IIV-6 Inhibits NF-κB Responses in Drosophila

West, Cara C.; Rus, Florentina; Chen, Ying; Kleino, Anni; Gangloff, Monique; Gammon, Don B.; Silverman, Neal S.

doi:10.3390/v11050409

Cited by 15 publications

(9 citation statements)

References 48 publications

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“…Interestingly, however, we find several AMP and IM genes that normally are upregulated in NF-kB-dependent way upon bacterial and fungal infections including the fly microbiota ( Broderick et al 2014 ; Kounatidis et al 2017 ), to be downregulated following FHV infection at both 24- and 48 h p.i., even in aged flies. The role of NF-kB pathways in Drosophila antiviral immunity is complex and still not fully elucidated; however, the pattern of expression that we see here in comparison to Tris-injected controls aligns with previous findings, where infection of S2* cells with the DNA virus IIV-6 leads to downregulation of AMP genes, despite intact cleavage and nuclear translocation of Relish ( West et al 2019 ). In the same study the authors report that although the expression of several AMP genes increases at 12-h post-IIV-6 infection in vivo , in comparison to PBS-injected controls, it returns to baseline or below baseline at 24- and 48 h p.i.…”

Section: Discussionsupporting

confidence: 90%

“…In the same study the authors report that although the expression of several AMP genes increases at 12-h post-IIV-6 infection in vivo , in comparison to PBS-injected controls, it returns to baseline or below baseline at 24- and 48 h p.i. Repression of AMP gene expression following IIV-6 infection appears downstream of Relish and likely occurs at the level of Relish binding to the AMP gene promoter or at the level of transcriptional activation ( West et al 2019 ). Whether in the case of FHV infection in aged flies the strong AMP and IM gene repression is mediated by similar mechanisms will remain a focus of future research.…”

Section: Discussionmentioning

confidence: 99%

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Age-dependent impairment of disease tolerance is associated with a robust transcriptional response following RNA virus infection in Drosophila

Sheffield

Sciambra

Evans

et al. 2021

G3 Genes|Genomes|Genetics

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Advanced age in humans is associated with greater susceptibility to and higher mortality rates from infections, including infections with some RNA viruses. The underlying innate immune mechanisms, which represent the first line of defense against pathogens, remain incompletely understood. Drosophila melanogaster is able to mount potent and evolutionarily conserved innate immune defenses against a variety of microorganisms including viruses and serves as an excellent model organism for studying host-pathogen interactions. With its relatively short lifespan, Drosophila also is an organism of choice for aging studies. Despite numerous advantages that this model offers, Drosophila has not been used to its full potential to investigate the response of the aged host to viral infection. Here we show that, in comparison to younger flies, aged Drosophila succumb more rapidly to infection with the RNA-containing Flock House Virus (FHV) due to an age-dependent defect in disease tolerance. Relative to younger individuals, we find that older Drosophila mount transcriptional responses characterized by differential regulation of more genes and genes regulated to a greater extent. We show that loss of disease tolerance to FHV with age associates with a stronger regulation of genes involved in apoptosis, some genes of the Drosophila Immune deficiency (IMD) NF-kB pathway and genes whose products function in mitochondria and mitochondrial respiration. Our work shows that Drosophila can serve as a model to investigate host-virus interactions during aging and furthermore sets the stage for future analysis of the age-dependent mechanisms that govern survival and control of virus infections at older age.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Age-dependent impairment of disease tolerance is associated with a robust transcriptional response following RNA virus infection in Drosophila

Sheffield

Sciambra

Evans

et al. 2021

G3 Genes|Genomes|Genetics

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“…Therefore, it is possible that PQ-mediated activation of Relish and AMP expression might be regulated through an alternative noncanonical pathway as observed in ATM mutants 30 . A recent study demonstrated that Relish becomes activated in response to infection with the invertebrate iridescent virus 6 (IIV6) and that its translocation to the nucleus results in suppression of AMPs gene expression 75 . The failure of active Relish to induce downstream AMP gene expression upon PQ exposure suggests that transcriptional inhibition could occur at the promoter-binding site.…”

Section: Discussionmentioning

confidence: 99%

Innate immune responses to paraquat exposure in a Drosophila model of Parkinson’s disease

Maitra

Scaglione

Chtarbanova

et al. 2019

Sci Rep

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Parkinson’s disease (PD) is a progressive, neurodegenerative movement disorder characterized by the loss of dopaminergic (DA) neurons. Limited understanding of the early molecular pathways associated with the demise of DA neurons, including those of inflammatory exacerbation of neurodegeneration, is a major impediment to therapeutic development. Recent studies have implicated gene-environment interactions in PD susceptibility. We used transcriptomic profiling in a Drosophila PD model in response to paraquat (PQ)-induced oxidative stress to identify pre-symptomatic signatures of impending neuron dysfunction. Our RNAseq data analysis revealed extensive regulation of innate immune response genes following PQ ingestion. We found that PQ exposure leads to the activation of the NF-κB transcription factor, Relish, and the stress signaling factor JNK, encoded by the gene basket in Drosophila . Relish knockdown in the dopaminergic neurons confers PQ resistance and rescues mobility defects and DA neuron loss. Furthermore, PQ-induced toxicity is mediated through the immune deficiency signaling pathway. Surprisingly, the expression of Relish-dependent anti-microbial peptide (AMPs) genes is suppressed upon PQ exposure causing increased sensitivity to Gram-negative bacterial infection. This work provides a novel link between PQ exposure and innate immune system modulation underlying environmental toxin-induced neurodegeneration, thereby underscoring the role of the innate immune system in PD pathogenesis.

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“…IIV6 infection has also been shown to supress the induction of a large number of NF-κB-regulated genes associated with both the Toll and IMD pathways in S2* cells, with only a modest and transient induction of AMPs and a greater susceptibility to bacterial infection observed in flies in vivo [92]. This immune evasion appeared to be mediated by an immediate-early gene product [92].…”

Section: Viral Nf-κb Evasion In D Melanogastermentioning

confidence: 99%

The antiviral role of NF-κB-mediated immune responses and their antagonism by viruses in insects

Cheung

Park

Pagtalunan

et al. 2022

Journal of General Virology

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The antiviral role of innate immune responses mediated by the NF-κB family of transcription factors is well established in vertebrates but was for a long time less clear in insects. Insects encode two canonical NF-κB pathways, the Toll and Imd (‘immunodeficiency’) pathways, which are best characterised for their role in antibacterial and antifungal defence. An increasing body of evidence has also implicated NF-κB-mediated innate immunity in antiviral responses against some, but not all, viruses. Specific pattern recognition receptors (PRRs) and molecular events leading to NF-κB activation by viral pathogen-associated molecular patterns (PAMPs) have been elucidated for a number of viruses and insect species. Particularly interesting are recent findings indicating that the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway detects viral RNA to activate NF-κB-regulated gene expression. We summarise the literature on virus-NF-κB pathway interactions across the class Insecta, with a focus on the dipterans Drosophila melanogaster and Aedes aegypti. We discuss potential reasons for differences observed between different virus-host combinations, and highlight similarities and differences between cGAS-STING signalling in insects versus vertebrates. Finally, we summarise the increasing number of known molecular mechanisms by which viruses antagonise NF-κB responses, which suggest that NF-κB-mediated immunity exerts strong evolutionary pressures on viruses. These developments in our understanding of insect antiviral immunity have relevance to the large number of insect species that impact on humans through their transmission of human, livestock and plant diseases, exploitation as biotechnology platforms, and role as parasites, pollinators, livestock and pests.

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IIV-6 Inhibits NF-κB Responses in Drosophila

Cited by 15 publications

References 48 publications

Age-dependent impairment of disease tolerance is associated with a robust transcriptional response following RNA virus infection in Drosophila

Age-dependent impairment of disease tolerance is associated with a robust transcriptional response following RNA virus infection in Drosophila

Innate immune responses to paraquat exposure in a Drosophila model of Parkinson’s disease

The antiviral role of NF-κB-mediated immune responses and their antagonism by viruses in insects

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