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...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.展开更多
基金supported by the National Natural Science Foundation of China(81830101 and 82301991)。
文摘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.
