ADAR-mediated RNA editing of Influenza A virus genomes may be age-dependent and inversely correlates with viral load

Background Seasonal influenza epidemics cause significant mortality, especially among the elderly. Influenza A virus triggers the host innate immune system through various mechanisms. Human enzymes belonging to the group of RNA-acting adenosine deaminases (ADARs) play a role in the innate antiviral immune response, partly by inducing mutations in viral RNA. The effect of this mechanismin influenza A virus infection remains unexplained in humans.Objective The aim of this study was to assess the clinical impact of ADAR-induced mutations on influenza A virus in hospitalised patients.Methods Full-genome deep sequencing of Influenza A virus was performed on respiratory samples from 75 hospitalised, Influenza A(H3N2) virus infected patients, aged 41 to 95 years. ADAR-associated mutations in minor viral subpopulations were analysed in relation to demographic and clinical factors.Results ADAR-associated mutations showed a significant inverse correlation with viral load (p < 0.0001) and age (p = 0.0051), especially in patients older than 75 years. The association between ADAR-associated mutations and viral load was independent of age, inflammation, and disease severity (p < 0.001).Conclusions We found an association between ADAR-induced mutations and viral load, which may indicate an antiviral function of ADAR on influenza A virus. The lower mutation rate and associated higher viral load in the elderly suggest an age-dependent reduced ADAR activity, which may contribute to increased disease severity.