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

PLoS Pathogens

Guillermo Gómez¹  Juan Carlos Oliveros²  Sonia Rey²  Jasmina Vasilijevic²  Guadalupe Rodriguez²  Francisco Pozo³  Amelia Nieto⁴  Inmaculada Casas⁵  Ana Falcón⁶  Ariel Rodriguez-Frandsen⁷  Noelia Zamarreño⁷  Mercedes Pérez-Ruiz⁷  Isabel Barba⁸ 

[1] Bioinformatics for Genomics and Proteomics, National Center for Biotechnology, Spanish National Research Council (CNB-CSIC), Madrid, Spain;Department of Molecular and Cellular Biology, National Center for Biotechnology, Spanish National Research Council (CNB-CSIC), Madrid, Spain;Hospital Virgen de las Nieves, Granada, Spain;Microbiology Department, Complejo Hospitalario de Ciudad Real, Spain;Microbiology Department, University Hospital of Vigo, Vigo, Spain;National Influenza Center, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain;Network CIBER de Enfermedades Respiratorias (CIBERES), Madrid, Spain;University Hospital San Pedro de Alcantara, Cáceres, Spain

关键词: Influenza viruses;    Microbial mutation;    Viral pathogens;    Influenza;    Influenza A virus;    Polymerases;    Pathogenesis;    Virions;   

DOI  :  10.1371/journal.ppat.1006650

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY