Antiviral effects of micafungin against pteropine orthoreovirus, an emerging zoonotic virus carried by bats.

Bat-borne emerging zoonotic viruses cause major outbreaks, such as the Ebola virus, Nipah virus, and/or beta coronavirus. Pteropine orthoreovirus (PRV), whose spillover event occurred from fruits bats to humans, causes respiratory syndrome in humans widely in South East Asia. Repurposing approved drugs against PRV is an effective tool to confront future PRV pandemics. We screened 2,943 compounds in an FDA-approved drug library and identified eight hit compounds that reduce viral cytopathic effects on cultured Vero cells. Real-time quantitative PCR analysis revealed that six of eight hit compounds significantly inhibited PRV replication. Among them, micafungin used clinically as an antifungal drug, displayed a prominent antiviral effect on PRV. Secondly, the antiviral effects of micafungin on PRV infected human cell lines (HEK293T and A549), and their transcriptome changes by PRV infection were investigated, compared to four different bat-derived cell lines (FBKT1 (Ryukyu flying fox), DEMKT1 (Leschenault's rousette), BKT1 (Greater horseshoe bat), YUBFKT1 (Eastern bent-wing bats)). In two human cell lines, unlike bat cells that induce an IFN-γ response pathway, an endoplasmic reticulum stress response pathway was commonly activated. Additionally, micafungin inhibits viral release rather than suppressing PRV genome replication in human cells, although it was disturbed in Vero cells. The target of micafungin's action may vary depending on the animal species, but it must be useful for human purposes as a first choice of medical care.

Distinct interferon response in bat and other mammalian cell lines infected with Pteropine orthoreovirus.

Bats serve as natural hosts of Pteropine orthoreovirus (PRV), an emerging group of bat-borne, zoonotic viruses. Bats appear to possess unique innate immune system responses that can inhibit viral replication, thus reducing clinical symptoms. We examined the innate immune response against PRV and assessed viral replication in cell lines derived from four bat species (Miniopterus fuliginosus, Pteropus dasymallus, Rhinolophus ferrumequinum, and Rousettus leschenaultii), one rodent (Mesocricetous auratus), and human (Homo sapiens). The expression levels of pattern recognition receptors (PRRs) (TLR3, RIG-I, and MDA5) and interferons (IFNB1 and IFNL1) were higher and PRV replication was lower in cell lines derived from M. fuliginosus, R. ferrumequinum, and R. leschenaultii. Reduction of IFNB1 expression by the knockdown of PRRs in the cell line derived from R. ferrumequinum was associated with increased PRV replication. The knockdown of RIG-I led to the most significant reduction in viral replication for all cell lines. These results suggest that RIG-I production is important for antiviral response against PRV in R. ferrumequinum.