Differential Contribution of PB1-F2 to the Virulence of Highly Pathogenic H5N1 Influenza A Virus in Mammalian and Avian Species

PLoS Pathogens

Daniel R. Pérez¹  Rong Hai²  Mirco Schmolke²  John Steel²  Zsuzsanna T. Varga²  Balaji Manicassamy²  Benjamin G. Hale²  Troy Sutton³  Lindomar Pena³  Adolfo García-Sastre³ 

[1] Department of Microbiology and Immunology, School of Medicine, Emory University, Rollins Research Center, Atlanta, Georgia, United States of America;Department of Microbiology, Mount Sinai School of Medicine, New York, New York, United States of America;Department of Veterinary Medicine, University of Maryland, College Park, Maryland, United States of America

关键词: Viral pathogens;    Viral replication;    Ducks;    Pathogenesis;    Influenza A virus;    H5N1;    Birds;    Mouse models;   

DOI  :  10.1371/journal.ppat.1002186

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Highly pathogenic avian influenza A viruses (HPAIV) of the H5N1 subtype occasionally transmit from birds to humans and can cause severe systemic infections in both hosts. PB1-F2 is an alternative translation product of the viral PB1 segment that was initially characterized as a pro-apoptotic mitochondrial viral pathogenicity factor. A full-length PB1-F2 has been present in all human influenza pandemic virus isolates of the 20th century, but appears to be lost evolutionarily over time as the new virus establishes itself and circulates in the human host. In contrast, the open reading frame (ORF) for PB1-F2 is exceptionally well-conserved in avian influenza virus isolates. Here we perform a comparative study to show for the first time that PB1-F2 is a pathogenicity determinant for HPAIV (A/Viet Nam/1203/2004, VN1203 (H5N1)) in both mammals and birds. In a mammalian host, the rare N66S polymorphism in PB1-F2 that was previously described to be associated with high lethality of the 1918 influenza A virus showed increased replication and virulence of a recombinant VN1203 H5N1 virus, while deletion of the entire PB1-F2 ORF had negligible effects. Interestingly, the N66S substituted virus efficiently invades the CNS and replicates in the brain of Mx+/+ mice. In ducks deletion of PB1-F2 clearly resulted in delayed onset of clinical symptoms and systemic spreading of virus, while variations at position 66 played only a minor role in pathogenesis. These data implicate PB1-F2 as an important pathogenicity factor in ducks independent of sequence variations at position 66. Our data could explain why PB1-F2 is conserved in avian influenza virus isolates and only impacts pathogenicity in mammals when containing certain amino acid motifs such as the rare N66S polymorphism.

【 授权许可】

CC BY