STING agonists enable antiviral cross-talk between human cells and confer protection against genital herpes in mice

In recent years, there has been an increasing interest in immunomodulatory therapy as a means to treat various conditions, including infectious diseases. For instance, Toll-like receptor (TLR) agonists have been evaluated for treatment of genital herpes. However, although the TLR7 agonist imiquimod was shown to have antiviral activity in individual patients, no significant effects were observed in clinical trials, and the compound also exhibited significant side effects, including local inflammation. Cytosolic DNA is detected by the enzyme cyclic GMP-AMP (2’3’-cGAMP) synthase (cGAS) to stimulate antiviral pathways, mainly through induction of type I interferon (IFN)s. cGAS is activated upon DNA binding to produce the cyclic dinucleotide (CDN) 2’3’-cGAMP, which in turn binds and activates the adaptor protein Stimulator of interferon genes (STING), thus triggering type I IFN expression. In contrast to TLRs, STING is expressed broadly, including in epithelial cells. Here we report that natural and non-natural STING agonists strongly induce type I IFNs in human cells and in mice in vivo, without stimulating significant inflammatory gene expression. Systemic treatment with 2’3’-cGAMP reduced genital herpes simplex virus (HSV) 2 replication and improved the clinical outcome of infection. More importantly, local application of CDNs at the genital epithelial surface gave rise to local IFN activity, but only limited systemic responses, and this treatment conferred total protection against disease in both immunocompetent and immunocompromised mice. In direct comparison between CDNs and TLR agonists, only CDNs acted directly on epithelial cells, hence allowing a more rapid and IFN-focused immune response in the vaginal epithelium. Thus, specific activation of the STING pathway in the vagina evokes induction of the IFN system but limited inflammatory responses to allow control of HSV2 infections in vivo.

近年来，免疫调节疗法作为治疗包括感染性疾病在内多种病症的手段，受到了越来越多的关注。例如，Toll样受体（Toll-like receptor, TLR）激动剂已被评估用于治疗生殖器疱疹。然而，尽管TLR7激动剂咪喹莫特（imiquimod）在个别患者中展现出抗病毒活性，但临床试验未观察到显著疗效，且该化合物还存在包括局部炎症在内的严重不良反应。胞质DNA可由环GMP-AMP（2’3’-cGAMP）合酶（cyclic GMP-AMP synthase, cGAS）识别，进而激活抗病毒信号通路，该过程主要通过诱导I型干扰素（IFN）完成。cGAS在结合DNA后被激活，生成环二核苷酸（cyclic dinucleotide, CDN）2’3’-cGAMP；后者可结合并激活接头蛋白干扰素基因刺激因子（Stimulator of interferon genes, STING），进而触发I型干扰素的表达。与TLRs不同，STING的表达范围更广，包括上皮细胞。在本研究中，我们发现天然与非天然STING激动剂可在人体细胞及活体小鼠中强力诱导I型干扰素的表达，且不会触发显著的炎症基因表达。全身给予2’3’-cGAMP可降低生殖器单纯疱疹病毒（herpes simplex virus, HSV）2型的复制，并改善感染后的临床结局。更重要的是，在生殖器上皮表面局部施用CDNs可诱导局部干扰素活性，但仅引发有限的全身应答；该疗法可在免疫健全与免疫缺陷小鼠中均提供完全的疾病保护效果。在CDNs与TLR激动剂的直接对比实验中，仅CDNs可直接作用于上皮细胞，因此能在阴道上皮中引发更快速、以干扰素为核心的免疫应答。因此，在阴道内特异性激活STING通路可诱导干扰素系统活化，同时仅引发有限的炎症反应，从而在活体中实现对HSV2感染的控制。