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Literature detail

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

Scott A Kerr1 Eleisha L Jackson2 Oana I Lungu1 Austin G Meyer2 Ann Demogines1 Andrew D Ellington1 George Georgiou3 Claus O Wilke4 Sara L Sawyer5
Affiliations 5 institutions
  1. Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, USA.
  2. Department of Integrative Biology,The University of Texas at Austin, Austin, Texas, USA.
  3. Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, USA Department of Chemical Engineering, The University of Texas at Austin, Austin, Texas, USA.
  4. Department of Integrative Biology,The University of Texas at Austin, Austin, Texas, USA [email protected] [email protected].
  5. Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, USA Department of Molecular, Cellular, and Developmental Biology and the BioFrontiers Institute, University of Colorado Boulder, Boulder, Colorado, USA [email protected] [email protected].
PMID 26355089 2015 J Virol eng ppublish
PubMed DOI Browse context

Article

Publication summary

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 trade-offs, 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. We 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.

Host Specificity Virus Attachment Algorithms Animals Antigens, CD Arenaviruses, New World Cell Line, Tumor Computational Biology Disease Resistance Dogs HEK293 Cells Humans Molecular Docking Simulation Receptors, Transferrin Receptors, Virus Virus Internalization CD71 antigen Tfrc protein, mouse

Structured evidence records

Evidence records

11 total
Host Range Experiment 3 records
Host Range Experiment Extraction confidence 0.85
Key finding

Cell-based entry assays showed that human TfR1 polymorphism L212V reduces Machupo virus entry but enhances Junin and Sabia virus entry, indicating species-specific receptor effects on arenavirus host range.

Host
Rodentia
Location
Not specified
Supporting text

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. ... 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.

Method
cell-entry assay; experimental infection
Experimental system
in vitro cell culture
Host Range Experiment Extraction confidence 0.85
Key finding

Entry experiments demonstrate that human TfR1 variant L212V enhances Junin virus cell entry relative to wild-type TfR1.

Host
Rodentia
Location
Not specified
Supporting text

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.

Method
cell-entry assay; experimental infection
Experimental system
in vitro cell culture
Host Range Experiment Extraction confidence 0.85
Key finding

Functional assays show that the human TfR1 polymorphism L212V increases Sabia virus entry, indicating receptor-based differences in host range among New World arenaviruses.

Virus
SBAV
Host
Rodentia
Location
Not specified
Supporting text

The human single nucleotide polymorphism (SNP) L212V makes human TfR1 a weaker receptor for one arenavirus, Machupo virus, but a stronger receptor for two other arenaviruses, Junin and Sabia viruses.

Method
cell-entry assay; experimental infection
Experimental system
in vitro cell culture
Molecular Adaptation 3 records
Molecular Adaptation Extraction confidence 0.95
Key finding

The human TfR1 L212V mutation reduces Machupo virus entry but enhances Junin and Sabia virus entry, showing molecular adaptation affecting host range.

Host
Not specified
Location
Not specified
Supporting text

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.

Genes or proteins
TfR1
Receptors
TfR1
Mutations
L212V
Mechanism types
receptor_binding; cell_entry
Molecular Adaptation Extraction confidence 0.95
Key finding

The human TfR1 L212V mutation enhances Junin virus entry, demonstrating host receptor-based molecular adaptation affecting viral host range.

Host
Not specified
Location
Not specified
Supporting text

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.

Genes or proteins
TfR1
Receptors
TfR1
Mutations
L212V
Mechanism types
receptor_binding; cell_entry
Molecular Adaptation Extraction confidence 0.95
Key finding

The human TfR1 L212V mutation enhances Sabia virus entry, illustrating receptor-based molecular adaptation and cross-species susceptibility.

Virus
SBAV
Host
Not specified
Location
Not specified
Supporting text

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.

Genes or proteins
TfR1
Receptors
TfR1
Mutations
L212V
Mechanism types
receptor_binding; cell_entry
Receptor Usage 3 records
Receptor Usage Extraction confidence 1.00
Key finding

Human TfR1 receptor variant L212V reduces Machupo virus entry but enhances Junin and Sabia virus receptor-mediated entry.

Location
Not specified
Supporting text

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.

Method
functional assay
Receptors
TfR1
Receptor Usage Extraction confidence 1.00
Key finding

Human TfR1 receptor variant L212V increases receptor compatibility and entry efficiency for Junin virus.

Location
Not specified
Supporting text

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.

Method
functional assay
Receptors
TfR1
Receptor Usage Extraction confidence 1.00
Key finding

Human TfR1 receptor variant L212V strengthens receptor-mediated entry for Sabia virus.

Virus
SBAV
Location
Not specified
Supporting text

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.

Method
functional assay
Receptors
TfR1
Genomic Evolution 2 records
Genomic Evolution Extraction confidence 0.80
Key finding

Evolutionary analysis of TfR1 receptor sequences revealed a motif under positive selection that determines species-specific entry for New World arenaviruses, with different mutations producing distinct host-specific effects among Machupo, Junin, and Sabia viruses.

Virus
Arenaviridae
Host
Rodentia
Location
Not specified
Supporting text

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.

Genes or proteins
TfR1
Analysis methods
evolutionary analysis; signatures of positive selection
Genomic Evolution Extraction confidence 0.80
Key finding

Computational docking and homology modeling accurately predicted receptor compatibility for Machupo virus across multiple host species, illustrating genomic and structural evolution in host range.

Host
Not specified
Location
Not specified
Supporting text

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.

Genes or proteins
TfR1
Analysis methods
homology modeling; computational docking