Molnupiravir inhibits Bourbon virus infection and disease-associated pathology in mice

Bourbon virus (BRBV) is an emerging tick-borne virus that can cause severe and fatal disease in humans. BRBV is vectored via the <i>Amblyomma americanum</i> tick, which is widely distributed throughout the central, eastern, and southern United States. Serosurveillance studies in Missouri and North Carolina identified BRBV-neutralizing antibodies in approximately 0.6% of tested individuals. To date, no specific antiviral therapy exists. As part of an initial screen, several nucleoside analogs were tested for their ability to inhibit BRBV replication in cell culture. Among the compounds assessed, molnupiravir, an antiviral drug with oral availability and broad spectrum antiviral activity against RNA viruses, showed antiviral activity against BRBV production <i>in vitro. In vivo</i>, pre-exposure administration of molnupiravir protected susceptible type I interferon receptor knockout (<i>Ifnar1</i>^-/-) mice against lethal BRBV infection. The protection by molnupiravir was associated with lower virus burden in mouse tissues, improvement of T-cell (CD4⁺, CD8⁺) and B-cell (follicular) profiles in the spleen, improvement of severe thrombocytopenia, and reduced pathology in the spleen and liver of BRBV-infected mice. Finally, therapeutic administration of molnupiravir starting 24 or 48 hours after infection ameliorated weight loss, clinical signs of disease, and lethality associated with BRBV infection. Overall, our experiments suggest that molnupiravir is a potential antiviral therapy for evaluation in humans with BRBV infections.IMPORTANCEBourbon virus (BRBV) is an emerging tick-borne pathogen that can cause severe and fatal illness in humans. Currently, there are no approved antiviral therapies or vaccines against this disease. In this study, we evaluated the efficacy of molnupiravir, a broad-spectrum antiviral drug that is approved in the United States for other RNA viruses, using a mouse model of lethal BRBV disease. Molnupiravir significantly inhibited virus replication, improved survival rates, and suppressed clinical signs of disease, including thrombocytopenia and liver and spleen pathology. These findings support further investigation of molnupiravir as a potential therapeutic candidate for treating BRBV infections in humans.