Abstract
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.
Highlights
Virus infections may cause acute and chronical diseases, and there is a need for development of efficient treatments
In this work we show that natural and nonnatural cyclic dinucleotide (CDN) activate strong type I IFN responses in vivo without stimulating significant expression of genes driven by the transcription factor nuclear factor (NF)-κB, which induces inflammation
The data suggest that monocytes produce much higher levels of type I IFN in response to Stimulator of interferon genes (STING) agonists than keratinocytes, which are more responsive to IFN stimulation than monocytes
Summary
Virus infections may cause acute and chronical diseases, and there is a need for development of efficient treatments. Satisfactory treatments are not available for many virus infections, and there is a need for treatments acting in a broader manner, and which are less sensitive to viral development of resistance. The need for new and better anti-HSV2 treatments is underpinned by several factors, including the ability of this virus to cause neonatal herpes [3], the role of HSV2 in amplifying HIV-transmission, which has been reported to account for up to half of all new transmissions in areas of high HSV2 seroprevalence [7, 8], and the recently reported association to increased rates of autism-spectrum disorders [9]
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