Lio Chan-Wang J, McDonald Bryan, Takahashi Mariko, Dhanwani Rekha, Sharma Nikita, Huang Jenny, Pham Elise, Benedict Chris A, Sharma Sonia
La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
La Jolla Institute for Allergy and Immunology, La Jolla, California, USA Functional Genomics Center, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
J Virol. 2016 Aug 12;90(17):7789-97. doi: 10.1128/JVI.01040-16. Print 2016 Sep 1.
Several innate sensing pathways contribute to the control of early cytomegalovirus (CMV) infection, leading to a multiphasic type I interferon (IFN-I) response that limits viral replication and promotes host defenses. Toll-like receptor (TLR)-dependent pathways induce IFN-I production in CMV-infected plasmacytoid dendritic cells; however, the initial burst of IFN-I that occurs within the first few hours in vivo is TLR independent and emanates from stromal cells. Here we show that primary human endothelial cells mount robust IFN-I responses to human CMV that are dependent upon cyclic GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3) signaling. Disruption of STING expression in endothelial cells by clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 revealed that it is essential for the induction of IFN-I and restriction of CMV replication. Consistently, STING was necessary to mount the first phase of IFN-I production and curb CMV replication in infected mice. Thus, DNA sensing through STING is critical for primary detection of both human and mouse CMV in nonhematopoietic cells and drives the initial wave of IFN-I that is key for controlling early viral replication .
Cytomegalovirus (CMV) is one of the most common viral pathogens, with the majority of people contracting the virus in their lifetime. Although acute infection is mostly asymptomatic in healthy persons, significant pathology is observed in immunocompromised individuals, and chronic CMV infection may exacerbate a myriad of inflammatory conditions. Here we show that primary human endothelial cells mount robust IFN-I responses against CMV via a cGAS/STING/IRF3 pathway. Disruption of STING expression by CRISPRs revealed an essential role in eliciting IFN-I responses and restricting CMV replication. Consistently, in mice, STING is necessary for the first phase of IFN-I production that limits early CMV replication. Our results demonstrate a pivotal role for the cGAS-STING pathway in the initial detection of CMV infection.
几种先天感应途径有助于控制早期巨细胞病毒（CMV）感染，导致多相I型干扰素（IFN-I）反应，限制病毒复制并促进宿主防御。Toll样受体（TLR）依赖性途径在CMV感染的浆细胞样树突状细胞中诱导IFN-I产生；然而，体内最初几小时内出现的IFN-I初始爆发是TLR非依赖性的，源自基质细胞。在这里，我们表明原代人内皮细胞对人CMV产生强大的IFN-I反应，这依赖于环鸟苷酸-腺苷酸合成酶（cGAS）、干扰素基因刺激蛋白（STING）和干扰素调节因子3（IRF3）信号传导。通过成簇规律间隔短回文重复序列（CRISPR）-Cas9破坏内皮细胞中STING的表达表明，它对于诱导IFN-I和限制CMV复制至关重要。同样，STING对于在感染小鼠中产生第一阶段的IFN-I和抑制CMV复制是必需的。因此，通过STING进行的DNA感应对于在非造血细胞中初步检测人和小鼠CMV至关重要，并驱动IFN-I的初始浪潮，这是控制早期病毒复制的关键。
巨细胞病毒（CMV）是最常见的病毒病原体之一，大多数人在一生中都会感染该病毒。虽然急性感染在健康人中大多无症状，但在免疫功能低下的个体中会观察到明显的病理变化，慢性CMV感染可能会加剧多种炎症状态。在这里，我们表明原代人内皮细胞通过cGAS/STING/IRF3途径对CMV产生强大的IFN-I反应。CRISPR破坏STING表达揭示了其在引发IFN-I反应和限制CMV复制中的重要作用。同样，在小鼠中，STING对于限制早期CMV复制的第一阶段IFN-I产生是必需的。我们的结果证明了cGAS-STING途径在CMV感染初始检测中的关键作用。
