Microglia, as central nervous system (CNS)-resident macrophages, are the first line of defense against neurotropic virus infection, the immune response of which is implicated in numerous CNS diseases, including Alzheimer's disease (AD). Indeed, the infectious hypothesis for AD has long been recognized, of note herpes simplex virus type 1 (HSV-1), the most common human neurotropic virus. However, the mechanism linking HSV-1 and AD remains obscure. In this study, we analyzed the transcriptome data of microglia in AD mice. We found that MAM domain containing 2 (MAMDC2) is significantly upregulated in microglia isolated from both a series of AD mice established by numerous genetic strategies and mice with HSV-1 infection. Mamdc2-deficient (Mamdc2^−/−) mice are susceptible to HSV-1 infection and show an impaired type I interferon (I-IFN)-based innate antiviral response upon neurotropic HSV-1 infection. The in vitro experiments suggest a similar result. Moreover, lentivirus-mediated overexpression of Mamdc2 in mouse brains enhances the innate antiviral response in microglia and ameliorates herpes simplex encephalitis (HSE) symptoms. Mechanistically, MAMDC2 interacts with STING via its first MAM domain within and enhances the polymerization of STING, activating downstream TBK1-IRF3 signaling to facilitate the expression of I-IFNs. The sulfated glycosaminoglycan-mediated polymerization of STING also largely depends on MAMDC2. Our study uncovers the function of MAMDC2 in the innate antiviral response in microglia, revealing a potential mechanism linking HSV-1 and AD, especially the contribution of Mamdc2 overexpression to the upregulation of I-IFN in the AD brain.

Infection of HSV-1 in human and mouse microglia induces the expression of MAMDC2. The accumulated MAMDC2 enhances the polymerization of STING, activating TBK1-IRF3 downstream signaling to initiate the expression of type I interferon (I-IFN). MAMDC2 interacts with STING via the first MAM domain within MAMDC2. In the absence of MAMDC2, the polymerization of STING induced by cGAMP or HSV-1 in fection is impaired significantly, leading to a reduced expression of I-IFN.