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.

甲状旁腺病毒会导致人类致命的出血性疾病。旧世界的槟榔病毒糖蛋白（GPs）主要与α-dystroglycan结合作为细胞表面受体，而新大陆的槟榔病毒劫持了转铁蛋白受体。但是，Lujo病毒（LUJV）GP不会与新的或旧的竞技场病毒一起聚集。使用包含LUJV GP作为其唯一附件和融合蛋白（VSV-LUJV）的重组水泡性口腔炎病毒，我们证明感染独立于已知的沙粒病毒受体基因。全基因组的单倍体遗传筛选确定跨膜蛋白Neuropilin 2（NRP2）和四跨膜CD63是LUJV GP介导的感染的因素。LUJV GP结合NRP2的N末端域，而CD63刺激pH激活的LUJV GP介导的膜融合。NRP2或其N末端结构域的过表达增强了VSV-LUJV感染，缺乏NRP2的细胞缺乏野生型LUJV感染。这些发现揭示了LUJV感染中这组独特的宿主细胞进入因子，并且是治疗干预的有吸引力的焦点。