The proprotein convertase SKI-1/S1P is a critical host factor for Nairobi sheep disease virus infectivity

Nairobi sheep disease virus (NSDV) is a tick-borne viral disease of sheep and goats belongs to Orthonairovirus from Bunyavirales order and characterized by fever, haemorrhagic gastroenteritis, abortion, and high mortality. This virus is genetically related to human-pathogenic Crimean-Congo haemorrhagic fever virus (CCHFV) made it proposed as a model organism for researching CCHFV pathogenesis. However, little is known about NSDV pathogenesis and virus-host interactions. The life cycle of human-pathogenic CCHFV is depends on SKI-1/S1P, an important enzyme in the cell’s cholesterol control mechanism. Previous studies have demonstrated that the CCHFV GPC is cleaved by SKI-1/S1P at the consensus motif RRLL519 (amino acid position refers to CCHFV-IbAr 10,200), and this proteolytic cleavage has a strong impact on virus infectivity. Therefore, the aim of this study was to observe the role of SKI-1/S1P expression in NSDV replication and infectivity. The result presented in this study highlights the critical role played by the host cell protease SKI-1/S1P in NSDV replication and infectivity. The findings imply that SKI-1/S1P may be an essential orthonairovirus host factor, which is consistent with the early observation on the function of SKI-1/S1P in the CCHFV life cycle. This study also offers the first proof of the inhibitory small molecule, PF-429242’s antiviral action against NSDV. These results could be the base for further research to assess PF-429242 effectiveness against different orthonairovirus, such as the human pathogenic CCHFV.

(MA)