Background: The underlying mechanism of viral infection as a risk factor for Parkinson's disease (PD), the second most common neurodegenerative disease, remains unclear. Objective: We used Mac-1(-/-) and gp91(phox-/-) transgene animal models to investigate the mechanisms by which poly I:C, a mimic of virus double-stranded RNA, induces PD neurodegeneration. Method: Poly I:C was stereotaxically injected into the substantia nigra (SN) of wild-type (WT), Mac-1-knockout (Mac-1(-/-)) and gp91 (phox)-knockout (gp91(phox-/-)) mice (10 mu g/mu l), and nigral dopaminergic neurodegeneration, alpha-synuclein accumulation and neuroinflammation were evaluated. Result: Dopaminergic neurons in the nigra and striatum were markedly reduced in WT mice after administration of poly I:C together with abundant microglial activation in the SN, and the expression of alpha-synuclein was also elevated. However, these pathological changes were greatly dampened in Mac-1(-/-) and gp91(phox-/-) mice. Conclusions: Our findings demonstrated that viral infection could result in the activation of microglia as well as NADPH oxidase, which may lead to neuron loss and the development of Parkinson's-like symptoms. Mac-1 is a key receptor during this process. (C) 2020 Elsevier Inc. All rights reserved.