Elevation of CpG frequencies in influenza A genome attenuates pathogenicity but enhances host response to infection
Open accessAbstract
Previously, we demonstrated that frequencies of CpG and UpA dinucleotides profoundly influence the replication ability of echovirus 7 (Tulloch et al., 2014). Here, we show that that influenza A virus (IAV) with maximised frequencies of these dinucleotides in segment 5 showed comparable attenuation in cell culture compared to unmodified virus and a permuted control (CDLR). Attenuation was also manifested in vivo, with 10-100 fold reduced viral loads in lungs of mice infected with 200PFU of CpG-high and UpA-high mutants. However, both induced powerful inflammatory cytokine and adaptive (T cell and neutralising antibody) responses disproportionate to their replication. CpG-high infected mice also showed markedly reduced clinical severity, minimal weight loss and reduced immmunopathology in lung, yet sterilising immunity to lethal dose WT challenge was achieved after low dose (20PFU) pre-immunisation with this mutant. Increasing CpG dinucleotide frequencies represents a generic and potentially highly effective method for generating safe, highly immunoreactive vaccines.
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The level of attenuation achieved by the elevation of CpG/UpA dinucleotide frequencies appears to be much weaker than that by CPD.
“Although these studies are not directly comparable, the level of attenuation achieved by the elevation of CpG/UpA dinucleotide frequencies (Gaunt et al., 2016) appears to be much weaker than that by CPD (Yang et al., 2013).”
From Mechanism of Virus Attenuation by Codon Pair Deoptimization (2020) · cites this paper as Gaunt et al., 2016
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Ficarelli, M., Wilson, H., Pedro Galão, R., Mazzon, M., Antzin-Anduetza, I., Marsh, M., Neil, S. J., & Swanson, C. M. (2019) · eLife · doi:10.7554/elife.46767 · Cited by 135 · see citing works
Mechanism of Virus Attenuation by Codon Pair Deoptimization
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“Two different studies evaluated the effect of CPD, and CpG/UpA dinucleotide frequencies on replication and pathogenicity of recoded influenza A virus mutants (strain A/PR8/34 [H1N1]) (Gaunt et al., 2016; Yang et al., 2013).”
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- Authors
- Gaunt, E., Wise, H. M., Zhang, H., Lee, L. N., Atkinson, N. J., Nicol, M. Q., Highton, A. J., Klenerman, P., Beard, P. M., Dutia, B. M., Digard, P., & Simmonds, P.
- Affiliations
- Roslin Institute (GB)
- University of Oxford (GB)
- Infection and Immunity Division, Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2016-02-16
- Volume
- 5
- Pages
- e12735-e12735
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC4798949
- OpenAlex
- W2284718369
- Cited by
- 107
- References
- 6
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 4 · 2023: 12 · 2022: 4 · 2021: 19 · 2020: 16 · 2019: 13 · 2018: 4 · 2017: 13 · 2016: 2
- FWCI
- 10.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (WT103767MA)
- Biotechnology and Biological Sciences Research Council (BB/J004324/1)
- Oxford Martin School, University of Oxford (WT091663MA)
- Medical Research Council (MR/K000276/1)
- Topics
- Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
- Health Sciences › Medicine › Epidemiology › Virology and Viral Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Keywords
- influenza A virus, CpG, viral genome sequence, vaccine attenuation, host immune response, inflammatory cytokines, T cell response, neutralizing antibodies, lung viral load, immunopathology, vaccine safety
- MeSH terms
- Animals, Disease Models, Animal, Immunity, Innate, Lung, Orthomyxoviridae Infections, Influenza A virus, Severity of Illness Index, Virulence, Virus Replication, Genome, CpG Islands, Viral Load, Mice, Adaptive Immunity
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