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

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（Influenza A virus, IAV）感染可对幼儿、老年人及患有基础疾病的患者造成重症甚至致命性后果。然而，看似健康个体的甲型流感病毒感染仍会引发大量重症病例与死亡案例，这提示致病性增强的毒株与大流行或流行毒株共同循环传播。为探寻潜在的毒力因子，我们在一例致命甲型流感病毒感染病例中鉴定出聚合酶PA D529N突变；将该突变引入两种不同的重组病毒骨架后，可降低缺陷型病毒基因组（defective viral genomes, DVGs）的产生水平。该突变可降低感染细胞的抗病毒应答诱导程度，并增强小鼠体内的病毒致病力。为分析人体中低水平DVGs产生与致病力之间的关联，我们对两组分离得到的病毒开展了基因组分析：一组来自既往健康、因重症甲型流感病毒感染需入住重症监护病房（Intensive Care Unit, ICU）的患者，以及伴有基础疾病且预后致命的患者；另一组则来自轻症甲型流感病毒感染患者。相较于轻症患者分离得到的病毒，重症/致命预后患者体内分离的病毒其DVGs积累量更低，这表明低丰度DVGs可作为人体中新的毒力致病标志物。