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...
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doaj-4ef01a80f8f8483bafe8e9514f8f5aa72020-11-25T00:43:35ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742018-04-01144e100697610.1371/journal.ppat.1006976STING agonists enable antiviral cross-talk between human cells and confer protection against genital herpes in mice.Morten K SkouboeAlice KnudsenLine S ReinertCedric BoularanThierry LiouxEric PerouzelMartin K ThomsenSøren R PaludanIn 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.http://europepmc.org/articles/PMC5897032?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Morten K Skouboe Alice Knudsen Line S Reinert Cedric Boularan Thierry Lioux Eric Perouzel Martin K Thomsen Søren R Paludan |
spellingShingle |
Morten K Skouboe Alice Knudsen Line S Reinert Cedric Boularan Thierry Lioux Eric Perouzel Martin K Thomsen Søren R Paludan STING agonists enable antiviral cross-talk between human cells and confer protection against genital herpes in mice. PLoS Pathogens |
author_facet |
Morten K Skouboe Alice Knudsen Line S Reinert Cedric Boularan Thierry Lioux Eric Perouzel Martin K Thomsen Søren R Paludan |
author_sort |
Morten K Skouboe |
title |
STING agonists enable antiviral cross-talk between human cells and confer protection against genital herpes in mice. |
title_short |
STING agonists enable antiviral cross-talk between human cells and confer protection against genital herpes in mice. |
title_full |
STING agonists enable antiviral cross-talk between human cells and confer protection against genital herpes in mice. |
title_fullStr |
STING agonists enable antiviral cross-talk between human cells and confer protection against genital herpes in mice. |
title_full_unstemmed |
STING agonists enable antiviral cross-talk between human cells and confer protection against genital herpes in mice. |
title_sort |
sting agonists enable antiviral cross-talk between human cells and confer protection against genital herpes in mice. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Pathogens |
issn |
1553-7366 1553-7374 |
publishDate |
2018-04-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC5897032?pdf=render |
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