MAMDC2, a gene highly expressed in microglia in experimental models of Alzheimers Disease, positively regulates the innate antiviral response during neurotropic virus infection

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.