IFNα subtype-specific susceptibility of HBV in the course of infection
Final Report Abstract
IFN alpha subtypes represent an important effector cytokine of the innate immune system in defending pathogens. IFN alpha is induced upon recognition by specific host sensors and it triggers an antiviral state within cells. Autocrine and paracrine binding of IFN alpha to its receptors results in the expression of hundreds of ISGs, which act directly antiviral through various mechanisms. It is known that the twelve human IFN alpha subtypes exhibit unique biological effects during different viral infections. The exact molecular mechanisms for these differences have not yet been elucidated so far. In this project, type I IFN induction, the antiviral and immunomodulatory effect of the different IFN alpha subtypes were investigated during HBV infection. HBV infection of human hepatic cell lines or primary human hepatocytes did not significantly induce type I IFNs, whereas the Ifna subtype mRNA expression during acute and chronic HBV infection in mice by using the well-established hydrodynamic injection (HDI) mouse model revealed a transient but strong expression of a panel of Ifna subtypes in the spleen of HBV persistent replication mice compared to HDI controls. Human IFN alpha14 was identified as the most effective subtype in suppressing HBV replication. Human IFN alpha14 alone elicited IFN alpha and IFNγ signaling crosstalk in a manner similar to the combined use of human IFN alpha and human IFN gamma, inducing multiple potent antiviral effectors, which synergistically restricted HBV replication. In addition, we comprehensively analysed the antiviral activity of all human IFNα subtypes against SARS-CoV-2 to identify the underlying immune signatures and explore their therapeutic potential. Prophylactic treatment of primary human airway epithelial cells with different IFNα subtypes during SARS-CoV-2 infection uncovered distinct functional classes with high, intermediate and low antiviral IFNs. In particular human IFN alpha5 showed superior antiviral activity against SARS-CoV-2 infection due to its high expression of antiviral key molecules. Taken together, our data provide a systemic, multi-modular definition of antiviral host responses mediated by defined type I IFNs during different viral infections.
Publications
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Functional Comparison of Interferon‐α Subtypes Reveals Potent Hepatitis B Virus Suppression by a Concerted Action of Interferon‐α and Interferon‐γ Signaling. Hepatology, 73(2), 486-502.
Chen, Jieliang; Li, Yaming; Lai, Fritz; Wang, Yang; Sutter, Kathrin; Dittmer, Ulf; Ye, Jianyu; Zai, Wenjing; Liu, Min; Shen, Fang; Wu, Min; Hu, Kongying; Li, Baocun; Lu, Mengji; Zhang, Xiaonan; Zhang, Jiming; Li, Jianhua; Chen, Qingfeng & Yuan, Zhenghong
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Differential interferon-α subtype induced immune signatures are associated with suppression of SARS-CoV-2 infection. Proceedings of the National Academy of Sciences, 119(8).
Schuhenn, Jonas; Meister, Toni Luise; Todt, Daniel; Bracht, Thilo; Schork, Karin; Billaud, Jean-Noel; Elsner, Carina; Heinen, Natalie; Karakoese, Zehra; Haid, Sibylle; Kumar, Sriram; Brunotte, Linda; Eisenacher, Martin; Di, Yunyun; Lew, Jocelyne; Falzarano, Darryl; Chen, Jieliang; Yuan, Zhenghong; Pietschmann, Thomas; ... & Pfaender, Stephanie
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IFNα subtype-specific susceptibility of HBV in the course of chronic infection. Frontiers in Immunology, 13 (2022, 10, 14).
Xie, Xiaohong; Karakoese, Zehra; Ablikim, Dilhumare; Ickler, Julia; Schuhenn, Jonas; Zeng, Xiaoqing; Feng, Xuemei; Yang, Xuecheng; Dittmer, Ulf; Yang, Dongliang; Sutter, Kathrin & Liu, Jia
