Cells contain numerous immune sensors to detect virus infection. The cyclic GMP-AMP (cGAMP) synthase (cGAS) recognizes cytosolic DNA and activates innate immune responses via stimulator of interferon genes (STING), but the impact of DNA sensing pathways on host protective responses has not been fully defined. We demonstrate that cGAS/STING activation is required to resist lethal poxvirus infection. We identified viral Schlafen (vSlfn) as the main STING inhibitor, and ectromelia virus was severely attenuated in the absence of vSlfn. Both vSlfn-mediated virulence and STING inhibitory activity were mapped to the recently discovered poxin cGAMP nuclease domain. Animals were protected from subcutaneous, respiratory, and intravenous infection in the absence of vSlfn, and interferon was the main antiviral protective mechanism controlled by the DNA sensing pathway. Our findings support the idea that manipulation of DNA sensing is an efficient therapeutic strategy in diseases triggered by viral infection or tissue damage–mediated release of self-DNA.

细胞包含许多免疫传感器来检测病毒感染。环状 GMP-AMP (cGAMP) 合酶 (cGAS) 通过干扰素基因刺激物 (STING) 识别胞质 DNA 并激活先天免疫反应，但 DNA 传感途径对宿主保护反应的影响尚未完全确定。我们证明需要 cGAS/STING 激活来抵抗致命的痘病毒感染。我们将病毒 Schlafen (vSlfn) 确定为主要的 STING 抑制剂，并且在没有 vSlfn 的情况下，ectromelia 病毒被严重减毒。vSlfn 介导的毒力和 STING 抑制活性均被映射到最近发现的痘素 cGAMP 核酸酶结构域。在没有 vSlfn 的情况下，保护动物免受皮下、呼吸道和静脉内感染，干扰素是受DNA传感通路控制的主要抗病毒保护机制。我们的研究结果支持这样一种观点，即在病毒感染或组织损伤介导的自身 DNA 释放引发的疾病中，操纵 DNA 传感是一种有效的治疗策略。