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Transcriptome Analyses Implicate Endogenous Retroviruses Involved in the Host Antiviral Immune System through the Interferon Pathway.

ABSTRACT: Human endogenous retroviruses (HERVs) are the remains of ancient retroviruses that invaded our ancestors' germline cell and were integrated into the genome. The expression of HERVs has always been a cause for concern because of its association with various cancers and diseases. However, few previous studies have focused on specific activation of HERVs by viral infections. Our previous study has shown that dengue virus type 2 (DENV-2) infection induces the transcription of a large number of abnormal HERVs loci; therefore, the purpose of this study was to explore the relationship between exogenous viral infection and HERV activation further. In this study, we retrieved and reanalyzed published data on 21 transcriptomes of human cells infected with various viruses. We found that infection with different viruses could induce transcriptional activation of HERV loci. Through the comparative analysis of all viral datasets, we identified 43 key HERV loci that were up-regulated by DENV-2, influenza A virus, influenza B virus, Zika virus, measles virus, and West Nile virus infections. Furthermore, the neighboring genes of these HERVs were simultaneously up-regulated, and almost all such neighboring genes were interferon-stimulated genes (ISGs), which are enriched in the host's antiviral immune response pathways. Our data supported the hypothesis that activation of HERVs, probably via an interferon-mediated mechanism, plays an important role in innate immunity against viral infections.

SUBMITTER: Wang M

PROVIDER: S-EPMC8131884 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The global amphibian declines are compounded by infections with members of the Ranavirus genus such as Frog Virus 3 (FV3). Premetamorphic anuran amphibians are believed to be significantly more susceptible to FV3 while this pathogen targets the kidneys of both pre- and postmetamorphic animals. Paradoxically, FV3-challenged Xenopus laevis tadpoles exhibit lower kidney viral loads than adult frogs. Presently, we demonstrate that X. laevis tadpoles are intrinsically more resistant to FV3 kidney infections than cohort-matched metamorphic and postmetamorphic froglets and that this resistance appears to be epigenetically conferred by endogenous retroviruses (ERVs). Using a X. laevis kidney-derived cell line, we show that enhancing ERV gene expression activates cellular double-stranded RNA-sensing pathways, resulting in elevated mRNA levels of antiviral interferon (IFN) cytokines and thus greater anti-FV3 protection. Finally, our results indicate that large esterase-positive myeloid-lineage cells, rather than renal cells, are responsible for the elevated ERV/IFN axis seen in the tadpole kidneys. This conclusion is supported by our observation that CRISPR-Cas9 ablation of colony-stimulating factor-3 results in abolished homing of these myeloid cells to tadpole kidneys, concurrent with significantly abolished tadpole kidney expression of both ERVs and IFNs. We believe that the manuscript marks an important step forward in understanding the mechanisms controlling amphibian antiviral defenses and thus susceptibility and resistance to pathogens like FV3. IMPORTANCE Global amphibian biodiversity is being challenged by pathogens like the Frog Virus 3 (FV3) ranavirus, underlining the need to gain a greater understanding of amphibian antiviral defenses. While it was previously believed that anuran (frog/toad) amphibian tadpoles are more susceptible to FV3, we demonstrated that tadpoles are in fact more resistant to this virus than metamorphic and postmetamorphic froglets. We showed that this resistance is conferred by large myeloid cells within the tadpole kidneys (central FV3 target), which possess an elevated expression of endogenous retroviruses (ERVs). In turn, these ERVs activate cellular double-stranded RNA-sensing pathways, resulting in a greater expression of antiviral interferon cytokines, thereby offering the observed anti-FV3 protection.

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Transcriptome Analyses Implicate Endogenous Retroviruses Involved in the Host Antiviral Immune System through the Interferon Pathway.

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