Animal Models for the Study of Nucleic Acid Immunity: Novel Tools and New Perspectives

Activation of transposable elements (TEs) can cause cellular damage. Cytoplasmic nucleic acid sensing pathways evolved to detect pathogens, but can also serve to cull cells with inappropriate TE activation as TEs can be viral mimetics. Epigenetic silencing of TEs is mediated in part by DNA methylation, but it is not clear if TE activation or the immune system contribute to the cellular damage caused by loss of DNA methylation. Here, we provide mechanistic insight into the observation of an activated interferon response in the liver of zebrafish larvae with deletion in critical components of the DNA methylation machinery, uhrf1 and dnmt1. We focus on dissecting the relationship between DNA methylation, TE activation and induction of an immune response through cytoplasmic DNA and double stranded RNA sensing pathways and identify tnfa as a mediator of cell death in the liver of these mutants. Integrated RNAseq and methylome analysis identified LTR transposons as the most upregulated in these mutants and also the most methylated in control larvae, indicating a direct role of DNA methylation in suppressing this TE subclass. RNAseq analysis from these same samples revealed expression signatures of a type-I interferon response and of tnfa activation, mimicking the pattern of gene expression in virally infected cells. CRISPR/Cas9 mediated depletion of the cellular antiviral sensors sting and mavs reduced expression of interferon response genes and tnfa depletion dramatically reduced cell death in uhrf1 mutant livers. This suggests that the antiviral response induced by DNA hypomethylation and TE activation in the liver is mediated by the signaling pathways activated by both cytoplasmic double stranded RNA and DNA and that tnfa mediates cell death as a potential mechanism to eliminate these damaged cells.

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“…Zebrafish are a powerful and widely used model for studying inflammation and immunity (58). We leveraged these advantages for our studies.…”

Section: Discussionmentioning

confidence: 99%

uhrf1 and dnmt1 Loss Induces an Immune Response in Zebrafish Livers Due to Viral Mimicry by Transposable Elements

et al. 2021

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“…Studies investigating the cell biology of fish viruses have used the zebrafish model extensively [14]. However, in the case of mammalian-tropic viruses, zebrafish embryos are mostly employed to study immune responses as well as pathogenesis, antiviral agent potency, and toxicity [15][16][17][18][19][20][21][22]. This model is also powerful for identification of viral tropism, as it has recently been exemplified for the human norovirus, which can be detected in cells of the hematopoietic lineage and the intestine [16].…”

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confidence: 99%

Tracking Mechanisms of Viral Dissemination In Vivo

Gaudin

Goetz

2021

Trends in Cell Biology

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Dissemination and replication of viruses into hosts is a multistep process where viral particles infect, navigate, and indoctrinate various cell types. Viruses can reach tissues that are distant from their infection site by subverting subcellular mechanisms in ways that are, sometimes, disruptive. Modeling these steps, at appropriate resolution and within animal models, is cumbersome. Yet, mimicking these strategies in vitro fails to recapitulate the complexity of the cellular ecosystem. Here, we will discuss relevant in vivo platforms to dissect the cellular and molecular programs governing viral dissemination and briefly discuss organoid and ex vivo alternatives. We will focus on the zebrafish model and will describe how it provides a transparent window to unravel new cellular mechanisms of viral dissemination in vivo .

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“…In addition to the many direct regulators of the cGAS-STING pathway, alternative receptors such as IFI16 and DNA-PK, may mediate stimulus-specific Interferon responses. Therefore, previously overlooked nucleic acid sensors should be re-examined ( 117 ). In particular, the recently uncovered cooperation between DDR and nucleic acid immunity can be expected to contribute to the health alterations witnessed in patients presenting with chronic inflammation while feeding cancer susceptibility directly.…”

Section: Discussionmentioning

confidence: 99%

Nucleic Acid Immunity and DNA Damage Response: New Friends and Old Foes

et al. 2021

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The maintenance of genomic stability in multicellular organisms relies on the DNA damage response (DDR). The DDR encompasses several interconnected pathways that cooperate to ensure the repair of genomic lesions. Besides their repair functions, several DDR proteins have emerged as involved in the onset of inflammatory responses. In particular, several actors of the DDR have been reported to elicit innate immune activation upon detection of cytosolic pathological nucleic acids. Conversely, pattern recognition receptors (PRRs), initially described as dedicated to the detection of cytosolic immune-stimulatory nucleic acids, have been found to regulate DDR. Thus, although initially described as operating in specific subcellular localizations, actors of the DDR and nucleic acid immune sensors may be involved in interconnected pathways, likely influencing the efficiency of one another. Within this mini review, we discuss evidences for the crosstalk between PRRs and actors of the DDR. For this purpose, we mainly focus on cyclic GMP-AMP (cGAMP) synthetase (cGAS) and Interferon Gamma Inducible Protein 16 (IFI16), as major PRRs involved in the detection of aberrant nucleic acid species, and components of the DNA-dependent protein kinase (DNA-PK) complex, involved in the repair of double strand breaks that were recently described to qualify as potential PRRs. Finally, we discuss how the crosstalk between DDR and nucleic acid-associated Interferon responses cooperate for the fine-tuning of innate immune activation, and therefore dictate pathological outcomes. Understanding the molecular determinants of such cooperation will be paramount to the design of future therapeutic approaches.

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Animal Models for the Study of Nucleic Acid Immunity: Novel Tools and New Perspectives

Cited by 9 publications

References 118 publications

uhrf1 and dnmt1 Loss Induces an Immune Response in Zebrafish Livers Due to Viral Mimicry by Transposable Elements

uhrf1 and dnmt1 Loss Induces an Immune Response in Zebrafish Livers Due to Viral Mimicry by Transposable Elements

Tracking Mechanisms of Viral Dissemination In Vivo

Nucleic Acid Immunity and DNA Damage Response: New Friends and Old Foes

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