Host-species transferrin receptor 1 orthologs are cellular receptors for nonpathogenic new world clade B arenaviruses.

Jonathan Abraham,Jo Ann Kwong,Jorge Salazar-Bravo,Sheli R. Radoshitzky,Jiajie G. Lu,Michael Farzan,César G. Albariño,Christina F. Spiropoulou,Hyeryun Choe,Michael J. Buchmeier

doi:10.1371/journal.ppat.1000358

Abstract

The ability of a New World (NW) clade B arenavirus to enter cells using human transferrin receptor 1 (TfR1) strictly correlates with its ability to cause hemorrhagic fever. Amapari (AMAV) and Tacaribe (TCRV), two nonpathogenic NW clade B arenaviruses that do not use human TfR1, are closely related to the NW arenaviruses that cause hemorrhagic fevers. Here we show that pseudotyped viruses bearing the surface glycoprotein (GP) of AMAV or TCRV can infect cells using the TfR1 orthologs of several mammalian species, including those of their respective natural hosts, the small rodent Neacomys spinosus and the fruit bat Artibeus jamaicensis. Mutation of one residue in human TfR1 makes it a functional receptor for TCRV, and mutation of four residues makes it a functional receptor for AMAV. Our data support an in vivo role for TfR1 in the replication of most, if not all, NW clade B arenaviruses, and suggest that with modest changes in their GPs the nonpathogenic arenaviruses could use human TfR1 and emerge as human pathogens.

Highlights

Arenaviruses are enveloped viruses that carry single-stranded, bi-segmented, RNA genomes [1]
Author Summary Several arenaviruses found in the New World cause hemorrhagic fever when they are transmitted from their natural reservoirs to humans
These pathogenic arenaviruses use human transferrin receptor 1 (TfR1), a protein involved in cellular iron uptake, to infect human cells

Summary

Introduction

Arenaviruses are enveloped viruses that carry single-stranded, bi-segmented, RNA genomes [1]. The New World (NW) arenavirus cluster is subdivided into clades A, B, and C. Several North American viruses are recombination products of clades A and B (A/B) (Figure 1). All NW arenaviruses that cause hemorrhagic fever in humans are in the B clade. These include the Junın (JUNV), Machupo (MACV), Guanarito (GTOV), and Sabia (SABV) viruses, which respectively cause Argentine, Bolivian, Venezuelan, and Brazilian hemorrhagic fevers with high (10–30%) case fatality rates [2,8,9]. A novel NW clade B arenavirus, Chapare virus, was recently isolated from a fatal case of hemorrhagic fever in Bolivia [3]

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