Manganese Mediates Its Antiviral Functions in a cGAS-STING Pathway Independent Manner

The innate immune system is the first line of host defense sensing viral infection. Manganese (Mn) has recently been found to be involved in the activation of the innate immune DNA-sensing cGAS-STING pathway and subsequent anti-DNA virus function. However, it is still unclear whether Mn(2+) mediates host defense against RNA viruses. In this study, we demonstrate that Mn(2+) exhibited antiviral effects against various animal and human viruses, including RNA viruses such as PRRSVs and VSV, as well as DNA viruses such as HSV1, in a dose-dependent manner. Moreover, cGAS and STING were both investigated in the Mn(2+) mediated antiviral roles using the knockout cells made by the CRISPR-Cas9 approach. Unexpectedly, the results revealed that neither cGAS knockout nor STING knockout had any effect on Mn(2+)-mediated antiviral functions. Nevertheless, we verified that Mn(2+) promoted the activation of the cGAS-STING signaling pathway. These findings suggest that Mn(2+) has broad-spectrum antiviral activities in a cGAS-STING pathway independent manner. This study also provides significant insights into redundant mechanisms participating in the Mn(2+) antiviral functions, and also indicates a new target for Mn(2+) antiviral therapeutics.