Sensing of HSV-1 by the cGAS-STING pathway in microglia orchestrates antiviral defence in the CNS
Line S. Reinert,Katarína Lopušná,Katarína Lopušná,Henriette Winther,Chenglong Sun,Martin K. Thomsen,Ramya Nandakumar,Trine H. Mogensen,Trine H. Mogensen,Morten Meyer,Christian Bjerggaard Vaegter,Jens R. Nyengaard,Katherine A. Fitzgerald,Søren R. Paludan +13 more
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TLDR
Sensing of HSV-1 infection in the CNS by microglia through the cGAS–STING pathway orchestrates an antiviral program that includes type I IFNs and immune-priming of other cell types.Abstract:
Herpes simplex encephalitis (HSE) is the most common form of acute viral encephalitis in industrialized countries. Type I interferon (IFN) is important for control of herpes simplex virus (HSV-1) in the central nervous system (CNS). Here we show that microglia are the main source of HSV-induced type I IFN expression in CNS cells and these cytokines are induced in a cGAS-STING-dependent manner. Consistently, mice defective in cGAS or STING are highly susceptible to acute HSE. Although STING is redundant for cell-autonomous antiviral resistance in astrocytes and neurons, viral replication is strongly increased in neurons in STING-deficient mice. Interestingly, HSV-infected microglia confer STING-dependent antiviral activities in neurons and prime type I IFN production in astrocytes through the TLR3 pathway. Thus, sensing of HSV-1 infection in the CNS by microglia through the cGAS-STING pathway orchestrates an antiviral program that includes type I IFNs and immune-priming of other cell types.read more
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cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein–DNA ladders
Liudmila Andreeva,Björn Hiller,Dirk Kostrewa,Charlotte Lässig,Carina C. de Oliveira Mann,Carina C. de Oliveira Mann,David Jan Drexler,Andreas Maiser,Moritz M. Gaidt,Heinrich Leonhardt,Heinrich Leonhardt,Veit Hornung,Veit Hornung,Karl-Peter Hopfner,Karl-Peter Hopfner +14 more
TL;DR: The results suggest a nucleation-cooperativity-based mechanism for sensitive detection of mitochondrial DNA and pathogen genomes, and identify HMGB/TFAM proteins as DNA-structuring host factors.
Journal ArticleDOI
Attenuation of cGAS-STING Signaling Is Mediated by a p62/SQSTM1-dependent Autophagy Pathway Activated by TBK1
Thaneas Prabakaran,Chiranjeevi Bodda,Chiranjeevi Bodda,Christian Krapp,Bao-Cun Zhang,Maria H Christensen,Chenglong Sun,Line S. Reinert,Yujia Cai,Søren B. Jensen,Morten K Skouboe,Jens R. Nyengaard,Craig B. Thompson,Robert Jan Lebbink,Ganes C. Sen,Geert van Loo,Rikke Nielsen,Masaaki Komatsu,Lene N. Nejsum,Martin R. Jakobsen,Mads Gyrd-Hansen,Søren R. Paludan +21 more
TL;DR: It is reported 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.
Journal ArticleDOI
cGAS is activated by DNA in a length-dependent manner.
Stefanie Luecke,Andreas Holleufer,Maria H Christensen,Kasper L Jønsson,Gerardo A Boni,Lambert K. Sørensen,Mogens Johannsen,Martin R. Jakobsen,Rune Hartmann,Søren R. Paludan +9 more
TL;DR: In vitro studies reveal that long DNA activates recombinant human cGAS more efficiently than short DNA, showing that length‐dependent DNA recognition is an intrinsic property of cGas independent of accessory proteins.
Journal ArticleDOI
TBK1 recruitment to STING activates both IRF3 and NF-κB that mediate immune defense against tumors and viral infections.
TL;DR: In this paper, the authors showed that STING can function independently of type I interferons and autophagy, and that TBK1 recruitment to STING is essential for antiviral and antitumor immunity.
Journal ArticleDOI
Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response.
TL;DR: A comprehensive understanding of the modulatory pattern of the cGAS-STING pathway under multifarious pathologic states is provided.
References
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TL;DR: Human TLR3 appears to be redundant in host defense to most microbes but is vital for natural immunity to HSV-1 in the CNS, which suggests that neurotropic viruses have contributed to the evolutionary maintenance ofTLR3.
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