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IFN-Stimulated Genes in Zebrafish and Humans Define an Ancient Arsenal of Antiviral Immunity

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IFN-Stimulated Genes in Zebrafish and Humans Define an Ancient Arsenal of Antiviral Immunity IFN-Stimulated Genes in Zebrafish and Humans Define an Ancient Arsenal of Antiviral Immunity This information is current as Jean-Pierre Levraud, Luc Jouneau, Valérie Briolat, Valerio of September 23, 2021. Laghi and Pierre Boudinot J Immunol published online 15 November 2019 http://www.jimmunol.org/content/early/2019/11/14/jimmun ol.1900804 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2019/11/15/jimmunol.190080 Material 4.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 23, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published November 15, 2019, doi:10.4049/jimmunol.1900804 The Journal of Immunology IFN-Stimulated Genes in Zebrafish and Humans Define an Ancient Arsenal of Antiviral Immunity Jean-Pierre Levraud,* Luc Jouneau,† Vale´rie Briolat,* Valerio Laghi,* and Pierre Boudinot† The evolution of the IFN system, the major innate antiviral mechanism of vertebrates, remains poorly understood. According to the detection of type I IFN genes in cartilaginous fish genomes, the system appeared 500 My ago. However, the IFN system integrates many other components, most of which are encoded by IFN-stimulated genes (ISGs). To shed light on its evolution, we have used deep RNA sequencing to generate a comprehensive list of ISGs of zebrafish, taking advantage of the high-quality genome annotation in this species. We analyzed larvae after inoculation of recombinant zebrafish type I IFN, or infection with chikungunya virus, a potent IFN inducer. We identified more than 400 zebrafish ISGs, defined as being either directly induced by IFN or induced by the virus in an IFNR-dependent manner. Their human orthologs were highly enriched in ISGs, particularly for Downloaded from highly inducible genes. We identified 72 orthology groups containing ISGs in both zebrafish and humans, revealing a core ancestral ISG repertoire that includes most of the known signaling components of the IFN system. Many downstream effectors were also already present 450 My ago in the common ancestor of tetrapods and bony fish and diversified as multigene families independently in the two lineages. A large proportion of the ISG repertoire is lineage specific; around 40% of protein-coding zebrafish ISGs had no human ortholog. We identified 14 fish-specific gene families containing multiple ISGs, including finTRIMs. This work illuminates the evolution of the IFN system and provides a rich resource to explore new antiviral mechanisms. http://www.jimmunol.org/ The Journal of Immunology, 2019, 203: 000–000. ll living organisms are targeted by viruses, and evolution containing recognizable type I IFN genes (4, 5), suggesting that has given rise to various antiviral strategies. Vertebrates this system appeared ∼500 My ago with jawed vertebrates. The A possess many unique immune features, including their IFN system integrates many components, most of which are principal innate antiviral system based on signaling by type I encoded by ISGs, which can be traced back in genomes from IFNs. Type I IFNs induce the expression of hundreds of proteins distant clades. However, finding the ortholog(s) of a human ISG in encoded by IFN-stimulated genes (ISGs), making cells refrac- another taxon does not imply that this gene is part of its IFN system. by guest on September 23, 2021 tory to viral infection (1). The origin of the IFN system, which To understand the evolution of antiviral immunity, it is therefore seems to have replaced the RNA interference antiviral system still desirable to establish how the repertoire of ISGs changed from early used by plants and most invertebrates (2, 3), is shrouded in to modern vertebrates. This can be inferred by comparing the ISGs mystery. Cartilaginous fish are the most basal clade with genomes of current living representatives of distant vertebrate taxa. Bony fishes (hereafter simply called fish) diverged from the tetrapod lineage ∼450 My ago, and because viral infections are a *Macrophages et De´veloppement de l’Immunite´, Institut Pasteur, CNRS UMR3738, 75015 Paris, France; and †Institut National de la Recherche Agronomique, Virologie major problem in aquaculture, their IFN system has been the et Immunologie Mole´culaires, Universite´ Paris-Saclay, 78352 Jouy-en-Josas, France subject of many studies, as reviewed in Ref. 6–9. Teleost fish ORCIDs: 0000-0001-6775-2416 (J.-P.L.); 0000-0003-0726-073X (V.L.). possess several subgroups of type I IFNs (but no type III genes), Received for publication July 12, 2019. Accepted for publication October 8, 2019. with strong variation in gene numbers among fish taxa (8). The This work was supported by Agence Nationale de la Recherche Project Fish-RNAvax zebrafish possess four type I IFN genes, named ifnphi1-4; only (Grants ANR-16-CE20-0002-02 and ANR-16-CE20-0002-03) and the European Union ifnphi1 and ifnphi3 are active at the larval stage (10). Their re- Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie ceptors have been identified (10). Even before fish IFNs were Grant Agreement 721537–ImageInLife. known, the first fish ISGs were identified by homology cloning The sequences presented in this article have been submitted to BioProject National Center for Biotechnology Information (https://www.ncbi.nlm.nih.gov/bioproject) un- from cells stimulated by poly(I:C) (11) or by differential transcript der the Sequence Read Archive accession number PRJNA531581. analysis of cells infected by viruses (12, 13). Because many virus- Address correspondence and reprint requests to Dr. Jean-Pierre Levraud or Dr. Pierre induced genes (vig) were homologous to well-known mammalian Boudinot, Macrophages et De´veloppement de l’Immunite´, Institut Pasteur, CNRS ISGs, they were hypothesized to be IFN inducible, which was often UMR3738, 25 Rue du Docteur Roux, 75015 Paris, France (J.-P.L.) or Institut National de la Recherche Agronomique, Virologie et Immunologie Mole´culaires, confirmed by later studies, as in the case of vig-1,thersad2/viperin Universite´ Paris-Saclay, Alle´e de Vilvert, 78352 Jouy-en-Josas, France (P.B.). ortholog (12, 14). Similarly, upon cloning of fish IFNs, induction E-mail addresses: [email protected] (J.-P.L.) or [email protected] (P.B.) of Mx (11) was used as a readout for their activity (15–17), con- The online version of this article contains supplemental material. firming it was an ISG. The list of fish homologs of known ISGs Abbreviations used in this article: ADAR, adenosine deaminase acting on dsRNA; rapidly grew with the release of new fish genomes and expressed btr, bloodthirsty-like TRIM; CHIKV, chikungunya virus; dpf, day postfertilization; FC, fold change; hpi, hour postinfection; ISG, IFN-stimulated gene; LCATT, last sequence tag (EST) collections, allowing the development of common ancestor of teleosts and tetrapods; PARP, poly (ADP-ribose) polymerase; microarrays to study fish response to virus or recombinant type I PKR, protein kinase R; qRT-PCR, quantitative RT-PCR; RNAseq, RNA sequencing; IFNs (18, 19). Candidate gene approaches were also developed, vig, virus-induced gene. testing orthologs of known mammalian ISGs in quantitative Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 RT-PCR (qRT-PCR) assays in multiple fish infection models www.jimmunol.org/cgi/doi/10.4049/jimmunol.1900804 2 COMPARING ISG REPERTOIRES OF ZEBRAFISH AND HUMANS (14, 20, 21). In parallel, approaches without a priori identified fish morpholino (59-CGCCAAGATCATACCTGTAAAGTAA-39) was injected ISGs that had no ortholog in mammals, although they belonged together with 2 ng of crfb2 splice morpholino (59-CTATGAATCCT- 9 to gene families involved in antiviral immunity. A large set of CACCTAGGGTAAAC-3 ), knocking down all type I IFNR (10). Control morphants were injected with 4 ng of control morpholino (59-GAA- tripartite-motif protein–encoding genes, called fintrims (ftr), dis- AGCATGGCATCTGGATCATCGA-39) with no known target. tantly related to trim25 was identified in rainbow trout cells as a induced by virus infection (13) and later shown to form multigene RNA extraction families in teleosts, particularly extensive in zebrafish (22). Simi- For RNAseq analysis, total RNA was extracted from replicate pools of larly, a family of IFN-induced ADP-ribosyltransferases named gig2 10 injected larvae (at 6 h postinjection for IFNw1 treatment, or 24 h was identified in crucian carp cells treated with UV-inactivated postinjection for CHIKV infections), using TRIzol (Invitrogen), following the manufacturer’s protocol. The integrity of the RNA was confirmed by grass carp hemorrhage virus (23, 24). Some ISG were restricted laboratory-on-chip analysis using the 2100 Bioanalyzer (Agilent Tech- to particular fish groups, such as the noncoding RNA vig-2 that is nologies),
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