Viral cGAMP nuclease reveals the essential role of DNA sensing in protection against acute lethal virus infection.
Viral cGAMP nuclease reveals the essential role of DNA sensing in protection against acute lethal virus infection.
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DOI：
10.1126/sciadv.abb4565
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发表时间：
2020-09
期刊：
影响因子：
13.6
通讯作者：
Alcamí A
中科院分区：
文献类型：
--
作者：
Hernáez B;Alonso G;Georgana I;El-Jesr M;Martín R;Shair KHY;Fischer C;Sauer S;Maluquer de Motes C;Alcamí A
病毒cGAMP核酸酶的DNA传感抑制损害抗病毒应答和保护性免疫。细胞含有许多免疫传感器来检测病毒感染。环GMP-AMP（cGAMP）合酶（cGAS）识别胞质DNA并通过干扰素基因刺激物（STING）激活先天性免疫应答，但DNA传感途径对宿主保护性应答的影响尚未完全确定。我们证明了cGAS/STING激活是抵抗致死性痘病毒感染所必需的。我们鉴定了病毒Schlafen（vSlfn）作为主要的STING抑制剂，并且在不存在vSlfn的情况下，肢脱病病毒被严重减毒。vSlfn介导的毒力和STING抑制活性都被映射到最近发现的痘素cGAMP核酸酶结构域。在不存在vSlfn的情况下保护动物免受皮下、呼吸道和静脉内感染，并且干扰素是由DNA传感途径控制的主要抗病毒保护机制。我们的研究结果支持这样的想法，即操纵DNA传感是一种有效的治疗策略，在由病毒感染或组织损伤介导的自我DNA释放引发的疾病。
DNA sensing inhibition by viral cGAMP nuclease impairs anti-viral responses and protective immunity. 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.
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