Reduced accumulation of defective viral genomes contributes to severe outcome in influenza virus infected patients

PLoS Pathog. 2017 Oct 12;13(10):e1006650. doi: 10.1371/journal.ppat.1006650. eCollection 2017 Oct.

Abstract

Influenza A virus (IAV) infection can be severe or even lethal in toddlers, the elderly and patients with certain medical conditions. Infection of apparently healthy individuals nonetheless accounts for many severe disease cases and deaths, suggesting that viruses with increased pathogenicity co-circulate with pandemic or epidemic viruses. Looking for potential virulence factors, we have identified a polymerase PA D529N mutation detected in a fatal IAV case, whose introduction into two different recombinant virus backbones, led to reduced defective viral genomes (DVGs) production. This mutation conferred low induction of antiviral response in infected cells and increased pathogenesis in mice. To analyze the association between low DVGs production and pathogenesis in humans, we performed a genomic analysis of viruses isolated from a cohort of previously healthy individuals who suffered highly severe IAV infection requiring admission to Intensive Care Unit and patients with fatal outcome who additionally showed underlying medical conditions. These viruses were compared with those isolated from a cohort of mild IAV patients. Viruses with fewer DVGs accumulation were observed in patients with highly severe/fatal outcome than in those with mild disease, suggesting that low DVGs abundance constitutes a new virulence pathogenic marker in humans.

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Child
  • Child, Preschool
  • Female
  • Genome, Viral / genetics*
  • Humans
  • Influenza A Virus, H1N1 Subtype / genetics*
  • Influenza A Virus, H1N1 Subtype / pathogenicity
  • Influenza A Virus, H5N1 Subtype / genetics*
  • Influenza A Virus, H5N1 Subtype / pathogenicity
  • Influenza, Human / virology*
  • Male
  • Mice
  • Middle Aged
  • Orthomyxoviridae Infections / genetics
  • Orthomyxoviridae Infections / virology*
  • Virulence / genetics
  • Virus Replication / genetics*
  • Young Adult

Grant support

JV is a PhD fellow of the La Caixa Foundation International Fellowship Programme (La Caixa/CNB). This work was supported by the Spanish Ministry of Economy and Competitiveness (Plan Nacional de Investigacion Científica, Desarrollo e Innovacion Tecnológica BFU2011-26175 and BFU2014-57797-R to AN) and the network Ciber de Enfermedades Respiratorias (CIBERES). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.