Transferrin receptor 1 in the zoonosis and pathogenesis of New World hemorrhagic fever arenaviruses

Abstract

At least five New World arenaviruses cause severe human hemorrhagic fevers. These viruses are transmitted to humans through contact with their respective South American rodent hosts. Each uses human transferrin receptor 1 (TfR1) as its obligate receptor. Accidental similarities between human TfR1 and TfR1 orthologs of arenaviral host species enable zoonoses, whereas mice and rats are not infectable because they lack these TfR1 determinants of infection. All pathogenic New World arenaviruses bind to a common region of the apical domain of TfR1. The ability of a New World arenavirus to use human TfR1 is absolutely predictive of its ability to cause hemorrhagic fevers in humans. Nonpathogenic arenaviruses, closely related to hemorrhagic fever arenaviruses, cannot utilize human TfR1 but efficiently enter cells through TfR1 orthologs of their native rodent hosts. Mutagenesis studies suggest that minor changes in the entry glycoproteins of these nonpathogenic viruses may allow human transmission. TfR1 is upregulated as a result of iron sequestration during the acute-phase response to infection, and the severity of disease may result from amplification of viral replication during this response.

Figure 1

Phylogenetic relationships among representative arenaviruses. Analysis is based on GP regions alone. Asterisks indicate viruses that cause human diseases. Only clade B viruses, which include all New World hemorrhagic fever arenaviruses, are fully represented.

Figure 2

Cocrystal complex of human TfR1 dimer with MACV GP1. The dimer of TfR1 is shown in dark gray and white [16]. TfR1 residues within 5.5 Å of transferrin, as described in Ref. [21], are indicated with magenta. Two MACV GP domains are shown, with key TfR1 residues tyrosine 211 and threonine 348 indicated as red and orange spheres, respectively [18]. The protease-like, helical, and apical domains of TfR1 are indicated on one monomer. Note that transferrin interacts solely with the helical and protease-like domains, whereas MACV GP1 interacts solely with the TfR1 apical domain [16].