PB1-F2 Proteins from H5N1 and 20th Century Pandemic Influenza Viruses Cause Immunopathology

PLoS Pathogens

Jerry E. Chipuk¹  Douglas R. Green¹  Jonathan A. McCullers²  Nick Van De Velde²  Julie L. McAuley²  Kelli L. Boyd³ 

[1] Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America;Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America;Department of Pathology, Division of Comparative Medicine, Vanderbilt University, Nashville, Tennessee, United States of America.

关键词: Mitochondria;    Inflammation;    Apoptosis;    Cell death;    H1N1;    H5N1;    Influenza viruses;    Viral pathogens;   

DOI  :  10.1371/journal.ppat.1001014

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

With the recent emergence of a novel pandemic strain, there is presently intense interest in understanding the molecular signatures of virulence of influenza viruses. PB1-F2 proteins from epidemiologically important influenza A virus strains were studied to determine their function and contribution to virulence. Using 27-mer peptides derived from the C-terminal sequence of PB1-F2 and chimeric viruses engineered on a common background, we demonstrated that induction of cell death through PB1-F2 is dependent upon BAK/BAX mediated cytochrome c release from mitochondria. This function was specific for the PB1-F2 protein of A/Puerto Rico/8/34 and was not seen using PB1-F2 peptides derived from past pandemic strains. However, PB1-F2 proteins from the three pandemic strains of the 20th century and a highly pathogenic strain of the H5N1 subtype were shown to enhance the lung inflammatory response resulting in increased pathology. Recently circulating seasonal influenza A strains were not capable of this pro-inflammatory function, having lost the PB1-F2 protein's immunostimulatory activity through truncation or mutation during adaptation in humans. These data suggest that the PB1-F2 protein contributes to the virulence of pandemic strains when the PB1 gene segment is recently derived from the avian reservoir.

【 授权许可】

CC BY