Investigation of Clade B New World Arenavirus Tropism by Using Chimeric GP1 Proteins

Martin, Vanessa K.; Droniou-Bonzom, Magali E.; Reignier, Therese; Oldenburg, Jill; Cox, Alex U.; Cannon, Paula M.

doi:10.1128/jvi.01625-09

Cited by 14 publications

(21 citation statements)

References 37 publications

(38 reference statements)

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“…Of the five residues that vary in two ShTfR1 clones, obtained from two different museum tissue samples, residues 214 and 216 are located in close vicinity to the region in the TfR1 apical domain, which is critical for arenavirus entry (Fig. 6B) (33,34,45). Of these, glutamate at position 214 is critical for all clade A/B viruses for efficient use of Sh(EP)TfR1 (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Old World and NW clade C arenaviruses use ␣-dystroglycan as their cellular receptor to enter target cells (27,28), while human transferrin receptor 1 (hTfR1) was identified as a receptor for pathogenic NW arenaviruses (29,30). Importantly, the ability to use hTfR1 is a characteristic feature of NW arenaviruses that cause hemorrhagic fevers in humans (29)(30)(31)(32)(33). These viruses also efficiently use the TfR1 orthologs of their respective natural host species (34), highlighting the role of TfR1 in efficient zoonotic transmission of pathogenic viruses.…”

Section: Importancementioning

confidence: 99%

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

Zong

Fofana

Choe

2014

J Virol

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Importancementioning

confidence: 99%

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

Zong

Fofana

Choe

2014

J Virol

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“…A cocrystal structure demonstrating the interaction between human TfR1 and the GP1 of one New World arenavirus, Machupo virus, has been solved (18). Each of the clade B arenaviruses has distinct patterns of compatibility with the TfR1s encoded by various mammalian species (18)(19)(20)(21)(22). For instance, Machupo virus enters cells through the TfR1 of its rodent host species, Calomys callosus, but not through the TfR1 of the closely related Junin virus host species, Calomys musculinus (19).…”

mentioning

confidence: 99%

Computational and Functional Analysis of the Virus-Receptor Interface Reveals Host Range Trade-Offs in New World Arenaviruses

Kerr

Jackson

Lungu

et al. 2015

J Virol

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Animal viruses frequently cause zoonotic disease in humans. As these viruses are highly diverse, evaluating the threat that they pose remains a major challenge, and efficient approaches are needed to rapidly predict virus-host compatibility. Here, we develop a combined computational and experimental approach to assess the compatibility of New World arenaviruses, endemic in rodents, with the host TfR1 entry receptors of different potential new host species. Using signatures of positive selection, we identify a small motif on rodent TfR1 that conveys species specificity to the entry of viruses into cells. However, we show that mutations in this region affect the entry of each arenavirus differently. For example, a human single nucleotide polymorphism (SNP) in this region, L212V, makes human TfR1 a weaker receptor for one arenavirus, Machupo virus, but a stronger receptor for two other arenaviruses, Junin and Sabia viruses. Collectively, these findings set the stage for potential evolutionary tradeoffs, where natural selection for resistance to one virus may make humans or rodents susceptible to other arenavirus species. Given the complexity of this host-virus interplay, we propose a computational method to predict these interactions, based on homology modeling and computational docking of the virus-receptor protein-protein interaction. We demonstrate the utility of this model for Machupo virus, for which a suitable cocrystal structural template exists. Our model effectively predicts whether the TfR1 receptors of different species will be functional receptors for Machupo virus entry. Approaches such at this could provide a first step toward computationally predicting the "host jumping" potential of a virus into a new host species. IMPORTANCEWe demonstrate how evolutionary trade-offs may exist in the dynamic evolutionary interplay between viruses and their hosts, where natural selection for resistance to one virus could make humans or rodents susceptible to other virus species. We present an algorithm that predicts which species have cell surface receptors that make them susceptible to Machupo virus, based on computational docking of protein structures. Few molecular models exist for predicting the risk of spillover of a particular animal virus into humans or new animal populations. Our results suggest that a combination of evolutionary analysis, structural modeling, and experimental verification may provide an efficient approach for screening and assessing the potential spillover risks of viruses circulating in animal populations. V iruses need to enter cells of a host organism in order to make more copies of themselves. Many viruses interact with protein receptors found on the surface of host cells in order to gain entry into those cells. Like all proteins, these host receptors can vary in sequence from species to species. Viruses tend to be acutely adapted to use the receptor of one species, with the unintentional consequence of being poorly adapted to the receptor encoded by related species. For instance...

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“…Retroviruses pseudotyped with arenavirus glycoproteins have been used successfully to characterize arenavirus cell entry determinants (10,13,15,16,(21)(22)(23)(24). We therefore produced enhanced green fluorescent protein (eGFP)-expressing Moloney murine leukemia virus (MoMLV) pseudotyped with control (TCRV, MACV, or LASV) GPC (15,16,25) or OCEV GPC (synthesized by DNA2.0 based on GenBank accession number JN897398) and evaluated transduction efficiencies in cells obtained from ATCC. Grivet (Chlorocebus aethiops) Vero E6 cells (Fig.…”

mentioning

confidence: 99%

“…Following published strategies (15,16,25), we aligned hTfR1 residues 201 to 216 with those of other orthologs (Fig. 4) and then created three FLAG-tagged h/reTfR1 chimeras.…”

mentioning

confidence: 99%

Nonhuman Transferrin Receptor 1 Is an Efficient Cell Entry Receptor for Ocozocoautla de Espinosa Virus

Caì

Yú

Mazur

et al. 2013

J Virol

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Investigation of Clade B New World Arenavirus Tropism by Using Chimeric GP1 Proteins

Cited by 14 publications

References 37 publications

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

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

Computational and Functional Analysis of the Virus-Receptor Interface Reveals Host Range Trade-Offs in New World Arenaviruses

Nonhuman Transferrin Receptor 1 Is an Efficient Cell Entry Receptor for Ocozocoautla de Espinosa Virus

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