Abstract
The PB1-F2 protein encoded by influenza A viruses can contribute to virulence, a feature that is dependent of its sequence polymorphism. Whereas PB1-F2 from some H1N1 viruses were shown to exacerbate the inflammatory response within the airways, the contribution of PB1-F2 to highly pathogenic avian influenza virus (HPAIV) virulence in mammals remains poorly described. Using a H5N1 HPAIV strain isolated from duck and its PB1-F2 knocked-out mutant, we characterized the dynamics of PB1-F2-associated host response in a murine model of lethal pneumonia. The mean time of death was 10 days for the two viruses, allowing us to perform global transcriptomic analyses and detailed histological investigations of the infected lungs at multiple time points. At day 2 post-infection (pi), while no histopathological lesion was observed, PB1-F2 expression resulted in a significant inhibition of cellular pathways involved in macrophage activation and in a transcriptomic signature suggesting that it promotes damage to the epithelial barrier. At day 4 pi, the gene profile associated with PB1-F2 expression revealed dysfunctions in NK cells activity. At day 8 pi, PB1-F2 expression was strongly associated with increased transcription of genes encoding chemokines and cytokines implicated in the recruitment of granulocytes, as well as expression of a number of genes encoding enzymes expressed by neutrophils. These transcriptomic data were fully supported by the histopathological analysis of the mice lungs which evidenced more severe inflammatory lesions and enhanced recruitment of neutrophils in the context of PB1-F2 expression, and thus provided a functional corroboration to the insight obtained in this work. In summary, our study shows that PB1-F2 of H5N1 HPAIV markedly influences the expression of the host transcriptome in a different way than its H1N1 counterparts: H5N1 PB1-F2 first delays the initial immune response but increases the pulmonary inflammatory response during the late stages of infection.
Highlights
Pathogenic avian influenza virus (HPAIV) infections result in case-fatality rates of up to 60% in humans, making this pathology one of the most severe infectious respiratory disease [1]
The viral factors contributing to this hypercytokinemia are mainly NS1, NA and HA [6,7,8,9], but more recently the small accessory protein PB1-F2 has been described to contribute to the viral pathogenesis of influenza A viruses (IAV) [10,11,12] and H5N1 Highly pathogenic avian influenza virus (HPAIV) [13,14]
Various factors are thought to be involved in the pathogenesis of H5N1 HPAIV; among them, the multibasic cleavage site of the hemagglutinin [9,39] and the enhanced ability of NS1 to suppress innate immunity have been very well described [40,41]
Summary
Pathogenic avian influenza virus (HPAIV) infections result in case-fatality rates of up to 60% in humans, making this pathology one of the most severe infectious respiratory disease [1]. Human-to-human transmission of HPAIV is a very rare event [2], the genetic reassortment of a HPAIV with seasonal influenza A viruses (IAV) could give rise to a virulent strain with pandemic capacities [3]. The emergence of such a virus is a global health concern. The viral factors contributing to this hypercytokinemia are mainly NS1, NA and HA [6,7,8,9], but more recently the small accessory protein PB1-F2 has been described to contribute to the viral pathogenesis of IAV [10,11,12] and H5N1 HPAIV [13,14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
