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

Manganese (Mn2+) is an essential trace element within organisms spanning the entire tree of life. It has reported that Mn2+ exerts strong immunocompetence and exhibits antiviral effects against various human and animal viruses, including DNA and RNA viruses. Recently, Mn2+ has recently been found to be involved in the activation of the innate immune DNA-sensing cGAS-STING pathway and subsequent anti-virus function. However, the antiviral mechanism of Mn2+ remains unclear. In current study, the results suggested that cGAS-STING pathway is essential for Mn2+ promoting the IFN signaling, but it is not essential for triggering antiviral functions. After knocking out the STING or IRF3 gene, Mn2+ still retains its antiviral activity against HSV-1 and VSV. Furthermore, the results from transcriptomic analysis indicated that Mn2+ could induce a significantly change of apoptotic process in STING⁻/⁻ 3D4/21 cells. Mn2+ could induce cell apoptosis through oxidative stress pathway, and inhibiting the apoptotic signal could suppress the 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 eliminate the antiviral effects of Mn2+. In summary, the current study has suggested that Mn2+ could exert antiviral effects not only through the cGAS-STING-IFN pathway but also via the ROS-apoptosis pathway.