NRP2 and CD63 Are Host Factors for Lujo Virus Cell Entry

Arenaviruses cause fatal hemorrhagic disease in humans. Old World arenavirus glycoproteins (GPs) mainly engage α-dystroglycan as a cell-surface receptor, while New World arenaviruses hijack transferrin receptor. However, the Lujo virus (LUJV) GP does not cluster with New or Old World arenaviruses. Using a recombinant vesicular stomatitis virus containing LUJV GP as its sole attachment and fusion protein (VSV-LUJV), we demonstrate that infection is independent of known arenavirus receptor genes. A genome-wide haploid genetic screen identified the transmembrane protein neuropilin 2 (NRP2) and tetraspanin CD63 as factors for LUJV GP-mediated infection. LUJV GP binds the N-terminal domain of NRP2, while CD63 stimulates pH-activated LUJV GP-mediated membrane fusion. Overexpression of NRP2 or its N-terminal domain enhances VSV-LUJV infection, and cells lacking NRP2 are deficient in wild-type LUJV infection. These findings uncover this distinct set of host cell entry factors in LUJV infection and are attractive focus points for therapeutic intervention. [Display omitted] •Haploid genetic screen identifies NRP2 and CD63 as host factors for LUJV cell entry•NRP2 encodes a cell entry receptor that is engaged by the LUJV glycoprotein•CD63 facilitates LUJV glycoprotein-mediated membrane fusion at low pH Raaben et al. demonstrate that the semaphorin and VEGF receptor NRP2 also functions as an entry receptor for Lujo virus, a causative agent of lethal hemorrhagic fever in humans. In addition, the molecule CD63 was identified as an intracellular factor facilitating membrane fusion mediated by the Lujo virus glycoprotein.