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.

抑郁症是一个严重的公共卫生问题。最近的报告表明，抑郁症患者对病毒感染的易感性更高。然而，抑郁症如何影响抗病毒先天免疫信号仍然未知。在这里，我们发现重度抑郁症 (MDD) 患者的外周血单个核细胞 (PBMC) 和巨噬细胞中 Abelson 辅助整合位点 1 (AHI1) 的表达减少，这导致抗病毒免疫反应减弱。我们发现抑郁症相关的精氨酸加压素 (AVP) 诱导巨噬细胞中 AHI1 的减少。进一步的研究表明，AHI1 是基础 I 型干扰素 (IFN-I) 信号传导的关键稳定剂。从机制上讲，AHI1 招募 OTUD1 去泛素化并稳定 Tyk2，而 AHI1 的减少会下调 MDD 患者和抑郁模型小鼠巨噬细胞中的 Tyk2 和 IFN-I 信号传导活性。有趣的是，我们发现了一种临床镇痛药美他嗪，可有效刺激 AHI1 表达，从而增强抑郁症模型小鼠的 IFN-I 抗病毒防御。我们的研究促进了对抑郁症介导的抗病毒免疫功能障碍信号机制的理解，并揭示了美普他嗪作为抑郁症患者抗病毒先天免疫的增强剂。