Invited
Novel metal-ion dependent cell entry mechanism of a deadly viral pathogen

The recently emerged Lujo virus (LUJV) is a highly fatal human pathogen. Despite its membership among the Arenaviridae, LUJV does not classify with other Arenaviruses. Likewise, LUJV was recently found to use neuropilin-2 (NRP2) as a cellular receptor instead of the canonical receptors utilized by other arenaviruses. The emergence of a deadly pathogen into human populations using an unprecedented entry route raises many questions regarding the mechanism of cell recognition. We used X-ray crystallography to reveal how the GP1 receptor-binding domain of LUJV (LUJVGP1) recognizes NRP2. Surprisingly, our structural data, which is further supported by experimental validations, indicates that NRP2 recognition by LUJVGP1 is metal ion dependent. LUJV binds a region of NRP2 that is highly conserved in mammals, which explains the putative zoonotic transmission of this virus to humans. Taken together, our data provide the mechanism for the cell attachment step of LUJV, and present indispensable information for combating this pathogen.