Elevation of CpG frequencies in influenza A genome attenuates pathogenicity but enhances host response to infection
- University of Edinburgh, United Kingdom
- Heriot Watt University, United Kingdom
- University of Oxford, United Kingdom
Abstract
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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Animal experimentation: All animal experiments were carried out under the authority of a UK Home Office Project Licence (60/4479) within the terms and conditions of the strict regulations of the UK Home Office 'Animals (scientific procedures) Act 1986' and the Code of Practice for the housing and care of animals bred, supplied or used for scientific purposes.
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© 2016, Gaunt et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Elevation of CpG frequencies in influenza A genome attenuates pathogenicity but enhances host response to infection
eLife 5:e12735.
https://doi.org/10.7554/eLife.12735
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