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Elevation of CpG frequencies in influenza A genome attenuates pathogenicity but enhances host response to infection

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  • Elevation of CpG frequencies in influenza A genome attenuates pathogenicity but enhances host response to infection

    Elife. 2016 Feb 16;5. pii: e12735. doi: 10.7554/eLife.12735. [Epub ahead of print]
    Elevation of CpG frequencies in influenza A genome attenuates pathogenicity but enhances host response to infection.

    Gaunt E1, Wise HM2, Zhang H1, Lee LN3, Atkinson NJ1, Nicol MQ1, Highton AJ3, Klenerman P3, Beard PM1, Dutia BM1, Digard P1, Simmonds P1.
    Author information

    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.


    KEYWORDS:

    infectious disease; microbiology; viruses

    PMID: 26878752 [PubMed - as supplied by publisher]
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