Favipiravir inhibits in vitro Usutu virus replication and delays disease progression in an infection model in mice.

Usutu virus (USUV) is an emerging flavivirus that causes Usutu disease mainly in birds, but infection of mammals such as rodents, bats and horses has also been demonstrated. In addition, human cases (both in immunocompromised and -competent individuals) were also reported. Large outbreaks with other flaviviruses, such as West Nile virus and Zika virus, indicate that one should be vigilant for yet other outbreaks. To allow the identification of inhibitors of USUV replication, we established in vitro antiviral assays, which were validated using a small selection of known flavivirus inhibitors, including the broad-spectrum viral RNA polymerase inhibitor favipiravir (T-705). Next, an USUV infection model in AG129 (IFN-α/ß and IFN-γ receptor knockout) mice was established. AG129 mice proved highly susceptible to USUV; an inoculum as low as 102 PFU (1.3 × 105 TCID50) resulted in the development of symptoms as early as 3 days post infection with viral RNA being detectable in various tissues. Treatment of mice with favipiravir (150 mg/kg/dose, BID, oral gavage) significantly reduced viral load in blood and tissues and significantly delayed virus-induced disease. This USUV mouse model is thus amenable for assessing the potential in vivo efficacy of (novel) USUV/flavivirus inhibitors.