<h2>Summary</h2> Manganese (Mn) is essential for many physiological processes, but its functions in innate immunity remain undefined. Here, we found that Mn<sup>2+</sup> was required for the host defense against DNA viruses by increasing the sensitivity of the DNA sensor cGAS and its downstream adaptor protein STING. Mn<sup>2+</sup> was released from membrane-enclosed organelles upon viral infection and accumulated in the cytosol where it bound directly to cGAS. Mn<sup>2+</sup> enhanced the sensitivity of cGAS to double-stranded DNA (dsDNA) and its enzymatic activity, enabling cGAS to produce secondary messenger cGAMP in the presence of low concentrations of dsDNA that would otherwise be non-stimulatory. Mn<sup>2+</sup> also enhanced STING activity by augmenting cGAMP-STING binding affinity. Mn-deficient mice showed diminished cytokine production and were more vulnerable to DNA viruses, and Mn-deficient STING-deficient mice showed no increased susceptibility. These findings indicate that Mn is critically involved and required for the host defense against DNA viruses.

Manganese Increases the Sensitivity of the cGAS-STING Pathway for Double-Stranded DNA and Is Required for the Host Defense against DNA Viruses