New Insights into the Evolution of IFNs: Zebrafish Group II IFNs Induce a Rapid and Transient Expression of IFN-Dependent Genes and Display Powerful Antiviral Activities

Abstract

The IFNs and their receptors have existed in early chordates for ∼500 million years and represent the early elements in innate and adaptive immunity. Both types I and II IFNs have been discovered in fish, and type I has recently been classified into two groups based on their primary protein sequences. However, the biological activities of fish IFNs and their roles in infection are largely unknown. Using the zebrafish and manageable bacterial (Streptococcus iniae) and viral (spring viremia of carp virus) infection models, we are reporting in this study that zebrafish IFN (zfIFN) γ failed to induce antiviral and proinflammatory genes when administered in vivo, which correlates with its inability to protect the fish against bacterial and viral infections. We also found that, although both group I (i.e., zfIFN1) and group II zfIFNs (i.e., zfIFN2 and zfIFN3) displayed strong in vivo antiviral activities, only group I zfIFN was able to protect the fish against bacterial infection, which may reflect the different patterns and kinetics of immune-related genes elicited by these two groups of IFNs. Thus, group II zfIFNs induced a rapid and transient expression of antiviral genes, whereas group I zfIFN exerted a slow but more powerful induction of several antiviral and proinflammatory genes. Collectively, our results suggest nonredundant, complementary roles of type I zfIFNs in viral infections and provide evidence for a pivotal role of the recently identified group II IFN of fish in the early stages of viral infections.

Fish virus-induced interferon exerts antiviral function through Stat1 pathway

“…Recently virus-induced IFN genes have been cloned in some teleost fish and their antiviral activities have been proved in vitro and in vivo (Altmann et al, 2003;Long et al, 2004;Lopez-Munoz et al, 2009;Lutfalla et al, 2003;Ooi et al, 2008;Robertsen et al, 2003;Zou et al, 2007). In the present study, using gain-of-and loss-of-function experiments, we demonstrated that fish IFN confers a strong resistance to virus infection through induction of a set of conserved ISGs and, importantly, IFN upregulates ISGs and itself through Stat1 pathway.…”

“…Therefore, some authors suggest a new name, IFN s, for fish virus-induced IFN (Stein et al, 2007). However, it is obvious that fish virus-induced IFNs are classified into two groups , which display powerful and complementary antiviral activities (Lopez-Munoz et al, 2009). The discrepancy between the two groups has been verified further by analysis of receptor usage (Aggad et al, 2009).…”

Regulation of immunity and disease resistance by commensal microbes and chromatin modifications during zebrafish development

“…We next evaluated the disease resistance of CONR and GF zebrafish larvae at 72 hpf using a spring viremia of carp virus (SVCV) infection model (43) in which the virus is cleared by the IFN system (43,44). Interestingly, the naturally primed CONR group showed increased resistance to SVCV as compared with GF larvae (Fig.…”

Fish viperin exerts a conserved antiviral function through RLR-triggered IFN signaling pathway

“…In zebrafish, there are four members of type I IFNs (Aggad et al, 2009;Lopez-Munoz et al, 2009), and two members of type II IFNs, IFNc1 and IFNc2 (Igawa et al, 2006;Sieger et al, 2009). Previously we confirmed both types of zebrafish IFNs activate zebrafish IRF9 promoter in epithelioma papulosum cyprini cells (EPC) (Shi et al, 2013).…”

“…For example, zebrafish Danio rerio genome has four IFNu genes (DrIFNu1/ 2/3/4, or named DrIFN1/2/3/4) most similar to mammalian type I IFN, and two IFNc genes (DrIFNc1/2) orthologous to mammalian type II IFN (Aggad et al, 2009;Lopez-Munoz et al, 2009;Sieger et al, 2009). To determine whether two types of fish IFNs could induce crucian carp viperin expression, the roles of these zebrafish IFNs in activation of crucian carp viperin promoter and induction of viperin mRNA and proteins were investigated.…”