Targeting β2-Adrenergic Receptor Stability With Lycorine Reveals a Host-Directed Pathway for Antiviral Defense...

Psychological stress is a pervasive yet poorly understood modulator of infectious disease outcomes. Here, we report a mechanistic link between chronic stress and severe viral pathogenesis, identifying the β2-adrenergic receptor (β2-AR) as a critical host factor and therapeutic target. Using a model of chronic restraint stress and cowpox virus (CPXV) infection, we demonstrate that psychological stress significantly exacerbates disease severity and mortality. This increased susceptibility is driven by autophagy-mediated downregulation of β2-AR, a process that is recapitulated during viral infection. Accordingly, genetic loss-of-function and pharmacological approaches established β2-AR as a critical host protective factor that suppresses CPXV replication. Leveraging this pathway, we identify the natural alkaloid lycorine as a novel β2-AR-stabilizing ligand that rescues the receptor from degradation. Lycorine exhibits potent antiviral activity by suppressing post-entry viral replication. In vivo, lycorine reduced viral burden and tissue pathology and improved survival following CPXV infection, and these protective effects required cluster of differentiation 8-positive (CD8⁺) T cells. Mechanistically, lycorine attenuates virus-induced TANK- binding kinase 1/interferon regulatory factor 3 (TBK1/IRF3)associated inflammatory signaling while enhancing antiviral Interferon (IFN)/interferon-stimulated gene (ISG) responses through β2-AR-associated and additional stimulator of interferon gene (STING)-independent regulatory mechanisms. Collectively, our findings reveal β2-AR as a molecular link between psychological stress and antiviral immunity and highlight lycorine-mediated β2-AR stabilization as a potential host-directed antiviral strategy for poxvirus infection.