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Unexpected Discovery and Expression of Amphibian Class II Endogenous Retroviruses.

ABSTRACT: Endogenous retroviruses (ERVs) are the remnants of past retroviral infections. Fossil records of class II retroviruses have been discovered in a range of vertebrates, with the exception of amphibians, which are known only to possess class I and class III-like ERVs. Through genomic mining of all available amphibian genomes, we identified, for the first time, class II ERVs in amphibians. The class II ERVs were found only in Gymnophiona (caecilians) and not in the genomes of the other amphibian orders, Anura (frogs and toads) and Caudata (salamanders and newts), which are phylogenetically closely related. Therefore, the ERV endogenization occurred after the split of Gymnophiona, Anura, and Caudata (323 million years ago). Investigation of phylogenetic relationship and genomic structure revealed that the ERVs may originate from alpha- or betaretroviruses. We offer evidence that class II ERVs infiltrated amphibian genomes recently and may still have infectious members. Remarkably, certain amphibian class II ERVs can be expressed in diverse tissues. This discovery closes the major gap in the retroviral fossil record of class II ERVs and provides important insights into the evolution of class II ERVs in vertebrates.IMPORTANCE Class II retroviruses, largely distributed among mammals and birds, are of particular importance for medicine and economics. Class II ERVs have been discovered in a range of vertebrates, with the exception of amphibians, which are known only to possess class I and class III-like ERVs. Here, for the first time, we discovered class II ERVs in amphibians. We also revealed that the ERVs may originate from alpha- or betaretroviruses. We revealed that class II ERVs were integrated into amphibian genomes recently and certain amphibian class II ERVs can be expressed in diverse tissues. Our discovery closes the major gap in the retroviral fossil record of class II ERVs, and also indicates that amphibians may be still infected by class II retroviruses.

SUBMITTER: Chen M

PROVIDER: S-EPMC7925117 | 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.

Project description:Endogenous retroviruses (ERVs) occupy a substantial fraction of mammalian genomes. However, whether ERVs extensively exist in ancient vertebrates remains unexplored. Here, we performed a genome-wide characterization of ERVs in a zebrafish (Danio rerio) model. Approximately 3,315 ERV-like elements (DrERVs) were identified as Gypsy, Copia, Bel, and class I-III groups. DrERVs accounted for approximately 2.3% of zebrafish genome and were distributed in all 25 chromosomes, with a remarkable bias on chromosome 4. Gypsy and class I are the two most abundant groups with earlier insertion times. The vast majority of the DrERVs have varied structural defects. A total of 509 gag and 71 env genes with coding potentials were detected. The env-coding elements were well-characterized and classified into four subgroups. A ERV-E4.8.43-DanRer element shows high similarity with HERV9NC-int in humans and analogous sequences were detected in species spanning from fish to mammals. RNA-seq data showed that hundreds of DrERVs were expressed in embryos and tissues under physiological conditions, and most of them exhibited stage and tissue specificity. Additionally, 421 DrERVs showed strong responsiveness to virus infection. A unique group of DrERVs with immune-relevant genes, such as fga, ddx41, ftr35, igl1c3, and tbk1, instead of intrinsic viral genes were identified. These DrERVs are regulated by transcriptional factors binding at the long terminal repeats. This study provided a survey of the composition, phylogeny, and potential functions of ERVs in a fish model, which benefits the understanding of the evolutionary history of ERVs from fish to mammals. IMPORTANCE Endogenous retroviruses (ERVs) are relics of past infection that constitute up to 8% of the human genome. Understanding the genetic evolution of the ERV family and the interplay of ERVs and encoded RNAs and proteins with host function has become a new frontier in biology. Fish, as the most primitive vertebrate host for retroviruses, is an indispensable integral part for such investigations. In the present study, we report the genome-wide characterization of ERVs in zebrafish, an attractive model organism of ancient vertebrates from multiple perspectives, including composition, genomic organization, chromosome distribution, classification, phylogeny, insertion time, characterization of gag and env genes, and expression profiles in embryos and tissues. The result helps uncover the evolutionarily conserved and fish-specific ERVs, as well as the immune-relevant ERVs in response to virus infection. This study demonstrates the previously unrecognized abundance, diversification, and extensive activity of ERVs at the early stage of ERV evolution.

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Unexpected Discovery and Expression of Amphibian Class II Endogenous Retroviruses.

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