Volume 32, No 10, Oct 2022

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 32 Issue 10, October 2022: 897-913

ORIGINAL ARTICLES

Depression compromises antiviral innate immunity via the AVP-AHI1-Tyk2 axis

Hong-Guang Zhang^1,2,† , Bin Wang^3,4,† , Yong Yang⁵ , Xuan Liu⁶ , Junjie Wang³ , Ning Xin³ , Shifeng Li⁷ , Ying Miao^1,2 , Qiuyu Wu^1,2 , Tingting Guo^1,2 , Yukang Yuan^1,2 , Yibo Zuo^1,2 , Xiangjie Chen^1,2 , Tengfei Ren^1,2 , Chunsheng Dong^1,2 , Jun Wang⁷ , Hang Ruan¹ , Miao Sun⁴ , Xingshun Xu^3,6,8,* , Hui Zheng^1,2,*

¹International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu, China
²Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, Jiangsu, China
³Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China
⁴Institute for Fetology, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
⁵Department of Psychiatry, the Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu, China
⁶Department of Neurology, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
⁷Department of Intensive Care Medicine, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
⁸Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu, China
^†These authors contributed equally: Hong-Guang Zhang, Bin Wang
Correspondence: Xingshun Xu(xingshunxu@suda.edu.cn)Hui Zheng(huizheng@suda.edu.cn)

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.

https://doi.org/10.1038/s41422-022-00689-9

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