.

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#Bourbon Virus in #Field-Collected #Ticks, #Missouri, #USA (@CDC_EIDjournal, abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 23, Number 12—December 2017 / Research

Bourbon Virus in Field-Collected Ticks, Missouri, USA

Harry M. Savage  , Kristen L. Burkhalter, Marvin S. Godsey, Nicholas A. Panella, David C. Ashley, William L. Nicholson, and Amy J. Lambert

Author affiliations: Centers for Disease Control and Prevention, Fort Collins, Colorado, USA (H.M. Savage, K.L. Burkhalter, M.S. Godsey, Jr., N.A. Panella, A.J. Lambert); Missouri Western State University, St. Joseph, Missouri, USA (D.C. Ashley); Centers for Disease Control and Prevention, Atlanta, Georgia, USA (W.L. Nicholson)

 

Abstract

Bourbon virus (BRBV) was first isolated in 2014 from a resident of Bourbon County, Kansas, USA, who died of the infection. In 2015, an ill Payne County, Oklahoma, resident tested positive for antibodies to BRBV, before fully recovering. We retrospectively tested for BRBV in 39,096 ticks from northwestern Missouri, located 240 km from Bourbon County, Kansas. We detected BRBV in 3 pools of Amblyomma americanum(L.) ticks: 1 pool of male adults and 2 pools of nymphs. Detection of BRBV in A. americanum, a species that is aggressive, feeds on humans, and is abundant in Kansas and Oklahoma, supports the premise that A. americanum is a vector of BRBV to humans. BRBV has not been detected in nonhuman vertebrates, and its natural history remains largely unknown.

Keywords: Bourbon Virus; USA; Missouri; Ticks.

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