Human and Host Species Transferrin Receptor 1 Use by North American Arenaviruses

Abstract

At least five New World (NW) arenaviruses cause hemorrhagic fevers in South America. These pathogenic clade B viruses, as well as nonpathogenic arenaviruses of the same clade, use transferrin receptor 1 (TfR1) of their host species to enter cells. Pathogenic viruses are distinguished from closely related nonpathogenic ones by their additional ability to utilize human TfR1 (hTfR1). Here, we investigate the receptor usage of North American arenaviruses, whose entry proteins share greatest similarity with those of the clade B viruses. We show that all six North American arenaviruses investigated utilize host species TfR1 orthologs and present evidence consistent with arenavirus-mediated selection pressure on the TfR1 of the North American arenavirus host species. Notably, one of these viruses, AV96010151, closely related to the prototype Whitewater Arroyo virus (WWAV), entered cells using hTfR1, consistent with a role for a WWAV-like virus in three fatal human infections whose causative agent has not been identified. In addition, modest changes were sufficient to convert hTfR1 into a functional receptor for most of these viruses, suggesting that a minor alteration in virus entry protein may allow these viruses to use hTfR1. Our data establish TfR1 as a cellular receptor for North American arenaviruses, highlight an "arms race" between these viruses and their host species, support the association of North American arenavirus with fatal human infections, and suggest that these viruses have a higher potential to emerge and cause human diseases than has previously been appreciated. IMPORTANCEhTfR1 use is a key determinant for a NW arenavirus to cause hemorrhagic fevers in humans. All known pathogenic NW arenaviruses are transmitted in South America by their host rodents. North American arenaviruses are generally considered nonpathogenic, but some of these viruses have been tentatively implicated in human fatalities. We show that these North American arenaviruses use the TfR1 orthologs of their rodent host species and identify TfR1 polymorphisms suggesting an ongoing "arms race" between these viruses and their hosts. We also show that a close relative of a North American arenavirus suggested to have caused human fatalities, the Whitewater Arroyo species complex virus AV96010151, uses human TfR1. Moreover, we present data that imply that modest changes in other North American arenaviruses might allow these viruses to infect humans. Collectively, our data suggest that North American arenaviruses have a higher potential to cause human disease than previously assumed.

Novel Arenavirus Entry Inhibitors Discovered by Using a Minigenome Rescue System for High-Throughput Drug Screening

“…Within clade B, we found that all three compounds retained broad and potent activity against each of the GPs tested, including those from human-pathogenic strains (MACV and GTOV) as well as nonpathogenic members (TCRV and AMAV) (28). Similarly, GPs from clade A/B recombinant viruses, which also use species-specific versions of TfR1 as the primary receptor (29,30,44,(48)(49)(50)(51)(52), were inhibited by all three compounds, although the levels of inhibition were not as severe as those observed for clade B GPs (Fig. 4B).…”

“…The OW and NW arenaviruses differ in the entry pathways that they use to enter host cells, recognizing distinct cell surface receptors (29,30,44,(48)(49)(50)(51)(52)(53)(54)(55) and following different intracellular pathways to reach the late endosomes, where virus-cell fusion occurs (reviewed in reference 56). For example, NW clade B viruses use TfR1 as a primary receptor (30,44,48), while both OW and NW clade C viruses use ␣-dystroglycan (␣-DG) (53,55). The lack of an effect of compounds 1 to 3 on LCMV compared to Cd1 therefore led us to hypothesize that they could be acting on the specific Cd1 entry pathway.…”

“…JUNV GPC derivatives were the F427I mutant and chimeric proteins C1X2 and X1C2 (13). Expression plasmids for the GPCs from Big Brushy Tank virus (BBTV), Skinner Tank virus (SKTV), Pichinde virus (PICV) (PICV-18, a guinea pig-adapted strain), and Oliveros virus (OLVV) were used (30)(31)(32). Latino virus (LATV) GPC (GenBank accession no.…”

Molecular Mechanism for LAMP1 Recognition by Lassa Virus

“…NW arenaviruses that belong to clades A and B use transferrin receptor 1 (TfR1) (5,6), whereas OW arenaviruses, as well as clade C NW arenaviruses, use ␣-dystroglycan (␣-DG) (7)(8)(9). A trimeric class 1 viral glycoprotein complex (the spike complex) recognizes the cellular receptors and mediates membrane fusion upon exposure to low pH at the lysosome (10).…”

Molecular-Biological Peculiarities of Arenavirus Reproduction in Sensitive Cells

“…пять вирусов из этого клада (мачупо, хунин, сабиа, гуанарито и чапаре) могут вызывать геморрагиче-ские лихорадки благодаря своей способности свя-зывания с человеческим трансфериновым рецеп-тором 1. в противоположность этому, другие три вируса из клада в (такарибе, амапари и купикси) являются непатогенными для человека в силу своей неспособности осуществлять указанное связывание. за исключением пяти вышеперечисленных, все аре-навирусы нового света, относящиеся к кладам а и в, в качестве рецептора могут использовать только трансфериновый рецептор 1 грызунов [16,28].…”