Collateral Damage during Dengue Virus Infection: Making Sense of DNA by cGAS

Aguirre, Sebastián; Fernández-Sesma, Ana

doi:10.1128/jvi.01081-16

Cited by 40 publications

(37 citation statements)

References 20 publications

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“…Through association with the N-terminal CARD-like domain and the C-terminal transmembrane domain of mitochondrial anti-viral signaling protein (MAVS), DENV NS4A protein prevents MAVS binding to retinoic acid-inducible gene I, and suppresses the downstream activation of IRF3 and NF-jB as well as IFN production [36]. These mechanisms mediated by different DENV non-structural proteins are proposed to affect the mitochondrion-ER interaction to avoid the accumulation of DENV proteins in that organelle and to minimize mtDNA leakage into the cytoplasm [38]. Furthermore, DENV NS4B protein can induce mitochondria elongation that physically interacts with convoluted membranes in the ER-mitochondria interface, promotes viral replication, and inhibits IFN responses [35].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, DENV NS4B protein can induce mitochondria elongation that physically interacts with convoluted membranes in the ER-mitochondria interface, promotes viral replication, and inhibits IFN responses [35]. These mechanisms mediated by different DENV non-structural proteins are proposed to affect the mitochondrion-ER interaction to avoid the accumulation of DENV proteins in that organelle and to minimize mtDNA leakage into the cytoplasm [38].…”

Section: Discussionmentioning

confidence: 99%

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Infection with the dengue RNA virus activates TLR9 signaling in human dendritic cells

et al. 2018

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Toll-like receptors (TLRs) are important sensors that recognize pathogen-associated molecular patterns. Generally, TLR9 is known to recognize bacterial or viral DNA but not viral RNA and initiate an immune response. Herein, we demonstrate that infection with dengue virus (DENV), an RNA virus, activates TLR9 in human dendritic cells (DCs). DENV infection induces release of mitochondrial DNA (mtDNA) into the cytosol and activates TLR9 signaling pathways, leading to production of interferons (IFNs). The DENV-induced mtDNA release involves reactive oxygen species generation and inflammasome activation. DENV infection disrupts the association between transcription factor A mitochondria (TFAM) and mtDNA and activates the mitochondrial permeability transition pores. The side-by-side comparison of TLR9 and cyclic GMP-AMP synthase (cGAS) knockdown reveals that both cGAS and TLR9 comparably contribute to DENV-induced immune activation. The significance of TLR9 in DENV-induced immune response is also confirmed in examination with the bone marrow-derived DCs prepared from -knockout mice. Our study unravels a previously unrecognized phenomenon in which infection with an RNA virus, DENV, activates TLR9 signaling by inducing mtDNA release in human DCs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Infection with the dengue RNA virus activates TLR9 signaling in human dendritic cells

et al. 2018

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“…432 As will be discussed below, flaviviruses deploy countermeasures to many immune mechanisms, and in this case DENV inactivates both cGAS and its downstream effector STING countering their activation of interferon-signaling pathways. 432,433 …”

Section: Antiviral Factorsmentioning

confidence: 99%

Biochemistry and Molecular Biology of Flaviviruses

et al. 2018

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Flaviviruses, such as dengue, Japanese encephalitis, tick-borne encephalitis, West Nile, yellow fever, and Zika viruses, are critically important human pathogens that sicken a staggeringly high number of humans every year. Most of these pathogens are transmitted by mosquitos, and not surprisingly, as the earth warms and human populations grow and move, their geographic reach is increasing. Flaviviruses are simple RNA–protein machines that carry out protein synthesis, genome replication, and virion packaging in close association with cellular lipid membranes. In this review, we examine the molecular biology of flaviviruses touching on the structure and function of viral components and how these interact with host factors. The latter are functionally divided into pro-viral and antiviral factors, both of which, not surprisingly, include many RNA binding proteins. In the interface between the virus and the hosts we highlight the role of a noncoding RNA produced by flaviviruses to impair antiviral host immune responses. Throughout the review, we highlight areas of intense investigation, or a need for it, and potential targets and tools to consider in the important battle against pathogenic flaviviruses.

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“…Several studies have shown that some retroviruses including HIV, murine leukemia virus, and simian immunodeficiency virus can induce a type I IFN response due to recognition of reverse-transcribed DNA by cGAS and subsequent production of cGAMP (Gao et al, 2013a; Lahaye et al, 2013; Rasaiyaah et al, 2013). DENV can antagonize STING signaling by utilizing viral NS2B3 proteases to bind and cleave human STING although this cleavage does not occur in mouse or nonhuman primate STING (Aguirre and Fernandez-Sesma, 2017; Aguirre et al, 2012; Stabell et al, 2018; Yu et al, 2012). HCV has also been shown to antagonize STING signaling, highlighting the multifaceted role of STING in pathogen evasion beyond direct DNA sensing through cGAS (Ding et al, 2013; Maringer and Fernandez-Sesma, 2014; Moriyama et al, 2007; Nitta et al, 2013).…”

Section: Intracellular Recognition Of Dnamentioning

confidence: 99%

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

Matz

Guzman

Goodman

2019

Nucleic Acid Sensing and Immunity - Part B

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Innate immunity, the first line of defense against invading pathogens, is an ancient form of host defense found in all animals, from sponges to humans. During infection, innate immune receptors recognize conserved molecular patterns, such as microbial surface molecules, metabolites produces during infection, or nucleic acids of the microbe’s genome. When initiated, the innate immune response activates a host defense program that leads to the synthesis proteins capable of pathogen killing. In mammals, the induction of cytokines during the innate immune response leads to the recruitment of professional immune cells to the site of infection, leading to an adaptive immune response. While a fully functional innate immune response is crucial for a proper host response and curbing microbial infection, if the innate immune response is dysfunctional and is activated in the absence of infection, autoinflammation and autoimmune disorders can develop. Therefore, it follows that the innate immune response must be tightly controlled to avoid an autoimmune response from host-derived molecules, yet still unencumbered to respond to infection. In this review, we will focus on the innate immune response activated from cytosolic nucleic acids, derived from the microbe or host itself. We will depict how viruses and bacteria activate these nucleic acid sensing pathways and their mechanisms to inhibit the pathways. We will also describe the autoinflammatory and autoimmune disorders that develop when these pathways are hyperactive. Finally, we will discuss gaps in knowledge with regard to innate immune response failure and identify where further research is needed.

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Collateral Damage during Dengue Virus Infection: Making Sense of DNA by cGAS

Cited by 40 publications

References 20 publications

Infection with the dengue RNA virus activates TLR9 signaling in human dendritic cells

Infection with the dengue RNA virus activates TLR9 signaling in human dendritic cells

Biochemistry and Molecular Biology of Flaviviruses

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

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