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Raaben, Matthijs; Jae, Lucas T.; Herbert, Andrew S.; Kühne, Ana I.; Stubbs, Sarah H.; Chou, Yi-ying; Blomen, Vincent A.; Kirchhausen, Tomas; Dye, John M.; Brummelkamp, Thijn R.; Whelan, Sean P. (2017): NRP2 and CD63 Are Host Factors for Lujo Virus Cell Entry. In: Cell Host & Microbe, Vol. 22, No. 5: pp. 688-696
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Arenaviruses cause fatal hemorrhagic disease in humans. Old World arenavirus glycoproteins (GPs) mainly engage alpha-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.