ABSTRACT
Five rodent-borne New World (NW) arenaviruses are known to cause recurrent hemorrhagic fever outbreaks in South America. Each of these viruses uses the ubiquitously expressed transferrin receptor 1 (TfR1) to enter human cells. In contrast, closely related but nonpathogenic NW arenaviruses use TfR1-independent mechanisms to enter human cells, although they do use the TfR1 orthologs of their rodent host species as receptors. Mutagenesis studies showed that two key human TfR1 (hTfR1) residues are essential for the entry of pathogenic NW arenaviruses: tyrosine 211 and asparagine 348. These residues are also conserved in the TfR1 orthologs of all known NW arenaviral host species, suggesting that fortuitous similarities between human and host-species TfR1 facilitate arenaviral zoonoses. Less is known about the critical residues on the virus side. Most of the arenavirus glycoprotein (GP) residues in direct contact with hTfR1 are poorly or moderately conserved, suggesting that at given positions variable GP residues can interact with the hTfR1 GP-binding site. This variability implies that the TfR1-binding regions of arenaviral GP molecules have multiple pathways to adapt to the TfR1 ortholog of a new host. In addition, properties of TfR1 may contribute to the severity of South American hemorrhagic fevers. For example, feedback mechanisms triggered by the early immune response to infection may upregulate hTfR1 expression and thereby amplify viral replication.
