Mn2+-Mediated Antiviral Activity Through Both the cGAS-STING-IFN and ROS-Apoptosis Pathways in Porcine Alveolar Macrophage Cells

Manganese ions (Mn2+) are an essential trace element within organisms spanning the entire tree of life. It has reported that Mn2+ exerts strong immunocompetence effects and exhibits antiviral effects against various human and animal viruses, including DNA and RNA viruses. Recently, Mn2+ has been found to be involved in the activation of the innate immune DNA-sensing cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway and subsequent antiviral function. However, the antiviral mechanism of Mn2+ remains unclear. In the current study, the results suggest that the cGAS-STING pathway is essential for Mn2+ to promote interferon (IFN) signaling, but it is not essential for triggering antiviral functions. After knocking out the STING or interferon regulatory factor 3 (IRF3) gene, Mn2+ still retains its antiviral activity against herpes simplex virus type 1 (HSV-1) and vesicular stomatitis virus (VSV). Furthermore, the results from transcriptomic analysis indicate that Mn2+ can induce a significant change in the apoptotic process in STING−/− 3D4/21 cells. Mn2+ can induce cell apoptosis through the oxidative stress pathway, and inhibiting the apoptotic signal could suppress Mn2+-mediated antiviral activity in STING−/− 3D4/21 cells. Additionally, dual knockout of IRF3 and caspase3, resulting in concurrent loss of IFN and apoptotic signals, eliminates the antiviral effects of Mn2+. In summary, the current study suggests that Mn2+ could exert antiviral effects not only through the cGAS-STING-IFN pathway but also via the reactive oxygen species (ROS)-apoptosis pathway.