Large-scale recoding of an arbovirus genome to rebalance its insect versus mammalian preference
Open accessAbstract
The protein synthesis machineries of two distinct phyla of the Animal kingdom, insects of Arthropoda and mammals of Chordata, have different preferences for how to best encode proteins. Nevertheless, arboviruses (arthropod-borne viruses) are capable of infecting both mammals and insects just like arboviruses that use insect vectors to infect plants. These organisms have evolved carefully balanced genomes that can efficiently use the translational machineries of different phyla, even if the phyla belong to different kingdoms. Using dengue virus as an example, we have undone the genome encoding balance and specifically shifted the encoding preference away from mammals. These mammalian-attenuated viruses grow to high titers in insect cells but low titers in mammalian cells, have dramatically increased LD50s in newborn mice, and induce high levels of protective antibodies. Recoded arboviruses with a bias toward phylum-specific expression could form the basis of a new generation of live attenuated vaccine candidates.
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DENV-2 and RVFV are biased for codon pairs that are overrepresented in the vertebrate host but not in the respective mosquito vector.
“Similar to our results, the data presented for DENV-2 and RVFV show that these viruses are biased for codon pairs that are overrepresented in the vertebrate host but not in the respective mosquito vector (Shen et al., 2015).”
From Codon Pair Bias Is a Direct Consequence of Dinucleotide Bias (2016) · cites this paper as Shen et al., 2015
The passage labeled Significance says RVFV favors codon pairs with high scores in both sheep and mosquitoes, and DENV favors pairs with high scores in both humans and mosquitoes (Fig. S1 A–B; Fig. 1 A–C). The Discussion likewise describes arboviruses as having a balanced codon-pair bias between hosts, contrary to the claim that the pairs are overrepresented in vertebrates but not mosquito vectors. (LLM, conf=0.91)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe prevailing hypothesis is that the large number of underrepresented codon pairs interferes with efficient protein production or processing.
“While different mechanisms have been proposed, the prevailing hypothesis is that the large number of underrepresented codon pairs interferes with efficient protein production or processing (Coleman et al., 2008;Shen et al., 2015).”
From Mechanism of Virus Attenuation by Codon Pair Deoptimization (2020) · cites this paper as Shen et al., 2015
The Discussion says that poor codon pairs might affect polyprotein synthesis or processing, which supports the proposed mechanism. It also says the precise mechanism remains unknown and lists other possibilities; it does not identify impaired production or processing as the prevailing hypothesis. (LLM, conf=0.85)
Experimental — accuracy not yet measuredClosely related species have similar codon pair bias.
“A comparison of CPSs derived from different organisms (Figure 1; Figure S1) confirmed that closely related species have a similar codon pair bias (CPB) (Moura et al., 2007;Shen et al., 2015).”
From Codon Pair Bias Is a Direct Consequence of Dinucleotide Bias (2016) · cites this paper as Shen et al., 2015
Dinucleotide bias appears to be linked with codon pair bias.
“Dinucleotide bias also appears to be linked with codon pair bias (Moura et al., 2007;Shen et al., 2015), but this relationship has not been thoroughly explored.”
From Codon Pair Bias Is a Direct Consequence of Dinucleotide Bias (2016) · cites this paper as Shen et al., 2015
The bias in analyzed arboviruses for overrepresented codon pairs of the corresponding vertebrates was identified only in a small set of codon pairs that are used with higher frequency.
“The bias in analyzed arboviruses for overrepresented codon pairs of the corresponding vertebrates was identified only in a small set of codon pairs that are used with higher frequency.”
From Codon Pair Bias Is a Direct Consequence of Dinucleotide Bias (2016) · cites this paper as Shen et al., 2015
The results of the echovirus study, although questioned, are in line with our observations, which also suggest that the basis of attenuation by SAVE is the increase of CpG dinucleotides in coding sequences.
“Therefore, the results of this study, although questioned (Shen et al., 2015), are in line with our observations, which also suggest that the basis of attenuation by SAVE is the increase of CpG dinucleotides in coding sequences.”
From Codon Pair Bias Is a Direct Consequence of Dinucleotide Bias (2016) · cites this paper as Shen et al., 2015
All of the viral constructs in question (from Simmonds et al. and Shen et al.) coordinately alter dinucleotides and codon pairs.
“Accordingly, all of the viral constructs in question (1, 2) coordinately alter dinucleotides and codon pairs (see below)”
From Reply to Simmonds et al.: Codon pair and dinucleotide bias have not been functionally distinguished (2015) · cites this paper as [2]
Properties of a virus variant in cultured cells and animals can be very different.
“Properties of a virus variant in cultured cells and animals can be very different (2).”
From Reply to Simmonds et al.: Codon pair and dinucleotide bias have not been functionally distinguished (2015) · cites this paper as [2]
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Codon Pair Bias Is a Direct Consequence of Dinucleotide Bias
Kunec, D., & Osterrieder, N. (2016) · Cell Reports · doi:10.1016/j.celrep.2015.12.011 · Cited by 159 · see citing works
“Definitions of virus name abbreviations are provided in Table S2. the number of TpA dinucleotides in recoded genes increased only moderately (30%–60% increase over the wild-type), the number of CpG dinucleotides increased dramatically (140%– 360% increase in the case of DENV-2 and 480%–630% in HRSV).”
BackgroundMethodResultInfluentialMechanism of Virus Attenuation by Codon Pair Deoptimization
Groenke, N., Trimpert, J., Merz, S., Conradie, A. M., Wyler, E., Zhang, H., Hazapis, O.-G., Rausch, S., Landthaler, M., Osterrieder, N., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107586 · Cited by 85 · see citing works
“While different mechanisms have been proposed, the prevailing hypothesis is that the large number of underrepresented codon pairs interferes with efficient protein production or processing (Coleman et al., 2008; Shen et al., 2015).”
BackgroundReply to Simmonds et al.: Codon pair and dinucleotide bias have not been functionally distinguished
Futcher, B., Gorbatsevych, O., Shen, S. H., Stauft, C. B., Song, Y., Wang, B., Leatherwood, J., Gardin, J., Yurovsky, A., Mueller, S., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1507710112 · Cited by 22 · see citing works
Self-citation
- Authors
- Shen, S. H., Stauft, C. B., Gorbatsevych, O., Song, Y., Ward, C. B., Yurovsky, A., Mueller, S., Futcher, B., & Wimmer, E.
- Affiliations
- Department of Molecular Genetics and Microbiology and
- Codagenix (United States) (US)
- Stony Brook University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-03-30
- Volume
- 112
- Issue
- 15
- Pages
- 4749-4754
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4403163
- OpenAlex
- W1975782217
- Cited by
- 99
- References
- 5
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 2 · 2023: 6 · 2022: 6 · 2021: 17 · 2020: 8 · 2019: 12 · 2018: 17 · 2017: 11 · 2016: 6 · 2015: 6
- FWCI
- 14.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (AI07521901, GM098400)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Mosquito-borne diseases and control
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
- Keywords
- arboviruses, dengue virus, translation machinery, codon usage bias, live attenuated vaccine, viral attenuation, host range, protective antibodies, mouse LD50
- MeSH terms
- Viral Proteases, Animals, Animals, Newborn, Antibodies, Viral, Arboviruses, Cell Line, Chlorocebus aethiops, Codon, Dengue Virus, Humans, Insect Vectors, Mammals, Mice, Inbred ICR, Molecular Sequence Data, Serine Endopeptidases, Vaccines, Attenuated, Vero Cells, Virus Diseases, Gene Expression Regulation, Viral, Genome, Viral, Viral Nonstructural Proteins, Reverse Transcriptase Polymerase Chain Reaction, RNA Helicases, Nucleoside-Triphosphatase, Cell Line, Tumor, DEAD-box RNA Helicases, Host-Pathogen Interactions
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