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.

甲型流感病毒（IAV）感染在幼儿，老年人和某些疾病患者中可能是严重的，甚至是致命的。然而，看似健康的个体的感染仍导致许多严重的疾病病例和死亡，这表明致病性增加的病毒与大流行或流行病毒共同传播。寻找潜在的毒力因子，我们已经鉴定出在致命IAV病例中检测到的聚合酶PA D529N突变，该突变被引入两个不同的重组病毒主链中，导致病毒基因组（DVGs）产量减少。这种突变赋予感染细胞抗病毒反应低诱导性，并增加了小鼠的发病机理。为了分析DVG的低产量与人类发病机理之间的关系，我们对从一批先前健康的人中分离出的病毒进行了基因组分析，这些人患有严重的IAV感染，需要入院重症监护病房，以及具有致命后果并另外表现出潜在医疗状况的患者。将这些病毒与从一组轻度IAV患者中分离出的病毒进行了比较。与重度/致命性结果较轻的患者相比，DVG积聚较少的病毒被观察到，这表明低DVGs丰度构成了人类新的致病性致病标记。