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

Nairobi sheep disease virus (NSDV) belongs to the Orthonairovirus genus in the Bunyavirales order and is genetically related to human-pathogenic Crimean-Congo hemorrhagic fever virus (CCHFV). NSDV is a zoonotic pathogen transmitted by ticks and primarily affects naïve small ruminants in which infection leads to severe and often fatal hemorrhagic gastroenteritis. Despite its veterinary importance and the striking similarities in the clinical picture between NSDV-infected ruminants and CCHFV patients, the molecular pathogenesis of NSDV and its interactions with the host cell are largely unknown. Here, we identify the membrane-bound proprotein convertase site-1 protease (S1P), also known as subtilisin/kexin-isozyme-1 (SKI-1), as a host factor affecting NSDV infectivity. Absence of S1P in SRD-12B cells, a clonal CHO-K1 cell variant with a genetic defect in the S1P gene (MBTPS1), results in significantly decreased NSDV infectivity while transient complementation of SKI-1/S1P rescues NSDV infection. SKI-1/S1P is dispensable for virus uptake but critically required for production of infectious virus progeny. Moreover, we provide evidence that SKI-1/S1P is involved in the posttranslational processing of the NSDV glycoprotein precursor. Our results demonstrate the role of SKI-1/S1P in the virus life cycle of NSDV and suggest that this protease is a common host factor for orthonairoviruses and may thus represent a promising broadly-effective, indirect antiviral target.