Cyprinid Herpesvirus 3 Il10 Inhibits Inflammatory Activities of Carp Macrophages and Promotes Proliferation of Igm+ B Cells and Memory T Cells in a Manner Similar to Carp Il10

Abstract

Cyprinid herpesvirus 3 (CyHV-3) is the causative agent of a lethal disease of carp and encodes for an Il10 homolog (ORF134). Our previous studies with a recombinant ORF134-deleted strain and the derived revertant strain suggested that cyprinid herpesvirus 3 Il10 (CyHV-3 Il10 [cyhv3Il10]) is not essential for viral replication in vitro, or virulence in vivo. In apparent contrast, cyhv3Il10 is one of the most abundant proteins of the CyHV-3 secretome and is structurally very similar to carp Il10 and also human IL10. To date, studies addressing the biological activity of cyhv3Il10 on cells of its natural host have not been performed. To address the apparent contradiction between the presence of a structurally conserved Il10 homolog in the genome of CyHV-3 and the lack of a clear phenotype in vivo using recombinant cyhv3Il10-deleted viruses, we used an in vitro approach to investigate in detail whether cyhv3Il10 exerts any biological activity on carp cells. In this study, we provide direct evidence that cyhv3Il10 is biologically active and, similarly to carp Il10, signals via a conserved Stat3 pathway modulating immune cells of its natural host, carp. In vitro, cyhv3Il10 deactivates phagocytes with a prominent effect on macrophages, while also promoting proliferation of Igm+ B cells and memory T cells. Collectively, this study demonstrates a clear biological activity of cyhv3Il10 on cells of its natural host and indicates that cyhv3Il10 is a true viral ortholog of carp Il10. Furthermore, to our knowledge, this is the first report on biological activities of a nonmammalian viral Il10 homolog.

What goes around comes around: an investigation of resistance to proliferative kidney disease in rainbow trout Oncorhynchus mykiss (Walbaum) following experimental re‐exposure

“…; Piazzon et al . ,b). In both groups, when IL‐10 was expressed, there was no major signs of innate response and IgM sec was upregulated in both groups.…”

The Function of Fish Cytokines

“…It exists as a single copy gene for most species but duplicated copies are present in rainbow trout. The herpesviruses of European eel and Koi carp also encode an IL-10 homologue [ 273 , 274 , 275 ].…”

“…A viral homologue of IL-10 has been identified recently in the Koi herpesvirus (Khv) genome and characterised functionally [ 273 , 274 , 275 ]. It has moderate homology with carp IL-10, and has a predicted signal peptide, but is not essential for viral replication in vitro or virulence in vivo [ 275 ].…”

“…The KhvIL-10 increases the number of lyz+ cells when injected into zebrafish embryos, similar to the effect seen with zebrafish IL-10, and this activity can be inhibited by co-injection with IL-10R1 morpholinos [ 274 ]. A recent study has extended the functional analysis where the KhvIL-10 is shown to exert overlapping functions with the host IL-10, as an anti-inflammatory factor via the STAT3 signalling pathway [ 273 ]. These data demonstrate that fish herpesviruses produce a functional IL-10 analogue to suppress the host immune response to establish infections.…”

Transcriptomic analysis of common carp anterior kidney during Cyprinid herpesvirus 3 infection: Immunoglobulin repertoire and homologue functional divergence

“…A particularly interesting group of ORFs seems to have evolved to evade the host’s immune response. These include a functional Interleukin-10 (IL-10), known as khvIL-10, which is homologous to the carp’s own IL-10 and may mediate an immunosuppression mechanism 12 13 14 . Moreover, ORF12 and ORF4 are viral homologues of tumor necrosis factor receptors (TNFRs), which are often used by large DNA viruses to regulate host immune responses 15 16 .…”