The intracellular DNA sensors cGAS and IFI16 do not mediate effective antiviral immune responses to HSV-1 in human microglial cells

AbstractGlia play a key role in immunosurveillance within the central nervous system (CNS) and can recognize a wide range of pathogen-associated molecular patterns (PAMPS) via members of multiple pattern recognition receptor (PRR) families. Of these, the expression of cytosolic/nuclear RNA and DNA sensors by glial cells is of particular interest as their ability to interact with intracellular nucleic acids suggests a critical role in the detection of viral pathogens. The recently discovered DNA sensors cyclic GMP-AMP synthase (cGAS) and interferon gamma-inducible protein 16 (IFI16) have been reported to be important for the recognition of DNA pathogens such as herpes simplex virus-1 (HSV-1) in peripheral human cell types, and we have recently demonstrated that human glia express cGAS and its downstream adaptor molecule stimulator of interferon genes (STING). Here, we have demonstrated that human microglial cells functionally express cGAS and exhibit robust constitutive IFI16 expression. While cGAS serves as a significant component in IRF3 activation and IFN- β production by human microglial cells in response to foreign intracellular DNA, IFI16 is not required for such responses. Surprisingly, neither of these sensors mediate effective antiviral responses to HSV-1 in microglia, and this may be due, at least in part, to viral suppression of cGAS and/or I FI16 expression. As such, this ability may represent an important HSV immune evasion strategy in glial cells, and approa...
Source: Journal of NeuroVirology - Category: Neurology Source Type: research

Related Links:

Abstract The cyclic GMP-AMP synthase (cGAS) protein is a pattern-recognition receptor of the mammalian innate immune system that is recognized as a main cytosolic sensor of pathogenic or damaged DNA. cGAS DNA binding initiates catalytic production of the second messenger, cyclic GMP-AMP, which activates the STING-TBK1-IRF3 signaling axis to induce cytokine expression. Post-translational modification (PTM) has started to be recognized as a critical component of cGAS regulation, yet the extent of these modifications remains unclear. Here, we report the identification and functional analysis of cGAS phosphorylations ...
Source: Molecular and Cellular Proteomics : MCP - Category: Molecular Biology Authors: Tags: Mol Cell Proteomics Source Type: research
In conclusion, our results have identified that TRIM21 is abnormally high expressed in HSV epithelial keratitis. TRIM21 enhances the replication of HSV-1 in corneal epithelial cells via suppressing the production of type I IFN by inhibiting STING/IRF3 signaling. It also promotes the secretion of IL-6 and TNF-a, thereby aggravating the severity of HSV epithelial keratitis.
Source: Frontiers in Microbiology - Category: Microbiology Source Type: research
In conclusion, HSV-2 reprogramming opens up DCs for HIV-1 infection and creates a microenvironment favoring HIV-1 transmission.
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
In this study, HEK 293T cells with low toll-like receptor (TLR) and stimulator of interferon genes protein (STING) expression were infected with HSV-1 and subjected to a quantitative proteomic analysis. By using a subcellular fractionation strategy and high-performance mass spectrometry, a total of 6607 host proteins were quantified, of which 498 proteins were differentially regulated. A bioinformatics analysis indicated that multiple signaling pathways might be involved in HSV-1 infection. A further functional study indicated the role of Interferon-induced transmembrane protein 3 (IFITM3), Coiled-coil-helix-coiled-coil-he...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research
At Aarhus University in Denmark, Vincent speaks with Trine Mogensen, Søren Paludan, Ole Søgaard, and Madalina Carter-Timofte about their careers and their work on sensing herpesviral DNA, immunodeficiencies that predispose to severe viral infections, and the path to a cure for HIV/AIDS. Click arrow to play Download TWiV 570 (61 MB .mp3, 101 min) Subscribe (free): iTunes, Google Podcasts, RSS, email […]
Source: virology blog - Category: Virology Authors: Tags: This Week in Virology Aarhus University AIDS AIDS cure cGAS DNA sensor herpes simplex virus HIV-1 HIV-1 latent reservoir host genetics polIII polio poliomyelitis poliovirus STING TLR9 varicella-zoster virus viral viruse Source Type: blogs
The innate immune system plays an essential role in initial recognition of pathogen infection by producing inflammatory cytokines and type I interferons. cGAS is a cytoplasmic sensor for DNA derived from DNA viruses. cGAS binding with DNA induces the production of cGAMP, a second messenger that associates with STING in endoplasmic reticulum (ER). STING changes its cellular distribution from ER to perinuclear Golgi, where it activates the protein kinase TBK1 that catalyzes the phosphorylation of IRF3. Here we found that STING trafficking is regulated by myotubularin-related protein (MTMR) 3 and MTMR4, members of protein tyr...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Immunology Source Type: research
Eduardo I. Tognarelli1, Tomás F. Palomino1, Nicolás Corrales1, Susan M. Bueno1, Alexis M. Kalergis1,2 and Pablo A. González1* 1Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile 2Departamento de Endocrinología, Facultad de Medicina, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile Herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) have co-evolved with humans for thousands o...
Source: Frontiers in cellular and infection microbiology - Category: Microbiology Source Type: research
In this study, we showed that KSHV-infected cells induce interferon-stimulated genes (ISGs) response but not type I interferon in uninfected bystander cells using EVs. mRNA microarray analysis showed that ISGs and IRF-activating genes were prominently activated in EVs from KSHV-infected cells (KSHV EVs)-treated human endothelial cells, which were validated by RT-qPCR and western blot analysis. We also found that this response was not associated with cell death or apoptosis by virus infection. Mechanistically, the cGAS-STING pathway was linked with these KSHV EVs-mediated ISGs expressions, and mitochondrial DNA on the surfa...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
María Maximina B. Moreno-Altamirano1*, Simon E. Kolstoe2 and Francisco Javier Sánchez-García1* 1Laboratorio de Inmunorregulación, Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico 2School of Health Sciences, University of Portsmouth, Portsmouth, United Kingdom Over the last decade, there has been significant advances in the understanding of the cross-talk between metabolism and immune responses. It is now evident that immune cell effector function strongly depends on the metabolic pathway in w...
Source: Frontiers in cellular and infection microbiology - Category: Microbiology Source Type: research
We report that variation of a single amino acid residue in the innate immune sensor cGAS determines species-specific inactivation by HSV-1. The HSV-1 UL37 tegument protein deamidates human and mouse cGAS. Deamidation impairs the ability of cGAS to catalyze cGAMP synthesis, which activates innate immunity. HSV-1 with deamidase-deficient UL37 promotes robust antiviral responses and is attenuated in mice in a cGAS- and STING-dependent manner. Mutational analyses identified a single asparagine in human and mouse cGAS that is not conserved in many non-human primates. This residue underpins UL37-mediated cGAS deamidation an...
Source: Cell Host and Microbe - Category: Microbiology Authors: Tags: Cell Host Microbe Source Type: research
More News: Brain | Cold Sores | Genetics | Herpes | Insect Bites & Stings | Neurology