The STING agonist 5,6-dimethylxanthenone-4-acetic acid (DMXAA) stimulates an antiviral state and protects mice against herpes simplex virus-induced neurological disease

The Stimulator of Interferon Genes (STING) pathway initiates potent immune responses upon recognition of DNA. To initiate signaling, serine 365 (S365) in the C-terminal tail (CTT) of STING is phosphorylated, leading to induction of type I interferons (IFNs). Additionally, evolutionary conserved responses such as autophagy also occur downstream of STING, but their relative importance during in vivo infections remains unclear. Here we report that mice harboring a serine 365-to-alanine (S365A) mutation in STING are unexpectedly resistant to Herpes Simplex Virus (HSV)-1, despite lacking STING-induced type I IFN responses. By contrast, resistance to HSV-1 is abolished in mice lacking the STING CTT, suggesting that the STING CTT initiates protective responses against HSV-1, independently of type I IFNs. Interestingly, we find that STING-induced autophagy is a CTT-and TBK1-dependent but IRF3independent process that is conserved in the STING S365A mice. Thus, interferonindependent functions of STING mediate STING-dependent antiviral responses in vivo.

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“…Type I IFNs are essential for control of HSV-1 45,48,[50][51][52] , a result we have confirmed ( Supplementary Fig. 6c, d).…”

Section: Discussionsupporting

confidence: 81%

“…3a). Given that type I IFNs are essential for resistance to HSV-1 50,51 , and that STING is required for type I IFN induction to HSV-1 24,45,46,52 , we were surprised that S365A mice were not as susceptible to infection as Gt and ΔCTT mice. One possibility to explain this result is that S365A is not required for STING-dependent type I IFN induction in vivo.…”

mentioning

confidence: 99%

Interferon-independent STING signaling promotes resistance to HSV-1 in vivo

et al. 2020

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“…Type I IFNs are essential for control of HSV-1 [41, 43, 46-48], a result we have confirmed (Supp. Fig.…”

Section: Discussionsupporting

confidence: 81%

“…S3a). Given that type I IFNs are essential for resistance to HSV-1 [46, 47], and that STING is required for type I IFN induction to HSV-1 [40-42, 48], we were surprised that S365A mice were not as susceptible to infection as Gt and ΔCTT mice. One possibility to explain this result is that S365A is not required for STING-dependent type I IFN induction in vivo .…”

Section: Resultsmentioning

confidence: 99%

STING controls Herpes Simplex Virusin vivoindependent of type I interferon induction

Yamashiro

Wilson

Morrison

et al. 2019

Preprint

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The Stimulator of Interferon Genes (STING) pathway initiates potent immune responses upon recognition of DNA derived from bacteria, viruses and tumors. To signal, the Cterminal tail (CTT) of STING recruits TBK1, a kinase that phosphorylates serine 365 (S365) in the CTT. Phospho-S365 acts as a docking site for IRF3, a transcription factor that is phosphorylated and activated by TBK1, leading to transcriptional induction of type I interferons (IFNs). IFNs are essential for antiviral immunity and are widely viewed as the primary output of STING signaling in mammals. However, other more evolutionarily ancestral responses, such as induction of NF-kB or autophagy, also occur downstream of STING. The relative importance of the various outputs of STING signaling during in vivo infections is unclear. Here we report that mice harboring a serine 365-to-alanine (S365A) point mutation in STING exhibit normal susceptibility to Mycobacterium tuberculosis infection but, unexpectedly, are resistant to Herpes Simplex Virus (HSV)-1, despite lacking STING-induced type I IFN responses. Likewise, we find Irf3 -/mice exhibit resistance to HSV-1. By contrast, resistance to HSV-1 is abolished in mice lacking the STING CTT or TBK1, suggesting that STING protects against HSV-1 upon TBK1 recruitment by the STING CTT, independent of IRF3 or type I IFNs. Interestingly, we find that STING-induced autophagy is a TBK1-dependent IRF3-independent process that is conserved in the STING S365A mice, and autophagy has previously been shown to be required for resistance to HSV-1. We thus propose that autophagy and perhaps other ancestral interferon-independent functions of STING are required for STING-dependent antiviral responses in vivo. Introduction 1 The immune response to pathogens is initiated upon detection of pathogen-2 associated molecular patterns (PAMPs) such as lipopolysaccharide, flagellin and nucleic 3 acids [1]. Double-stranded DNA (dsDNA) is an important PAMP for the detection of 4 many pathogens, including Mycobacterium tuberculosis and Herpes Simplex Virus-1 5 (HSV-1) [2-4]. In vertebrates, the intracellular presence of dsDNA is detected by cyclic-6 GMP-AMP Synthase (cGAS), a dsDNA-activated enzyme that produces a cyclic 7 dinucleotide (CDN) second messenger called 2′3′-cyclic-GMP-AMP (2′3′cGAMP) [5-8 10]. 2′3′cGAMP binds and activates the ER-resident transmembrane protein Stimulator 9 of Interferon Genes (STING). Transcriptional induction of type I IFNs is widely 10 presumed to be the primary output of STING signaling during antiviral defense. 11 However, STING is evolutionarily ancient, present even in bacteria [11] and in animals 12 such as the starlet sea anemone Nematostella vectensis and Drosophila melanogaster that 13 do not appear to encode type I interferons [12]. By contrast, autophagy and NF-κB 14 signaling are ancestral STING-induced signaling pathways, present in both N. vectensis 15 and D. melanogaster, raising the possibility that these pathways are the primary or 16 ancestral signaling outputs of STING [13-16]. 17 The ...

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“…Small antivirals that induce the IFN pathway, identified through high throughput screening, such as Chugai's RO8191 may provide a patient‐friendly “oral interferon treatment” that could complement direct acting antivirals (DAAs). Alternatively, compounds that activate the STING pathway may also provide useful adjuvant treatments …”

Section: Finding New Uses For Approved Drugsmentioning

confidence: 99%

Repurposing approved drugs on the pathway to novel therapies

Schein

2019

Medicinal Research Reviews

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The time and cost of developing new drugs have led many groups to limit their search for therapeutics to compounds that have previously been approved for human use. Many “repurposed” drugs, such as derivatives of thalidomide, antibiotics, and antivirals have had clinical success in treatment areas well beyond their original approved use. These include applications in treating antibiotic‐resistant organisms, viruses, cancers and to prevent burn scarring. The major theoretical justification for reusing approved drugs is that they have known modes of action and controllable side effects. Coadministering antibiotics with inhibitors of bacterial toxins or enzymes that mediate multidrug resistance can greatly enhance their activity. Drugs that control host cell pathways, including inflammation, tumor necrosis factor, interferons, and autophagy, can reduce the “cytokine storm” response to injury, control infection, and aid in cancer therapy. An active compound, even if previously approved for human use, will be a poor clinical candidate if it lacks specificity for the new target, has poor solubility or can cause serious side effects. Synergistic combinations can reduce the dosages of the individual components to lower reactivity. Preclinical analysis should take into account that severely ill patients with comorbidities will be more sensitive to side effects than healthy trial subjects. Once an active, approved drug has been identified, collaboration with medicinal chemists can aid in finding derivatives with better physicochemical properties, specificity, and efficacy, to provide novel therapies for cancers, emerging and rare diseases.

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The STING agonist 5,6-dimethylxanthenone-4-acetic acid (DMXAA) stimulates an antiviral state and protects mice against herpes simplex virus-induced neurological disease

Cited by 28 publications

References 41 publications

Interferon-independent STING signaling promotes resistance to HSV-1 in vivo

Interferon-independent STING signaling promotes resistance to HSV-1 in vivo

STING controls Herpes Simplex Virusin vivoindependent of type I interferon induction

Repurposing approved drugs on the pathway to novel therapies

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