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Comparison of PB1-F2 Proximity Interactomes Reveals Functional Differences between a Human and an Avian Influenza Virus.

ABSTRACT: Most influenza viruses express the PB1-F2 protein which is regarded as a virulence factor. However, PB1-F2 behaves differently in avian and mammalian hosts, suggesting that this protein may be involved in the species barrier crossings regularly observed in influenza viruses. To better understand the functions associated with this viral protein, we decided to compare the BioID2-derived proximity interactome of a human PB1-F2 from an H3N2 virus with that of an avian PB1-F2 from an H7N1 strain. The results obtained reveal that the two proteins share only a few interactors and thus common functions. The human virus protein is mainly involved in signaling by Rho GTPases while the avian virus protein is mainly involved in ribonucleoprotein complex biogenesis. PB1-F2 H3N2 interactors include several members of the 14-3-3 protein family, a family of regulatory proteins involved in many signaling pathways. We then validated the interaction with 14-3-3 proteins and were able to show that the association of H3N2-PB1-F2 with YWHAH increased the activity of the antiviral sensor MDA5, while H7N1-PB1-F2 had no effect. Collectively, these results show that PB1-F2 can associate with a large range of protein complexes and exert a wide variety of functions. Furthermore, PB1-F2 interactome differs according to the avian or human origin of the protein.

SUBMITTER: Mettier J

PROVIDER: S-EPMC9961899 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Comparison of PB1-F2 Proximity Interactomes Reveals Functional Differences between a Human and an Avian Influenza Virus.

Mettier Joëlle J Prompt Clémentine C Bruder Elise E Da Costa Bruno B Chevalier Christophe C Le Goffic Ronan R

Viruses 20230124 2

Most influenza viruses express the PB1-F2 protein which is regarded as a virulence factor. However, PB1-F2 behaves differently in avian and mammalian hosts, suggesting that this protein may be involved in the species barrier crossings regularly observed in influenza viruses. To better understand the functions associated with this viral protein, we decided to compare the BioID2-derived proximity interactome of a human PB1-F2 from an H3N2 virus with that of an avian PB1-F2 from an H7N1 strain. The ...[more]

PMID: 36851542

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Project description: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.

Dataset Information

Comparison of PB1-F2 Proximity Interactomes Reveals Functional Differences between a Human and an Avian Influenza Virus.

Publications

Comparison of PB1-F2 Proximity Interactomes Reveals Functional Differences between a Human and an Avian Influenza Virus.

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