Evolution of Rabies Virus Isolates: Virulence Signatures and Effects of Modulation by Neutralizing Antibodies
Abstract
:1. Introduction
2. Materials and Methods
2.1. Viruses and Cells
2.2. Serial Passages in Neuro-2a Cell Line
2.3. Serial Virus Neutralization (SVN) Assay in Neuro-2a Cell Line
2.4. RNA Extraction and Reverse Transcription Reaction (RT)
2.5. Primers for N and G genes Amplification
2.6. Polymerase Chain Reaction (PCR) for N and G genes
2.7. Purification of PCR Products and Sanger Sequencing
2.8. Sequence Editing and Analysis
2.9. Viral Titration
2.10. Replication Kinetics
2.11. In Vivo Assay—Neurotropism Assessment and Ethics Statement
2.12. Competition Assays
2.13. Quantification of Viral Load by qPCR
2.14. Three-Dimensional (3D) Modeling of G Protein, Optimization, Validation and Analysis
2.15. Molecular Dynamics Simulations
2.16. Molecular Docking
2.17. Statistical Analysis
3. Results
3.1. Amino Acid Substitutions during In Vitro Evolution of RABV Glycoprotein Gene Contribute to Increased Viral Loads in Neuronal Cell Line and Neurotropism In Vivo
3.2. G186E and G186R+S188P Glycoprotein Gene Variants Show Enhancement of Replicative Fitness In Vitro and Are Present in Natura
3.3. Amino Acid Substitutions G186E and G186R+S188P in the G gene Affects Glycoprotein Structure and Dynamics
3.4. Mutant G186R Shows Interaction with Heparin In Silico
3.5. Mutation in G Gene Can Promote Escape from Neutralizing Antibodies in a Field RABV Isolate
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Identification | Host Species | Common Name | Variant |
---|---|---|---|
1069/18 | Artibeus lituratus | Great fruit-eating bat | Bat |
IP3629/11 | Canis lupus familiaris | Dog | Cosmopolitan dog |
203/21 | Tadarida brasiliensis | Mexican free-tailed bat | Bat |
1833/21 | Artibeus lituratus | Great fruit-eating bat | Bat |
2193/21 | Artibeus lituratus | Great fruit-eating bat | Bat |
2253/21 | Didelphis albiventris | White-eared opossum | Bat |
Primer | Sense | Sequence | Size | Position * |
---|---|---|---|---|
N55 | F | 5′ ATGTAACACCTCTACAATGG 3′ | 842 bp | 55–74 |
N879 ** | R | 5′ CAGGCTCGAACATTCTTC 3′ | 842 bp | 879–896 |
N878 *** | R | 5′ CCCGGGCTCGAACATTCTTCT 3′ | 844 bp | 878–898 |
N750 | F | 5′ GCACAGTTGTCACTGCTT 3′ | 793 bp | 750–767 |
N1525B ** | R | 5′ GCACTTGGGCTGACAAAA 3′ | 793 bp | 1525–1542 |
N1525D *** | R | 5′ TGCACTAGGATTGACAAAG 3′ | 793 bp | 1525–1542 |
Isolate | Substitution | |||||
---|---|---|---|---|---|---|
Host | nt | Position * | aa | Position * | Passage no. | |
1069/18 | Great fruit-eating bat | GGG–GAG | 613 | G–E | 186 | 3 |
IP3629/11 | Dog | CGG–CAG | 1055 | R–Q | 333 | 6 |
203/21 | Mexican free-tailed bat | TCC–CCC | 550 | S–P | 165 | 6 |
1833/21 | Great fruit-eating bat | GGG–AGG | 613 | G–R | 186 | 5 |
TCT–TTT | 620 | S–F | 188 | 8 | ||
2193/21 | Great fruit-eating bat | GGG–AGG | 613 | G–R | 186 | 5 |
TCT–CCT | 619 | S–P | 188 | 6 | ||
2253/21 | White-eared opossum | GGG–AGG | 613 | G–R | 186 | 5 |
TCT–CCT | 619 | S–P | 188 | 6 |
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Conselheiro, J.A.; Barone, G.T.; Miyagi, S.A.T.; de Souza Silva, S.O.; Agostinho, W.C.; Aguiar, J.; Brandão, P.E. Evolution of Rabies Virus Isolates: Virulence Signatures and Effects of Modulation by Neutralizing Antibodies. Pathogens 2022, 11, 1556. https://doi.org/10.3390/pathogens11121556
Conselheiro JA, Barone GT, Miyagi SAT, de Souza Silva SO, Agostinho WC, Aguiar J, Brandão PE. Evolution of Rabies Virus Isolates: Virulence Signatures and Effects of Modulation by Neutralizing Antibodies. Pathogens. 2022; 11(12):1556. https://doi.org/10.3390/pathogens11121556
Chicago/Turabian StyleConselheiro, Juliana Amorim, Gisely Toledo Barone, Sueli Akemi Taniwaki Miyagi, Sheila Oliveira de Souza Silva, Washington Carlos Agostinho, Joana Aguiar, and Paulo Eduardo Brandão. 2022. "Evolution of Rabies Virus Isolates: Virulence Signatures and Effects of Modulation by Neutralizing Antibodies" Pathogens 11, no. 12: 1556. https://doi.org/10.3390/pathogens11121556
APA StyleConselheiro, J. A., Barone, G. T., Miyagi, S. A. T., de Souza Silva, S. O., Agostinho, W. C., Aguiar, J., & Brandão, P. E. (2022). Evolution of Rabies Virus Isolates: Virulence Signatures and Effects of Modulation by Neutralizing Antibodies. Pathogens, 11(12), 1556. https://doi.org/10.3390/pathogens11121556