1. Introduction
Aquatic viruses have been an essential part of the biosphere, and also a part of human and aquatic 3 animal lives. The virus-host interactions are ubiquitous on earth [1]. There are many aquatic 4 animals with more aquatic animal viruses, which have caused enormous harms to the aquaculture 5 development and water environment, and threaten global food security [2-4]. Although several 6 methods have been used in the virus prevention and control, it is still difficult in treatment of these 7 diseases [5].
Battles between host and virus determine whether or not the disease occurs. Host can 8 fight against virus with its immune system. The virus could resist or escape from host immune 9 system [6, 7]. If the latter occurs, the disease would happen. Compared with higher animals, the 10 aquatic animals have relative lower evolved immune system, which would benefit the virus 11 invading.
Information about virus-host interactions may give us inspiration in virus treatment, 12 which has attracted more and more attentions. 13 The host recognize viral components which is called pathogen-associated molecular patterns 14 (PAMPs) with pattern recognition receptors (PRRs). After recognition of PAMPs, several signal 15 cascades in host will be activated [8-10]. Ultimately, a lot of antiviral responses such as 16 inflammatory responses, interferon (IFN) responses, regulated cell death, and adaptive immune 17 responses will be induced.
Although these responses have been defined in mammals, researches on 18 the antiviral responses of several important aquatic animals such as Atlantic salmon, common carp, 19 gibel carp, grass carp, grouper, rainbow trout, and shrimp have been carried out in past several years 20 [11-18]. 21 Various antiviral responses have been revealed [19-22].
How they are overcome by different viruses? Here, we select twenty three strains of aquatic animal viruses which represent great harms to aquatic animals. The viruses belong to six families including three kinds of DNA viruses and three kinds of RNA viruses. They could utilize viral elements including their genes, gene products, and miRNAs to resist and escape from host immune systems (Table 1), which were known as immune evasion strategies. We focus on the viral elements and their targeted host molecular or pathways.
The three kinds of DNA viruses are briefly introduced as follows: (i) The herpesviruses (family 29 Alloherpesviridae), such as cyprinid herpesvirus 1 (CyHV-1), cyprinid herpesvirus 2 (CyHV-2), and 30 cyprinid herpesvirus 3 (CyHV-3, also known as Koi herpesvirus, KHV), which infect fish have gained more and more research interest in the past decade [23, 24]. Although host responses 2 including innate and adaptive immune responses have been reported in herpesvirus infected fish [12, 3 25, 26], knowledge on the herpesvirus mediated immune evasion is limited and mainly focus on the 4 virus encoded host homologous proteins (Table 1). (ii) Members of the family Iridoviridae have 5 been reported to cause high mortalities and threats in aquaculture or wild animals [27-29]. The 6 molecular and immunological events in ranavirus (genus Ranavirus, family Iridoviridae) replication 7 have been reported by researchers [30]. It is a remarkable fact that the interspecies infection or 8 transmission have occurred in ranaviruses [31-33].
Recent study on the transcriptomic responses of 9 Chinese giant salamander under different ranaviruses infection revealed the divergent host 10 responses and virus yields [34], which hinted the importance of virus mediated immune evasion. (iii) 11 Viruses in the family Nimaviridae have been isolated only from invertebrates. The type species is 12 White spot syndrome virus (WSSV), which has caused massive mortality and great loss in the 13 shrimp cultivation industry [35]. Recently, a nimavirus Procambarus clarkii virus (PCV) was 14 isolated from spontaneously infected crayfish (Genbank accession number: MH663976). Based 15 on the genomic comparison, the PCV 96R is predicted to encode a protein with high homologue to 16 WSSV VP38, which has anti-apoptosis activity. Several viral elements including gene, protein, and 17 miRNA are utilized by WSSV to modulate the shrimp antiviral responses. 18 The other three kinds of RNA viruses are as follows: (i) Birnaviruses from fish, molluscs, and 19 crustaceans are belonged to the genus Aquabirnavirus (Birnaviridae) and have double-stranded 20 RNA (dsRNA) genome with two linear segments [36, 37].
Anti-IFN induced responses and 21 anti-apoptosis have been reported in aquabirnaviruses. (ii) Another aquatic animal virus containing 22 dsRNA genome belongs to the Reoviridae, which contain 9 to 12 segments of linear dsRNA 23 segments [38]. Aquareoviruses constitute the genus Aquareovirus, which have been isolated from a 24 wide variety of aquatic animals [38-42]. Recently, the most noticed virus in Aquareovirus is the 25 grass carp reovirus (GCRV), which caused pandemic grass carp hemorrhagic disease in China and 26 East Asia. Although the virus-induced responses of grass carp from gene level to transcriptome 27 level, immunoprotection, and the immunogenicity of its proteins have been reported by several 28 researchers [43-48], the immune evasion mechanisms of GCRV is still limited. (iii) Genome of 29 rhabdoviruses (family Rhabdoviridae) are negative-sense, single-stranded RNA (ssRNA), which 30 encodes five structural proteins (N, P, M, G, and L) [49, 50]. Some rhabdoviruses including Scophthalmus maximus rhabdovirus (SMRV) and Paralichthys olivaceus rhabdovirus also encode 2 other proteins [51, 52]. It has been reported that infection of rhabdovirus such as Infectious 3 hematopoietic necrosis virus (IHNV) and SMRV induced host antiviral responses including immune 4 signaling and apoptosis [53-56]. However, viral proteins have important functions in rhabdovirus 5 mediated immune evasions. In addition, antibodies or vaccines with gene or protein have showed 6 significant protection effect against rhabdovirus infection [57-59], which revealed the 7 immunogenicity of the proteins. 8 Above mentioned viruses possess various interactions between viral elements and their targets to 9 escape from host antiviral responses (Table 1). The main representative immune evasion strategies 10 are described. It is a comprehensive summary on immune evasion around multiple groups of viruses 11 based on research advances of recent years.
2. Virus recognition and signal transduction
2.1 Virus recognition by innate immune system
Upon virus infection, the host recognize the non-natural components and develop a series of 16 responses such as type I interferon (IFN) response and regulated cell death to fight against the 17 invader. The first defense line of host is the innate immunity [8, 9], which recognizes the PAMPs 18 with PRRs.
PAMPs of virus include viral proteins, dsRNA, ssRNA, and double-stranded DNA (dsDNA). Among them, nucleic acids have been considered as the major object for innate immune 20 recognition [9]. Currently known PRRs that recognize viral nucleic acids and are involved in the 21 present review contain Toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I) -like 22 receptors (RLRs), and cytosolic DNA sensors. 23 TLRs are a large family of proteins with an extracellular leucine-rich-repeat domain, a 24 transmembrane domain, and a cytosolic Toll-IL1R domain [60].
At least 20 TLRs have been identified in several fishes [61-63]. Among them, TLR3, 7/8, and 9 localize on endosome 26 membrane and could recognize dsRNA, ssRNA, and unmethylated CpG DNA respectively. Several 27 viruses could enter into cells by endocytosis and the extracellular nucleic acids could also be 28 brought into cells by this pathway, which made the endosomal TLRs become important PRRs. After 29 recognizing PAMPs, TLRs are activated and further activate downstream signaling molecules. For 30 example, TLR3 transmits signals to adaptor molecule toll/interleukin-1 receptor (TIR) domain containing adapter inducing IFN-β (TRIF) and TLR 7/8/9 activate myeloid differentiation factor 88 2 (MyD88). Several molecules participate in the TLR induced signal cascades. It has been reported 3 that zebrafish TRIF interacts with Traf family member-associated NF-κB activator (TANK)-binding 4 kinase 1 (TBK1) and receptor-interacting protein 1(RIP1), and then activate interferon regulatory 5 factor (IRF) 3/7 and nuclear factor kappa-B (NF-κB) respectively [64, 65]. The activated IRF3/7 6 and NF-κB would translocate into nucleus, inducing the expression of IFN, IFN-stimulated genes 7 (ISGs), and proinflammatory cytokines [66, 67].
8 Cytosolic RNAs are usually recognized by three members of RLRs: RIG-I, melanoma 9 differentiation associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2), 10 which are a family of DExD/H RNA helicases [68-70]. There could be three domains in the three 11 proteins: two tandem N-terminal caspase-recruitment domain (CARD) which are found in RIG-I 12 and MDA5 but not in LGP2, a central DExD box helicase/ATPase domain (DExD/H), a C-terminal 13 domain (CTD). RLRs have been identified in fishes including zebrafish, common carp, crucian carp, 14 grass carp, atlantic salmon, channel catfish, rainbow trout, Japanese flounder, and so on [71]. After 15 activated by PAMPs, RIG-I or MDA5 bind to their adaptor protein mitochondrial antiviral-signaling 16 protein (MAVS, also known as IPS-1, VISA, or Cardif) which localizes in mitochondria. Activated 17 MAVS could further recruit and activate TBK1 and IκB kinase complex (IKKα/β/γ), and then 18 induce the downstream IRF and NF-κB activity. In addition, the other adaptor molecule, mediator 19 of IRF3 activation (MITA, also known as STING, ERIS, and MYPS), which localizes in 20 endoplasmic reticulum could transmit signals from RIG-I and MDA5 through MITA-TBK1-IRF3/7 21 pathway [72]. 22 The best known cytosolic DNA-sensing pathway is the cyclic GMP-AMP synthase (cGAS) - 23 STING pathway. Cytosolic DNA binds and leads to the activation of cGAS, which synthesizes 24 2’3’-cGAMP as second messenger. cGAMP further binds and activates STING, which then 25 activates TBK1 and IKK complex, leading to the activation of IRF3 and NF-κB [73].