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Signal Transduction and Targeted Therapy

Signal Transduction and Targeted Therapy

IF: 40.8
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Purine nucleoside phosphorylase dominates Influenza A virus replication and host hyperinflammation through purine salvage

Published:15 June 2025 DOI:
Yang Yue, Qingyu Li, Changguo Chen, Juntao Yang, Weian Song, Changdong Zhou, Yuke Cui, Zhenqiao Wei, Qi He, Chenhui Wang, Hongjun Lin, Jiangbo Li, Jian Li, Ji Xi, Xiang Song, Wen Yang, Ze Zhang, Wenjie Shu, Liang Guo, Shengqi Wang

Abstract

Influenza A virus (IAV) poses a significant threat to human health. The outcome of IAV results from the viral-host interaction, with the underlying molecular mechanisms largely unknown. By integrating the plasma proteomics data of the IAV-infected patients into the viral-inflammation protein-protein interaction (VI-PPI) network created in this study, purine nucleoside phosphorylase (PNP), the critical enzyme in purine salvage, was identified as a potential hub gene that connected the different stages of IAV infection. Extended survival rates and reduced pulmonary inflammatory lesions were observed in alveolar epithelial cell (AEC)-specific PNP conditional knockout mice upon H1N1 infection. Mechanistically, PB1-F2 of IAV was revealed as a novel viral transcriptional factor to bind to the TATA box of PNP promoter, leading to enhanced purine salvage in H1N1-challenged AECs. The activation of PNP-mediated purine salvage was verified in IAV-infected patients and A549 cells. PNP knockdown elicited a purine metabolic shift from augmented salvage pathway to de novo synthesis, constraining both viral infection and pro-inflammatory signaling through APRT-AICAR-AMPK activation. Moreover, durdihydroartemisinin (DHA), predicted by VI-PPI as a novel PNP inhibitor, exerted beneficial effects on the survival and weight gain of H1N1-challenged mice via its direct binding to PNP. To reveal for the first time, we found that PNP, activated by IAV, plays a hub role within H1N1-host interaction, simultaneously modulating viral replication and hyperinflammation through purine salvage. Our study sheds new light on a “two-for-one” strategy by targeting purine salvage in combating IAV-related pathology, suggesting PNP as a potential novel anti-influenza host target.

Substances (2)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Nucleoside phosphorylase 9030-21-1 C10H12N4O4 127 suppliers $165.00-$1060.00
Nucleoside phosphorylase 9030-21-1 C10H12N4O4 127 suppliers $165.00-$1060.00

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