Depression is a serious public-health issue.Recent reports have suggested higher susceptibility to viral infections in depressive patients.However,how depression affects antiviral innate immune signaling remains unknown.Here,we revealed a reduction in expression of Abelson helper integration site 1(AHI1)in the peripheral blood mononuclear cells(PBMCs)and macrophages from the patients with major depressive disorder(MDD),which leads to attenuated antiviral immune response.We found that depression-related arginine vasopressin(AVP)induces reduction of AHI1 in macrophages.Further studies demonstrated that AHI1 is a critical stabilizer of basal type-Ⅰ-interferon(IFN-Ⅰ)signaling.Mechanistically,AHI1 recruits OTUD1 to deubiquitinate and stabilize Tyk2,while AHI1 reduction downregulates Tyk2 and IFN-Ⅰ signaling activity in macrophages from both MDD patients and depression model mice.Interestingly,we identified a clinical analgesic meptazinol that effectively stimulates AHI1 expression,thus enhancing IFN-Ⅰ antiviral defense in depression model mice.Our study promotes the understanding of the signaling mechanisms of depression-mediated antiviral immune dysfunction,and reveals meptazinol as an enhancer of antiviral innate immunity in depressive patients.

Hong-Guang Zhang;Bin Wang;Yong Yang;Xuan Liu;Junjie Wang;Ning Xin;Shifeng Li;Ying Miao;Qiuyu Wu;Tingting Guo;Yukang Yuan;Yibo Zuo;Xiangjie Chen;Tengfei Ren;Chunsheng Dong;Jun Wang;Hang Ruan;Miao Sun;Xingshun Xu;Hui Zheng

International Institute of Infection and Immunity,Institutes of Biology and Medical Sciences,Soochow University,Suzhou,Jiangsu,China;Jiangsu Key Laboratory of Infection and Immunity,Soochow University,Suzhou,Jiangsu,China;Institute of Neuroscience,Soochow University,Suzhou,Jiangsu,China;Institute for Fetology,the First Affiliated Hospital of Soochow University,Suzhou,Jiangsu,China;Department of Psychiatry,the Affiliated Guangji Hospital of Soochow University,Suzhou,Jiangsu,China;Department of Neurology,the First Affiliated Hospital of Soochow University,Suzhou,Jiangsu,China;Department of Intensive Care Medicine,the First Affiliated Hospital of Soochow University,Suzhou,Jiangsu,China;Jiangsu Key Laboratory of Neuropsychiatric Diseases,Soochow University,Suzhou,Jiangsu,China

细胞研究（英文版）

[1]Hong-Guang Zhang;Bin Wang;Yong Yang;Xuan Liu;Junjie Wang;Ning Xin;Shifeng Li;Ying Miao;Qiuyu Wu;Tingting Guo;Yukang Yuan;Yibo Zuo;Xiangjie Chen;Tengfei Ren;Chunsheng Dong;Jun Wang;Hang Ruan;Miao Sun;Xingshun Xu;Hui Zheng-.Depression compromises antiviral innate immunity via the AVP-AHI1-Tyk2 axis)[J].细胞研究（英文版）,2022(10):897-913

AHI1,Abelson,deubiquitinate,meptazinol

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