Structural basis for receptor recognition by New World hemorrhagic fever arenaviruses

Open Access
Publisher Website
Google Scholar
Abstract
New World hemorrhagic fever arenaviruses are rodent transmitted agents that cause severe, often fatal human disease. The structure of the Machupo virus glycoprotein 1 subunit in complex with its human cellular receptor, transferrin receptor 1, was solved. The interaction interfaces between the two proteins and sequence alignments suggest that these viruses fortuitously acquired the ability to bind human transferrin receptor 1 while adapting to their natural hosts. New World hemorrhagic fever arenaviruses are rodent-borne agents that cause severe human disease. The GP1 subunit of the surface glycoprotein mediates cell attachment through transferrin receptor 1 (TfR1). We report the structure of Machupo virus (MACV) GP1 bound with human TfR1. Atomic details of the GP1-TfR1 interface clarify the importance of TfR1 residues implicated in New World arenavirus host specificity. Analysis of sequence variation among New World arenavirus GP1s and their host-species receptors, in light of the molecular structure, indicates determinants of viral zoonotic transmission. Infectivities of pseudoviruses in cells expressing mutated TfR1 confirm that contacts at the tip of the TfR1 apical domain determine the capacity of human TfR1 to mediate infection by particular New World arenaviruses. We propose that New World arenaviruses that are pathogenic to humans fortuitously acquired affinity for human TfR1 during adaptation to TfR1 of their natural hosts.