title: Elevation of CpG frequencies in influenza A genome attenuates pathogenicity but enhances host response to infection.
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.
authors.affiliation: Infection and Immunity Division, Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Gaunt
authors.affiliation: Infection and Immunity Division, Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Wise
authors.affiliation: Infection and Immunity Division, Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Huayu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Lian N
authors.initials: LN
authors.lastname: Lee
authors.affiliation: Infection and Immunity Division, Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Nicky J
authors.initials: NJ
authors.lastname: Atkinson
authors.affiliation: Infection and Immunity Division, Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Marlynne Quigg
authors.initials: MQ
authors.lastname: Nicol
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Highton
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.affiliation: Infection and Immunity Division, Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Philippa M
authors.initials: PM
authors.lastname: Beard
authors.affiliation: Infection and Immunity Division, Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Bernadette M
authors.initials: BM
authors.lastname: Dutia
authors.affiliation: Infection and Immunity Division, Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Digard
authors.affiliation: Infection and Immunity Division, Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom.|Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Peter
authors.identifier: http://orcid.org/0000-0002-7964-4700
authors.initials: P
authors.lastname: Simmonds
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D018899:CpG Islands; D004195:Disease Models, Animal; D016678:Genome; D007113:Immunity, Innate; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D008168:Lung / Q000821:virology; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000473:pathology / Q000821:virology; D012720:Severity of Illness Index; D019562:Viral Load; D014774:Virulence; D014779:Virus Replication
keywords: cpG dinucleotide; immunization; infectious disease; influenza A virus; microbiology; upA dinucleotide; vaccine; virus