PLoS Pathogens (Jun 2022)
The nonstructural p17 protein of a fusogenic bat-borne reovirus regulates viral replication in virus species- and host-specific manners
Abstract
Nelson Bay orthoreovirus (NBV), a member of the family Reoviridae, genus Orthoreovirus, is a bat-borne virus that causes respiratory diseases in humans. NBV encodes two unique nonstructural proteins, fusion-associated small transmembrane (FAST) protein and p17 protein, in the S1 gene segment. FAST induces cell–cell fusion between infected cells and neighboring cells and the fusogenic activity is required for efficient viral replication. However, the function of p17 in the virus cycle is not fully understood. Here, various p17 mutant viruses including p17-deficient viruses were generated by a reverse genetics system for NBV. The results demonstrated that p17 is not essential for viral replication and does not play an important role in viral pathogenesis. On the other hand, NBV p17 regulated viral replication in a bat cell line but not in other human and animal cell lines. Nuclear localization of p17 is associated with the regulation of NBV replication in bat cells. We also found that p17 dramatically enhances the cell–cell fusion activity of NBV FAST protein for efficient replication in bat cells. Furthermore, we found that a protein homologue of NBV p17 from another bat-borne orthoreovirus, but not those of avian orthoreovirus or baboon orthoreovirus, also supported efficient viral replication in bat cells using a p17-deficient virus-based complementation approach. These results provide critical insights into the functioning of the unique replication machinery of bat-borne viruses in their natural hosts. Author summary Bat-borne viruses including the severe acute respiratory syndrome coronavirus and Nipah virus generally cause highly pathogenic diseases in humans but not in their bat reservoirs. Nelson Bay orthoreovirus (NBV), a bat-borne virus associated with acute respiratory tract infections in humans, possesses two unique nonstructural proteins, FAST and p17. FAST enhances viral replication through its cell–cell fusion activity, while the function of p17 in the viral life cycle is poorly understood. In this study, we show that p17 is non-essential for viral replication in several human and animal cell lines and does not play a critical role in pathogenesis in vivo. However, p17 localizes to the nucleus and regulates viral replication specifically in cells derived from bats by enhancing the cell–cell fusion activity of FAST in a host-specific manner. Furthermore, the expression of NBV p17 or an NBV p17 homologue from another bat-borne orthoreovirus enhanced the replication of an NBV mutant deficient in p17 in bat cells, suggesting that the function of p17 is virus species-specific. These findings will contribute to our understanding of how the replication of viruses is regulated in their natural reservoirs.