Sensing of HSV-1 by the cGAS–STING pathway in microglia orchestrates antiviral defence in the CNS

Reinert, Line S.; Lopušná, Katarína; Winther, Henriette; Sun, Chaoyang; Thomsen, Martin K.; Nandakumar, Ramya; Mogensen, Trine H.; Meyer, Morten; Vægter, Christian Bjerggaard; Nyengaard, Jens Randel; Fitzgerald, Katherine A.; Paludan, Søren R.

doi:10.1038/ncomms13348

Cited by 284 publications

(322 citation statements)

References 38 publications

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“…Indeed, levels of cGAS protein expression actually showed a significant decrease in primary microglia at 24 hrs following transfection with the highest dose of BDNA, an effect that could not be attributed to a decrease in cell viability. The finding that human glial cells express components of the cGAS-STING DNA sensor pathway are in agreement with the recent study from Reinert and co-workers showing that murine microglia express cGAS [15], and the demonstration by this group [15] and our own [4] that murine glia possess STING.…”

Section: Discussionsupporting

confidence: 92%

“…The significance of cGAS is underscored by its apparent ability to recognize clinically important DNA viruses and retroviruses such as herpes simplex virus-1 (HSV-1) and human immunodeficiency virus-1 (HIV-1) that infect the human CNS [13, 14]. An antiviral role for cGAS in the CNS is supported by recent work in mice demonstrating that the microglial responses mediated by this sensor limit productive HSV-1 infection [15]. To date, the expression of cGAS and the critical adaptor protein STING has not been demonstrated in human glial cells.…”

Section: Introductionmentioning

confidence: 99%

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Human microglia and astrocytes express cGAS-STING viral sensing components

Jeffries

Marriott

2017

Neuroscience Letters

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While microglia and astrocytes are known to produce key inflammatory and anti-viral mediators following infection with replicative DNA viruses, the mechanisms by which these cell types perceive such threats are poorly understood. Recently, cyclic GMP-AMP synthase (cGAS) has been identified as an important cytosolic sensor for DNA viruses and retroviruses in peripheral leukocytes. Here we confirm the ability of human microglial and astrocytic cell lines and primary human glia to respond to foreign intracellular double stranded DNA. Importantly, we provide the first demonstration that human microglia and astrocytes show robust levels of cGAS protein expression at rest and following activation. Furthermore, we show these cell types also constitutively express the critical downstream cGAS adaptor protein, stimulator of interferon genes (STING). The present finding that human glia express the principle components of the cGAS-STING pathway provides a foundation for future studies to investigate the relative importance of these molecules in clinically relevant viral CNS infections.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Human microglia and astrocytes express cGAS-STING viral sensing components

Jeffries

Marriott

2017

Neuroscience Letters

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“…The RNA purification and qPCR was performed as described (Reinert et al , ), with the following primers from Applied Biosystems: Ifnb (Mm00439552_s1), Cxcl10 (Mm00445235_m1), IFNB1 (Hs01077958_s1), CXCL10 (Hs01124251_g1). Levels of mRNAs of interest were normalized to β‐actin using the formula 2 Ct(βactin) − Ct(mRNA X) .…”

Section: Methodsmentioning

confidence: 99%

Attenuation of c GAS ‐ STING signaling is mediated by a p62/ SQSTM 1‐dependent autophagy pathway activated by TBK1

et al. 2018

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Negative regulation of immune pathways is essential to achieve resolution of immune responses and to avoid excess inflammation. DNA stimulates type I IFN expression through the DNA sensor cGAS, the second messenger cGAMP, and the adaptor molecule STING Here, we report that STING degradation following activation of the pathway occurs through autophagy and is mediated by p62/SQSTM1, which is phosphorylated by TBK1 to direct ubiquitinated STING to autophagosomes. Degradation of STING was impaired in p62-deficient cells, which responded with elevated IFN production to foreign DNA and DNA pathogens. In the absence of p62, STING failed to traffic to autophagy-associated vesicles. Thus, DNA sensing induces the cGAS-STING pathway to activate TBK1, which phosphorylates IRF3 to induce IFN expression, but also phosphorylates p62 to stimulate STING degradation and attenuation of the response.

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“…Increased expression of IFN-a/b by microglia was further detected after direct administration of polyinosinic-polycytidylic acid (poly I:C) into the cerebrospinal fluid (CSF) via the cisterna magna in mice. Following HSV-1 infection, microglia are the main producers of type I IFNs that induce antiviral activity in neurons (Reinert et al, 2016). Following HSV-1 infection, microglia are the main producers of type I IFNs that induce antiviral activity in neurons (Reinert et al, 2016).…”

Section: Major Type I Ifn Producing Cells In the Cns Under Homeostamentioning

confidence: 99%

Type I interferon pathway in CNS homeostasis and neurological disorders

Blank

Prinz

2017

Glia

122

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Type I interferons (IFNs), IFN-α and IFN-β, represent the major effector cytokines of the host immune response against viruses and other intracellular pathogens. These cytokines are produced via activation of numerous pattern recognition receptors, including the Toll-like receptor signaling network, retinoic acid-inducible gene-1 (RIG-1), melanoma differentiation-associated protein-5 (MDA-5) and interferon gamma-inducible protein-16 (IFI-16). Whilst the contribution of type I IFNs to peripheral immunity is well documented, they can also be produced by almost every cell in the central nervous system (CNS). Furthermore, IFNs can reach the CNS from the periphery to modulate the function of not only microglia and astrocytes, but also neurons and oligodendrocytes, with major consequences for cognition and behavior. Given the pleiotropic nature of type I IFNs, it is critical to determine their exact cellular impact. Inappropriate upregulation of type I IFN signaling and interferon-stimulated gene expression have been linked to several CNS diseases termed "interferonopathies" including Aicardi-Goutieres syndrome and ubiquitin specific peptidase 18 (USP18)-deficiency. In contrast, in the CNS of mice with virus-induced neuroinflammation, type I IFNs can limit production of other cytokines to prevent potential damage associated with chronic cytokine expression. This capacity of type I IFNs could also explain the therapeutic benefits of exogenous type I IFN in chronic CNS autoimmune diseases such as multiple sclerosis. In this review we will highlight the importance of a well-balanced level of type I IFNs for healthy brain physiology, and to what extent dysregulation of this cytokine system can result in brain 'interferonopathies'.

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Sensing of HSV-1 by the cGAS–STING pathway in microglia orchestrates antiviral defence in the CNS

Cited by 284 publications

References 38 publications

Human microglia and astrocytes express cGAS-STING viral sensing components

Human microglia and astrocytes express cGAS-STING viral sensing components

Attenuation of c GAS ‐ STING signaling is mediated by a p62/ SQSTM 1‐dependent autophagy pathway activated by TBK1

Type I interferon pathway in CNS homeostasis and neurological disorders

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