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2018 ; 14
(4
): e1006976
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STING agonists enable antiviral cross-talk between human cells and confer
protection against genital herpes in mice
#MMPMID29608601
Skouboe MK
; Knudsen A
; Reinert LS
; Boularan C
; Lioux T
; Perouzel E
; Thomsen MK
; Paludan SR
PLoS Pathog
2018[Apr]; 14
(4
): e1006976
PMID29608601
show ga
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.