Severe outcome in influenza virus infected patients is associated with reduced accumulation of defective viral genomes

Abstract

I 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 viral genetic determinant that contributes to infection outcome. A polymerase mutation identified in a fatal IAV case, when introduced into two different recombinant virus backbones, led to reduced defective viral genomes (DGs) production and increased pathogenesis in mice. These data provide genetic support for the association of pathogenicity and low DGs accumulation induced by mutations present in pathogenic viruses circulating in humans. Testing this association, 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 from highly severe/fatal outcome patients showed significantly fewer DGs accumulation than control viruses, suggesting that low DGs abundance constitutes a new virulence viral pathogenic marker in humans, regardless of the mutations responsible.