Insights into the antiviral immunity against grass carp (Ctenopharyngodon idella) reovirus (GCRV) in grass carp

Abstract

Global fish production from aquaculture has rapidly grown over the past decades, and grass carp shares the largest portion. However, hemorrhagic disease caused by grass carp reovirus (GCRV) results in tremendous loss of grass carp (Ctenopharyngodon idella) industry. During the past years, development of molecular biology and cellular biology technologies has promoted significant advances in the understanding of the pathogen and the immune system. Immunoprophylaxis based on stimulation of the immune system of fish has also got some achievements. In this review, authors summarize the recent progresses in basic researches on GCRV; viral nucleic acid sensors, high-mobility group box proteins (HMGBs); pattern recognition receptors (PRRs), Toll-like receptors (TLRs) and retinoic acid inducible gene I- (RIG-I-) like receptors (RLRs); antiviral immune responses induced by PRRs-mediated signaling cascades of type I interferon (IFN-I) and IFN-stimulated genes (ISGs) activation. The present review also notices the potential applications of molecule genetic markers. Additionally, authors discuss the current preventive and therapeutic strategies (vaccines, RNAi, and prevention medicine) and highlight the importance of innate immunity in long term control for grass carp hemorrhagic disease.

Figure 1

Antiviral immune response of HMGBs induced by GCRV infection in CIK cells. GCRV infection induces diverse nucleocytoplasmic shuttling of grass carp HMGBs via two main methods: (1) upon GCRV infection, some HMGBs such as HMGB1a, HMGB1b, HMGB2b, and HMGB3a shuttle from nucleus to cytoplasm. Subsequently, a huge member of cells subject to apoptosis or karyotheca rupture, which result in cells death and passive release of HMGBs. On the other hand, some live cells can also actively secrete HMGBs to extracellular space; (2) even though GCRV fail to evoke nuclear exports of some HMGBs such as HMGB2a and HMGB3b, but the cells will undergo necrosis or damage. So those HMGBs are released to the extracellular matrix. Afterwards, the extracellular HMGBs initiate activation of TLRs- and RLRs-mediated antiviral immunity of neighboring cells.

Figure 2

Schematic overview of intracellular antiviral immune signaling in teleosts. Fishes have conserved intercellular PRRs to sense virus or viral PAMPs. TLR3 and TLR22 sense dsRNA and transmit signals to the downstream adaptor IRIF; endosome localized TLR7/8 and TLR9 recognize ssRNA and CpG DNA, respectively, and then deliver signal to MyD88. Like mammalian RLRs, RIG-I and MDA5 recognize dsRNA or ssRNA in different length and activate mitochondrion IPS-1. With no CARD domain, LGP2 is thought to fail to interact with IPS-1 but can transmit signal to TBK1. Studies also indicate that LGP2 can mediate signals of RIG-I and MDA5. Fish MITA localizes in ER, but it is in close vicinity with IPS-1 in mitochondrial-ER contact regions. MITA participates in antiviral activation of IFN or ISGs downstream of RIG-I and MDA5 through MITA-TBK1-IRF3 pathway. TRIF and IPS-1 transfer signal through NF-κB and TBK1-IRF3/7-IFN-I pathway. MyD88 signal activates IRF3/7 and NF-κB, not TBK1. Upon phosphorylation, IRF3 and IRF7 transmit to nucleus and induce the production of IFN-I which induces antiviral immune response along with the activated ISGs. The activated NF-κB also transmits to nucleus initiating the activation of proinflammatory cytokines. Cytoplasmic HMGBs can promiscuously sense immunogenic nucleic acid and delivery to the discriminative sensors: TLRs and RLRs.