Abstract
Transferrin receptor 1 (TfR1) is a cellular receptor for the New World hemorrhagic fever arenaviruses Machupo (MACV), Junín (JUNV), and Guanarito (GTOV). Each of these viruses is specifically adapted to a distinct rodent host species, but all cause human disease. Here we compare the ability of these viruses to use various mammalian transferrin receptor 1 (TfR1) orthologs, including those of the South American rodents that serve as reservoirs for MACV, JUNV, and GTOV (Calomys callosus, Calomys musculinus, and Zygodontomys brevicauda, respectively). Retroviruses pseudotyped with MACV and JUNV but not GTOV glycoproteins (GPs) efficiently used C. callosus TfR1, whereas only JUNV GP could use C. musculinus TfR1. All three viruses efficiently used Z. brevicauda TfR1. TfR1 orthologs from related rodents, including house mouse (Mus musculus) and rat (Rattus norvegicus), did not support entry of these viruses. In contrast, these viruses efficiently used human and domestic cat TfR1 orthologs. We further show that a local region of the human TfR1 apical domain, including tyrosine 211, determined the efficiency with which MACV, JUNV, and GTOV used various TfR1 orthologs. Our data show that these New World arenaviruses are specifically adapted to the TfR1 orthologs of their respective rodent hosts and identify key commonalities between these orthologs and human TfR1 necessary for efficient transmission of these viruses to humans.
Highlights
Introduction of Sixhuman transferrin receptor 1 (TfR1) (hTfR1) Residues Convert mTfR1 to an Efficient New World Arenavirus Receptor
Chinese hamster ovary (CHO) cells, which are refractory to transduction by Moloney murine leukemia virus (MLV) pseudotyped with the glycoproteins of MACV, JUNV, or GTOV [28, 41], were transfected with plasmids expressing these TfR1 orthologs tagged in their C-terminal ectodomains
The GTOV GP did not mediate entry into cells expressing either ccTfR1 or cmTfR1 (Fig. 1 C and E) [5]. It did mediate efficient entry into cells expressing the TfR1 of the GTOV host species Z. brevicauda, as did MACV and JUNV GP molecules (Fig. 1E). These data demonstrate that MACV, JUNV, and GTOV are adapted to the TfR1 orthologs of their respective hosts
Summary
Introduction of SixhTfR1 Residues Convert mTfR1 to an Efficient New World Arenavirus Receptor. Tyrosine 211 is located within an exposed loop of hTfR1 between -strands 1 and 2. All variants expressed as efficiently as hTfR1 and mTfR1 (Fig. 5A), only mTfR1 variants with the RLVYL loop bound MACV GP1⌬-Fc (Fig. 5B). MACV-MLV and GTOV-MLV could enter cells expressing the RLVYL mTfR1 variant and, more efficiently, the RLVYLϩK348N mTfR1 variant (Fig. 5C). The RLVYL variant mediated JUNV-MLV entry as efficiently as hTfR1, and the K348N change had no additional effect. These data show that hTfR1 residues 208–212, including tyrosine 211, are critical for MACV, JUNV, and GTOV entry and that MACV and GTOV entry is partially disrupted by lysine 348, which is present in mTfR1. JUNV may better tolerate this lysine because the TfR1 of its host species, C. musculinus, has a lysine at position 348 (Fig. 3D)
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