The Antiviral Innate Immune Response in Fish: Evolution and Conservation of the IFN System

Forkhead box O (FOXO)3, a member of the FOXO family of transcription factors, plays key roles in various cellular processes, including development, longevity, reproduction, and metabolism. Recently, FOXO3 has also been shown to be involved in modulating the immune response. However, how FOXO3 regulates immunity and the underlying mechanisms are still largely unknown. In this study, we show that zebrafish (Danio rerio) foxo3b, an ortholog of mammalian FOXO3, is induced by polyinosinic-polycytidylic acid stimulation and spring viremia of carp virus (SVCV) infection. We found that foxo3b interacted with irf3 and irf7 to inhibit ifr3/irf7 transcriptional activity, thus resulting in suppression of SVCV or polyinosinic-polycytidylic acid–induced IFN activation. By suppressing expression of key antiviral genes, foxo3b negatively regulated the cellular antiviral response. Furthermore, upon SVCV infection, the expression of the key antiviral genes was significantly enhanced in foxo3b-null zebrafish larvae compared with wild-type larvae. Additionally, the replication of SVCV was inhibited in foxo3b-null zebrafish larvae, leading to a higher survival rate. Our findings suggest that by suppressing irf3/irf7 activity, zebrafish foxo3b negatively regulates the antiviral response, implicating the vital role of the FOXO gene family in innate immunity.

Section: F Orkhead Box O (Foxo) Transcription Factors Homologsmentioning

confidence: 99%

Zebrafish foxo3b Negatively Regulates Antiviral Response through Suppressing the Transactivity of irf3 and irf7

Xing

Cai

Zhang

et al. 2016

“…In zebrafish, four type I IFNs are expressed (IFN-w 1-4). However, only IFN-w1 and IFN-w3 are functional during larval development (30). We took advantage of the transgenic ifnphi1:mCherry reporter line, embryos of which exhibit increased expression of mCherry in a subset of cells following viral infection, reflecting endogenous ifnphi1 expression (21).…”

Section: Knockdown Of Samhd1 Is Associated With Increased Expressionmentioning

confidence: 99%

Characterization of samhd1 Morphant Zebrafish Recapitulates Features of the Human Type I Interferonopathy Aicardi-Goutières Syndrome

Kasher

Jenkinson

Briolat

et al. 2015

Self Cite

In humans, loss of function mutations in the SAMHD1 (AGS5) gene cause a severe form of Aicardi-Goutières syndrome (AGS), an inherited inflammatory-mediated encephalopathy characterized by increased type I IFN activity and upregulation of IFN-stimulated genes (ISGs). In particular, SAMHD1-related AGS is associated with a distinctive cerebrovascular pathology that commonly leads to stroke. Although inflammatory responses are observed in immune cells cultured from Samhd1 null mouse models, these mice are physically healthy, specifically lacking a brain phenotype. We have investigated the use of zebrafish as an alternative system for generating a clinically relevant model of SAMHD1-related AGS. Using temporal gene knockdown of zebrafish samhd1, we observe hindbrain ventricular swelling and brain hemorrhage. Furthermore, loss of samhd1 or of another AGS-associated gene, adar, leads to a significant upregulation of innate immune-related genes and an increase in the number of cells expressing the zebrafish type I IFN ifnphi1. To our knowledge, this is the first example of an in vivo model of AGS that recapitulates features of both the innate immune and neurological characteristics of the disease. The phenotypes associated with loss of samhd1 and adar suggest a function of these genes in controlling innate immune processes conserved to zebrafish, thereby also contributing to our understanding of antiviral signaling in this model organism.

“…Although the IFN system has been found to be conserved in all tetrapods and fishes, gene models of IFNs have not been identified in the amphioxus genome (28,38). By seeking the target genes of amphioxus IRFs, we found that the putative target genes of amphioxus IRFs are mainly involved in innate immunity, cell death, and growth.…”

Section: Amphioxus Irfs Shed Light On the Evolution Of Ifn-based Antimentioning

confidence: 93%

“…For example, the IRF2 homolog identified in pearl oyster (Pinctada fucata) has been found to have similarity with vertebrate IRF1 and is involved in NF-kB activation (26). However, given that type I IFN genes have been found only in vertebrates, IFN-based antiviral responses are apparently not present in invertebrates (27,28), suggesting that the IRF family has an ancient evolutionary origin and arose much earlier than the IFN system (5,29). Thus, it is of interest to investigate the function of invertebrate IRFs in the absence of the IFN system and attempt to understand how the IFN-based antiviral response coevolved with the IRF family after the divergence of vertebrates from invertebrate-like ancestors.…”

mentioning

confidence: 99%

Characterization of Amphioxus IFN Regulatory Factor Family Reveals an Archaic Signaling Framework for Innate Immune Response

Yuan

Zheng

et al. 2015

The IFN regulatory factor (IRF) family encodes transcription factors that play important roles in immune defense, stress response, reproduction, development, and carcinogenesis. Although the origin of the IRF family has been dated back to multicellular organisms, invertebrate IRFs differ from vertebrate IRFs in genomic structure and gene synteny, and little is known about their functions. Through comparison of multiple amphioxus genomes, in this study we suggested that amphioxus contains nine IRF members, whose orthologs are supposed to be shared among three amphioxus species. As the orthologs to the vertebrate IRF1 and IRF4 subgroups, Branchiostoma belcheri tsingtauense (bbt)IRF1 and bbtIRF8 bind the IFN-stimulated response element (ISRE) and were upregulated when amphioxus intestinal cells were stimulated with poly(I:C). As amphioxus-specific IRFs, both bbtIRF3 and bbtIRF7 bind ISRE. When activated, they can be phosphorylated by bbtTBK1 and then translocate into nucleus for target gene transcription. As transcriptional repressors, bbtIRF2 and bbtIRF4 can inhibit the transcriptional activities of bbtIRF1, 3, 7, and 8 by competing for the binding of ISRE. Interestingly, amphioxus IRF2, IRF8, and Rel were identified as target genes of bbtIRF1, bbtIRF7, and bbtIRF3, respectively, suggesting a dynamic feedback regulation among amphioxus IRF and NF-κB. Collectively, to our knowledge we present for the first time an archaic IRF signaling framework in a basal chordate, shedding new insights into the origin and evolution of vertebrate IFN-based antiviral networks.