infectious haematopoietic necrosis virus
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PicturesTop of page
IdentityTop of page
Preferred Scientific Name
- infectious haematopoietic necrosis virus Amend et al., 1969
Other Scientific Names
- Sockeye salmon virus Wingfield et al., 1970
International Common Names
- English: IHN virus; infectious hematopoietic necrosis virus
Taxonomic TreeTop of page
- Domain: Virus
- Group: "Positive sense ssRNA viruses"
- Group: "RNA viruses"
- Order: Mononegavirales
- Family: Rhabdoviridae
- Genus: Novirhabdovirus
- Species: infectious haematopoietic necrosis virus
Distribution TableTop of page
The distribution in this summary table is based on all the information available. When several references are cited, they may give conflicting information on the status. Further details may be available for individual references in the Distribution Table Details section which can be selected by going to Generate Report.Last updated: 10 Jan 2020
|Continent/Country/Region||Distribution||Last Reported||Origin||First Reported||Invasive||Reference||Notes|
|Botswana||Absent, No presence record(s)||OIE Handistatus (2005)|
|Burundi||Absent, No presence record(s)||OIE Handistatus (2005)|
|Cabo Verde||Absent, No presence record(s)||OIE Handistatus (2005)|
|Cameroon||Absent, No presence record(s)||OIE Handistatus (2005)|
|Central African Republic||Absent, No presence record(s)||OIE Handistatus (2005)|
|Djibouti||Absent, No presence record(s)||OIE Handistatus (2005)|
|Egypt||Absent, No presence record(s)||OIE Handistatus (2005)|
|Eritrea||Absent, No presence record(s)||OIE Handistatus (2005)|
|Eswatini||Absent, No presence record(s)||OIE Handistatus (2005)|
|Ethiopia||Absent, No presence record(s)||OIE Handistatus (2005)|
|Ghana||Absent, No presence record(s)||OIE Handistatus (2005)|
|Kenya||Absent, No presence record(s)||OIE Handistatus (2005)|
|Madagascar||Absent, No presence record(s)||OIE Handistatus (2005)|
|Mauritius||Absent, No presence record(s)||OIE Handistatus (2005)|
|South Africa||Absent, No presence record(s)||OIE Handistatus (2005)|
|Sudan||Absent, No presence record(s)||OIE Handistatus (2005)|
|Togo||Absent, No presence record(s)||OIE Handistatus (2005)|
|Tunisia||Absent, No presence record(s)||OIE Handistatus (2005)|
|Uganda||Absent, No presence record(s)||OIE Handistatus (2005)|
|Zimbabwe||Absent, No presence record(s)||OIE Handistatus (2005)|
|Bahrain||Absent, No presence record(s)||OIE Handistatus (2005)|
|Brunei||Absent, No presence record(s)||OIE Handistatus (2005)|
|Georgia||Absent, No presence record(s)||OIE Handistatus (2005)|
|Hong Kong||Absent, No presence record(s)||OIE Handistatus (2005)|
|Indonesia||Absent, No presence record(s)||OIE Handistatus (2005)|
|Iraq||Absent, No presence record(s)||OIE Handistatus (2005)|
|Kazakhstan||Absent, No presence record(s)||OIE Handistatus (2005)|
|Lebanon||Absent, No presence record(s)||OIE Handistatus (2005)|
|-Peninsular Malaysia||Absent, No presence record(s)||OIE Handistatus (2005)|
|Mongolia||Absent, No presence record(s)||OIE Handistatus (2005)|
|North Korea||Absent, No presence record(s)||OIE Handistatus (2005)|
|Singapore||Absent, No presence record(s)||OIE Handistatus (2005)|
|South Korea||Present||OIE Handistatus (2005)|
|Sri Lanka||Absent, No presence record(s)||OIE Handistatus (2005)|
|Syria||Absent, No presence record(s)||OIE Handistatus (2005)|
|Taiwan||Absent, No presence record(s)||OIE Handistatus (2005)|
|Thailand||Absent, No presence record(s)||OIE Handistatus (2005)|
|Turkmenistan||Absent, No presence record(s)||OIE Handistatus (2005)|
|Uzbekistan||Absent, No presence record(s)||OIE Handistatus (2005)|
|Andorra||Absent, No presence record(s)||OIE Handistatus (2005)|
|Belarus||Absent, No presence record(s)||OIE Handistatus (2005)|
|Bosnia and Herzegovina||Absent, No presence record(s)||OIE Handistatus (2005)|
|Bulgaria||Absent, No presence record(s)||OIE Handistatus (2005)|
|Croatia||Absent, No presence record(s)||OIE Handistatus (2005)|
|Cyprus||Absent, No presence record(s)||OIE Handistatus (2005)|
|Denmark||Absent, No presence record(s)||OIE Handistatus (2005)|
|Estonia||Absent, No presence record(s)||OIE Handistatus (2005)|
|Finland||Absent, No presence record(s)||OIE Handistatus (2005)|
|France||Present||OIE Handistatus (2005)|
|Germany||Present||OIE Handistatus (2005)|
|Greece||Absent, No presence record(s)||OIE Handistatus (2005)|
|Hungary||Absent, No presence record(s)||OIE Handistatus (2005)|
|Iceland||Absent, No presence record(s)||OIE Handistatus (2005)|
|Ireland||Absent, No presence record(s)||OIE Handistatus (2005)|
|Isle of Man||Absent, No presence record(s)||OIE Handistatus (2005)|
|Italy||Present||OIE Handistatus (2005)|
|Jersey||Absent, No presence record(s)||OIE Handistatus (2005)|
|Latvia||Absent, No presence record(s)||OIE Handistatus (2005)|
|Liechtenstein||Absent, No presence record(s)||OIE Handistatus (2005)|
|Lithuania||Absent, No presence record(s)||OIE Handistatus (2005)|
|Luxembourg||Absent, No presence record(s)||OIE Handistatus (2005)|
|Malta||Absent, No presence record(s)||OIE Handistatus (2005)|
|Moldova||Absent, No presence record(s)||OIE Handistatus (2005)|
|Netherlands||Absent, No presence record(s)||OIE Handistatus (2005)|
|North Macedonia||Absent, No presence record(s)||OIE Handistatus (2005)|
|Norway||Absent, No presence record(s)||OIE Handistatus (2005)|
|Portugal||Absent, No presence record(s)||OIE Handistatus (2005)|
|Romania||Absent, No presence record(s)||OIE Handistatus (2005)|
|Slovakia||Absent, No presence record(s)||OIE Handistatus (2005)|
|Slovenia||Present||OIE Handistatus (2005)|
|Spain||Absent, No presence record(s)||OIE Handistatus (2005)|
|Sweden||Absent, No presence record(s)||OIE Handistatus (2005)|
|Switzerland||Present||OIE Handistatus (2005)|
|Ukraine||Absent, No presence record(s)||OIE Handistatus (2005)|
|United Kingdom||Absent, No presence record(s)||OIE Handistatus (2005)|
|-Northern Ireland||Absent, No presence record(s)||OIE Handistatus (2005)|
|Barbados||Absent, No presence record(s)||OIE Handistatus (2005)|
|Belize||Absent, No presence record(s)||OIE Handistatus (2005)|
|Bermuda||Absent, No presence record(s)||OIE Handistatus (2005)|
|British Virgin Islands||Absent, No presence record(s)||OIE Handistatus (2005)|
|Cayman Islands||Absent, No presence record(s)||OIE Handistatus (2005)|
|Costa Rica||Absent, No presence record(s)||OIE Handistatus (2005)|
|Cuba||Absent, No presence record(s)||OIE Handistatus (2005)|
|Dominica||Absent, No presence record(s)||OIE Handistatus (2005)|
|Dominican Republic||Absent, No presence record(s)||OIE Handistatus (2005)|
|Guatemala||Absent, No presence record(s)||OIE Handistatus (2005)|
|Haiti||Absent, No presence record(s)||OIE Handistatus (2005)|
|Honduras||Absent, No presence record(s)||OIE Handistatus (2005)|
|Jamaica||Absent, No presence record(s)||OIE Handistatus (2005)|
|Martinique||Absent, No presence record(s)||OIE Handistatus (2005)|
|Mexico||Absent, No presence record(s)||OIE Handistatus (2005)|
|Nicaragua||Absent, No presence record(s)||OIE Handistatus (2005)|
|Panama||Absent, No presence record(s)||OIE Handistatus (2005)|
|Saint Kitts and Nevis||Absent, No presence record(s)||OIE Handistatus (2005)|
|Saint Vincent and the Grenadines||Absent, No presence record(s)||OIE Handistatus (2005)|
|Trinidad and Tobago||Absent, No presence record(s)||OIE Handistatus (2005)|
|Australia||Absent, No presence record(s)||OIE Handistatus (2005)|
|French Polynesia||Absent, No presence record(s)||OIE Handistatus (2005)|
|New Zealand||Absent, No presence record(s)||OIE Handistatus (2005)|
|Vanuatu||Absent, No presence record(s)||OIE Handistatus (2005)|
|Argentina||Absent, No presence record(s)||OIE Handistatus (2005)|
|Bolivia||Absent, No presence record(s)||OIE Handistatus (2005)|
|Brazil||Absent, No presence record(s)||OIE Handistatus (2005)|
|Chile||Absent, No presence record(s)||OIE Handistatus (2005)|
|Colombia||Absent, No presence record(s)||OIE Handistatus (2005)|
|Falkland Islands||Absent, No presence record(s)||OIE Handistatus (2005)|
|Guyana||Absent, No presence record(s)||OIE Handistatus (2005)|
|Paraguay||Absent, No presence record(s)||OIE Handistatus (2005)|
|Peru||Absent, No presence record(s)||OIE Handistatus (2005)|
|Uruguay||Absent, No presence record(s)||OIE Handistatus (2005)|
|Venezuela||Absent, No presence record(s)||OIE Handistatus (2005)|
Pathogen CharacteristicsTop of page
There are several excellent reviews on work prior to 1991 that describe the biophysical properties of IHNV and its stability to various chemical and physical agents (Pilcher and Fryer, 1980a; Wolf, 1988; Winton, 1991).
Infectious haematopoietic necrosis virus in cell culture
Cell culture of IHNV was first made using salmonid fish cell lines, such as CHSE-214 (Fryer et al., 1965) and RTG-2 (Wolf and Quimby, 1962). These cells were used to isolate the virus from infected fish (Wingfield et al., 1969). The virus has since been found to grow well in fish cell lines such as EPC, fathead minnow (FHM), bluegill fry (BF-2) and steelhead trout embryo (STE-137) cells at temperatures ranging from 4 to 20°C. Other cell lines that are susceptible to IHNV cytopathogenicity include CHSE-114, sockeye salmon embryo (SSE-5), SSE-30, kokanee salmon ovary (KO-6), chum salmon heart (CHH-1), rainbow trout hepatoma (RTH-149), guppy embryo (GE-4), coho salmon embryo (CSE-119), rainbow trout spleen (RBS), rainbow trout fry (RTF-1) and Atlantic salmon (AS) cells (Wolf and Mann, 1980; Lannan et al., 1984; Wolf, 1988). The optimum temperature for growth is approximately 15°C (Mulcahy et al., 1984a) and 23-25°C does not support viral replication. The virus has been replicated in baby hamster kidney (BHK/21), reptilian (Clark and Soriano, 1974), Drosophila melanogaster (Bussereau et al., 1975) and Aedes albopictus cells at 16°C (Scott et al., 1980). A one-step growth curve in CHSE-214 cells at 18°C, reported by McAllister et al. (1974), showed new virus production by 4 h postinfection, followed by an exponential release of virus until approximately 16 h postinfection, when the maximum viral titre reached about 107 pfu ml-1. Different cell lines may produce viral titres of 108-108.5 pfu ml-1, but the majority of cell lines produce viral titres of approximately 107 pfu ml-1.
Cell cytopathology is evident at 10-15 h postinfection and is characteristically one of cells looking like ‘balloon-shaped cells with nuclei pushed to one side of the balloon’ (Engelking and Leong, 1981). Surrounding a region destined to become a plaque, the affected cells appear like grapes clustered at the periphery of a cleared region where the infected cells have pulled away from the surface substrate.
Infectious haematopoietic necrosis virus - genome structure and transcription
The virions of IHNV are typically bullet-shaped, with measurements of 110 nm × 70 nm in fixed and thin-sectioned preparations of the virus in infected cell cultures, and 111 nm × 11 nm in negatively stained preparations of purified virus (Hill, 1975).
Infectious haematopoietic necrosis virus is one of the first fish rhabdoviruses to be characterized biochemically, and it has five structural proteins (McAllister and Wagner, 1975). Each of these proteins was analysed using SDS-polyacrylamide gel electrophoresis (PAGE), and the relative migration pattern of the virion proteins tentatively placed IHNV in the lyssavirus genus of the family Rhabdoviridae (Wunner and Peters, 1991). In 1995, it was listed as an unassigned member of the family (Wunner et al., 1995). The five virion proteins include a high-molecular-mass L or polymerase protein (150-225.2 kDa), a glycoprotein G (67-70 kDa), a phosphorylated nucleoprotein N (40.5-44 kDa), a phosphorylated Por M1 protein (22.5-27 kDa) and a matrix protein M or M2 (17.5-21.8 kDa). A non-virion protein NV of 12 kDa has also been identified in infected cells (Kurath and Leong, 1985; Schutze et al., 1996). This protein is missing in the prototype rhabdoviruses that infect mammals and distinguishes IHNV from other members of the lyssavirus genus (Wunner et al., 1995). An estimate of the number of molecules per virion for each protein was made for IHNV (Leong et al., 1983a). The ratio of viral protein to ribonucleic acid (RNA) is 21 : 1, a very low figure in comparison with vesicular stomatitis virus (VSV) and rabies virus (RV), which have ratios of 92 : 1 to 72 : 1, respectively (Bishop and Roy, 1972; Coslett et al., 1980). The low protein-to- RNA ratio for IHNV is unusual and may reflect differences in the membrane structure of fish and mammalian cells (Moore et al., 1976). It is similar to that obtained for La Crosse virus, a bunyavirus, which has a ratio of 30:1 in BHK/21 cells (Obijeski et al., 1976).
The relative contribution of each protein to the total molecular weight of the virion was estimated from densitometer tracings of SDS-polyacrylamide gels of purified virus. For both silver- and Coomassie blue-stained gels, the relative proportion of each virion protein was different from that reported by McAllister and Wagner (1975) for 14C-amino acid-labelled virus. These differences may be a result of differences in the virus strain. More probably it reflects differences in the methods for determining the proportion of each virion protein. The numbers of molecules of IHNV virion proteins are 23-40 L, 198- 290 G, 560-774 N, 391-514 P, and 874-1044 M. These are strikingly different from those for RV which are 79 L, 1723 G, 1975 N, 402 P and 1156 M (Coslett et al., 1980). The remarkable difference is in the number of G molecules per virion. It is difficult to produce high-titre neutralizing antibody to IHNV in warm-blooded animals. The poor immunogenicity of G or the poor neutralizing activity of the antisera may be a direct result of the low numbers of G molecules on the surface of the IHNV virion.
Molecular analysis of RNA from purified IHNV (Round Butte (RB-1) strain isolated from an Oregon steelhead trout) indicates a genome of approximately 11 kb, a size very similar to that of other rhabdoviruses (Kurath and Leong, 1985). However, unlike the prototype rhabdoviruses, VSV or RV, there appear to be six instead of five viral genes. A complementary deoxyribonucleic acid (cDNA) library constructed to the viral messenger RNAs (mRNAs) contains clones for six viral genes. The sixth gene encodes a previously unknown viral protein, NV or non-virion protein. These genes were identified by hybridization to specific mRNA sequences in Northern blots and then used in R-loop mapping studies to determine the viral genome gene order from 3' to 5' as N-P-M-G- NV-L (Kurath et al., 1985). Since these initial findings, the viral genes for G and N for the RB-1 strain have been sequenced (Koener et al., 1987; Gilmore and Leong, 1988) and, recently, the complete genome sequence of IHNV was determined by Morzunov et al. (1995) on a Western Regional Aquaculture Consortium (WRAC) IHNV isolate and by Schutze et al. (1995) on a KS-1 IHNV isolate. The viral genome is 11,131 nucleotides (nt) in length and contains a 60 nt leader sequence at its 3' end and a 101 nt trailer sequence at its 5' end. The 3' and 5' ends of the IHNV genome are complementary, just like the ends of the VSV and RV genome, and are thought to provide the means for the viral RNA to form panhandle structures for priming the initiation of RNA synthesis (Banerjee and Barik, 1992).
The internal gene junctions of IHNV are different from those of other rhabdoviruses. Typically, the gene junctions for the VSV and RV contain the sequence, UC(U)7NNUUGU. In contrast, the consensus intergenic region for the fish rhabdoviruses is UC(U)7RCCGUG, where R is a T or C. Thus, during mRNA synthesis, the polymerase, which initiates transcription at the AACA sequence for both VSV and RV, initiates transcription at T/CGGCAC for IHNV (P.-W.P. Chiou, unpublished data).
The viral sequences have been the basis for a phylogenetic analysis of IHNV and its evolutionary relationship to other rhabdoviruses (Morzunov et al., 1995; Bjorklund et al., 1996). A comparison of the G, M and L genes indicates that there are three distinct clades in the Rhabdoviridae family tree. The members of the vesiculovirus genus (VSV, Piry and Chandipura viruses) form one clade and a second clade is composed of members of the lyssavirus genus (RV and Mokola viruses). In addition, there is a third distinct and well supported clade which is composed of the fish rhabdoviruses (IHNV, VHS virus (VHSV) and hirame rhabdovirus (HIRRV) (Basurco and Benmansour, 1995; Kurath et al., 1997). These findings and the discovery of a new viral gene encoding a non-virion protein have prompted investigators to seek a new genus grouping for the fish rhabdoviruses. The new genus has been approved by the International Committee on the Taxonomy of Viruses and named novirhabdovirus (Kurath et al., 1997).
MESSENGER RIBONUCLEIC ACID TRANSCRIPTION
Six viral mRNA species have been identified in cells infected with IHNV, and their molecular weights have been estimated in denaturing glyoxal or methylmercury agarose gels (Kurath and Leong, 1985). The six species are: L mRNA, 2.26 × 106 Da; G mRNA, 5.63 × 106 Da; N mRNA, 4.48 × 105 Da; P mRNA, 3.00 × 105 Da; M mRNA, 3.00 × 105 Da; and NV mRNA, 1.95 × 105 Da. The P and M mRNAs comigrate in both glyoxal and methylmercury gels. The N mRNA is presumably the first mRNA species produced during viral replication, since N is the first viral protein that appears in infected cells. When the relative concentration of each mRNA species is measured at the height of virus replication, the N concentration is 1.00, P and M mRNAs are 2.52 ± 0.40, G mRNA is 0.49 ± 0.03; NV mRNA is 0.41 ± 0.14 and L mRNA is 0.02 ± 0.01 (Kurath and Leong, 1985).
The mRNAs of rhabdoviruses are considered to be monocistronic although read-through transcription products have been identified for VSV (Masters and Samuel, 1984), RV (Ravkov et al., 1995), and the ephemeroviruses (Wang et al., 1995). No read-through transcripts have been identified for IHNV (P.P.-W. Chiou, unpublished data). However, there is a possibility that a single IHNV mRNA species might encode more than one translation product. Since there are many examples of different translation products either encoded in different reading frames, initiated at a different start codon or resulting from an internal frame shift that leads to a hybrid protein product, the possibility that there are additional proteins encoded by the IHNV genome is very high. For example, the paramyxoviruses and rhabdoviruses have encoded in their P mRNA transcripts for more than one protein (Lamb et al., 1976; Curran et al., 1992; Spiropoulou and Nichol, 1993). In fact, a seventh protein, S for small protein, at 6.5 kDa, has been described in IHNV-infected cells (Chiou, 1996). Whether this S protein is encoded by one of the IHNV mRNA transcripts has not been determined.
An in vitro transcription system for purified virions of IHNV was first described by McAllister and Wagner in 1977. They described a heterogeneous array of IHNV-specific transcripts, ranging in size from 9S to 17S with no discrete species identified. Later studies by Kurath and Leong (1987) demonstrated that optimal polymerase activity required HEPES buffer supplemented with S-adenosyl-L-methionine. In this case, RNA transcripts contained polyadenylated species, which comigrated with the IHNV N, P, M, G and NV mRNAs from IHNV-infected cells. These transcripts were fully functional in translation reactions with rabbit reticulocyte extracts to produce N, P and M proteins.
The process by which IHNV replicates its viral genome is unknown. If the process is similar to that of VSV, then the viral N protein provides the trigger that switches the RNA transcription process from mRNA synthesis to progeny genome plus synthesis. The viral N protein is present in such large quantities in the late phase of viral replication that it binds to the nascent RNA transcript and prevents the viral polymerase from recognizing the mRNA transcription termination signals. This results in the synthesis of a full length plus strand template for the production of progeny minus strand viral genomes.
VIRAL GENE EXPRESSION
Infection of salmon or trout cells with IHNV results in the inhibition of cellular protein synthesis. In this characteristic, IHNV differs from other members of the RV group of the Rhabdoviridae. Cellular protein synthesis is not inhibited after infection with RV (Coslett et al., 1980) and any studies of RV protein synthesis in the cell require exposure to hypertonic shock to reduce the background of host protein synthesis. However, it has been possible to examine the synthesis of IHNV proteins in the cell without resorting to this drastic treatment. In pulse-labelling studies with 35S-methionine, the first protein of IHNV to appear in the course of infection is the N, or nucleocapsid, protein, at 2-3 h after infection (Hsu et al., 1985). At 6-7 h after infection, the P and M proteins can be identified in autoradiograms. The two forms of the glycoprotein, G1 and G2, representing different glycosylation states of the protein, are found at 9-10 h after infection. It is not possible to distinguish the virion L protein from other host proteins in the gel until 15 h postinfection, when cellular host protein synthesis is completely inhibited. Virus production begins 12 h after infection (Leong et al., 1981a). The migration of the structural proteins of IHNV varies among different isolates of the virus and the differences in migration patterns form the basis for distinguishing different IHNV isolates by their electropherotype. The molecular weights of the N and G proteins for the different isolates were used to type serologically similar strains of IHNV.
Nucleocapsid protein. The N protein is the most abundant viral protein in the IHN virion and in virus-infected cells. It is present as a phosphorylated protein in the virion (McAllister and Wagner, 1975; Hsu et al., 1985) and is found tightly associated with the viral genome (Engelking and Leong, 1989a,b). The complete nucleotide sequence of the N gene has been determined for three different isolates of IHNV (RB-1 isolate, Gilmore and Leong, 1988; WRAC isolate, Morzunov et al., 1995; KS-1 isolate, Schutze et al., 1995) from cDNA clones to the viral N mRNA. The N gene encodes a protein of 413 amino acids which is highly hydrophilic at its amino and carboxyl terminal ends, with a hydrophobic region in the middle third of the protein .It has been speculated that the carboxyl terminal end of the IHNV N protein may be involved in binding of the N protein to the viral RNA (Gilmore and Leong, 1988). For the prototype rhabdovirus VSV, the N protein has been shown to play a crucial role in regulating the balance between viral transcription and replication.
Diagnostic tests have been developed for the viral N protein and nucleic acid sequence because the N protein is the first viral protein synthesized, as well as the most abundant viral protein (Rose and Schubert, 1987).
Phosphoprotein. The P or M1 protein is a phosphorylated protein of 230 amino acids with a calculated molecular weight of 25.6 kDa (McAllister and Wagner, 1975; Hsu et al., 1985; Ormonde, 1995). Sequence analysis of the gene encoding the P protein for IHNV RB-1 and KS-1 strains indicate that the deduced amino acid sequence contains 45 potential phosphorylation sites, SXXD/E, which are found predominantly in the first half of the protein (Ormonde, 1995). The M1 protein is a very basic protein with an estimated isoelectric point (pI) of 8.4, similar to that reported for the VHSV (Makah strain) M1 protein (Benmansour et al., 1994; Ormonde, 1995). The basic nature of these proteins contrasts sharply with the RV and VSV phosphoproteins, which have pIs of 4.36 and 4.84, respectively. The M1 or P proteins of the RB-1 strain and the European KS-1 strain of IHNV share a high degree of similarity, with 94% identity at the amino acid level (Ormonde, 1995; Morzunov et al., 1995). When compared with the M1 proteins for HIRRV and VHSV, a 63% and 38% similarity was observed between these proteins and the IHNV M1 protein (Ormonde, 1995). Sequence analysis of the M1 genes of different IHNV strains indicates that there might be a second overlapping open reading frame (ORF) encoding a highly basic, arginine-rich protein, with an estimated pI of 10.1-12.8. Located at position 121 from the end of the polyadenylated sequence of the N gene, this second ORF is 146 nucleotides in length and has the potential to encode a 42 amino acid protein with an estimated molecular weight of 4.8 kDa. The protein is similar in size to the 55 amino acid, arginine-rich C protein reported for VSV (Spiropoulou and Nichol, 1993) and RV (Chenik et al., 1995). The VSV C protein is also encoded by the P mRNA transcript in a second overlapping ORF within the gene. These proteins are found only in infected cells and their function is currently not known.
Matrix protein. The IHNV matrix protein (M), previously called M2, is similar to all reported rhabdovirus matrix proteins (Ormonde, 1995). The M protein is encoded by a sequence of 585 nucleotides to yield a protein of 195 amino acids, with 21.8 kDa estimated molecular weight. It is very basic, with an estimated pI of 10.08, similar to the M proteins of the other rhabdoviruses, and contains a high concentration of charged amino acids in the amino terminal half of the protein. Highly charged amino termini have also been found in the vesiculoviruses and the lyssaviruses (Rose and Gallione, 1981; Bourhy et al., 1993) and in paramyxoviruses (Chambers et al., 1986). In VSV, the first 51 amino acids were required for stable interaction with the plasma membrane (Chong and Rose, 1994), for viral assembly (Black et al., 1993) and possibly in the inhibition of RNA transcription (Ogden et al., 1986). This region is also conserved among IHNV, HIRRV and VHSV matrix proteins and whether this region is involved with viral assembly, transcription inhibition and membrane interaction is unknown.
The deduced IHNV M2 amino acid sequence does not share significant homology with either VSV, RV or the fish vesiculovirus, spring viraemia of carp virus (SVCV). However, it shares a 74% amino acid identity with HIRRV M2 protein and a 37% identity with the VHSV M2 protein at three localized regions of homology (Ormonde, 1995). Sequence conservation is highest in the N terminal region of the first 29 amino acids, which contains a large number of basic residues. This feature has also been described for the amino termini of RV and VSV.
Glycoprotein. The IHNV glycoprotein G is a membrane-associated protein which forms spike-like projections on the surface of the mature virion (McAllister and Wagner, 1975). Antiglycoprotein serum neutralizes viral infectivity, and immunization with purified glycoprotein prevents subsequent lethal infection with IHNV (Engelking and Leong, 1989b). Immunological studies with polyvalent antiglycoprotein sera have indicated that the glycoproteins are conserved among different geographical isolates of IHNV (Hsu and Leong, 1985) and that there is only one major serotype with several serovariants (Engelking and Leong, 1989a). This finding has been confirmed by studies with MAb (Huang et al., 1996) and sequence analysis of the G and NV genes (Nichol et al., 1995).
The IHNV glycoprotein has many of the features characteristic of membrane associated glycoproteins of negative-stranded RNA viruses. The predicted translation product of the IHNV G gene is a protein of 508 amino acids, with a hydrophobic domain of 20 amino acids at the N terminus forming the signal peptide. This includes a central core of hydrophobic amino acid residues, in the form of three repeated pairs of Leu-Ile (Koener et al., 1987) and a consensus signal peptide cleavage site, Ala-Asn-Ser, at position 18. The arrangement of the amino acids in this region is consistent with the signal peptidase cleavage sequences identified by Perlman and Halvorson (1983). There is an additional hydrophobic domain near the C terminus, which is the presumed transmembrane domain of the protein.
A comparison of the predicted amino acid sequences of the glycoproteins of the vertebrate rhabdoviruses suggests that these proteins are highly similar in structure. The cysteine residues of the IHNV G protein are highly conserved amino acids, whose positions in the G proteins of VSV-New Jersey (VSV-NJ), VSV-Indiana (VSV-Ind) and RV are largely identical. In the case of VSV-Ind, 12 of 15 cysteine residues are aligned with IHNV at 12 of its 16 cysteine residues. For RV, nine were aligned with the 17 cysteine residues in the IHNV G protein. When the positions of the proline residues were aligned, approximately one third of the proline positions between RV and IHNV, as well as between VSV and IHNV, were identical. However, a hydropathy plot of the G proteins did reveal a striking difference between them. The profiles revealed a very hydrophilic domain extending from IHNV G amino acid 365 to 450, which was not evident in either VSV or RV. Within this region were two possible glycosylation sites and no cysteine residues. The importance of this region as a possible antigenic domain was first suggested by Koener et al. (1987). A more recent study by Bjorklund et al. (1996) expanded the comparison of the fish rhabdovirus glycoproteins to the glycoproteins of other rhabdoviruses. The study included IHNV, SVCV, HIRRV, Chandipura virus, Adelaide River virus, bovine ephemeral fever virus, VHSV-07-71, VHSV-DK, Mokola virus, sigma virus, Sonchus yellow net virus, VSV-NJ, VSV-Ind, RV-ERA and RV-PV. The analysis found that the amino acids cysteine, proline, glycine and leucine were conserved in the aligned glycoprotein sequences.
Non-virion gene. The NV gene and its encoded protein was first identified in 1985 (Kurath and Leong, 1985; Kurath et al., 1985). Located between the G and L genes, NV is 371 nt in length and encodes a protein of 111 amino acids. The overall pI of the deduced protein is approximately 7, despite the fact that the protein has a high content of charged amino acids (38%) (Nichol et al., 1995). An NV protein has also been identified at the G-L junctions of HIRRV and VHSV, a finding that has prompted scientists to propose a new taxonomic classification for the salmonid fish rhabdoviruses (Schutze et al., 1996; Kurath et al., 1997). The gene is highly conserved. Among 14 different IHNV isolates, comprising 13 isolates from North America and one from Europe, more than 97% identity at the amino acid level was observed (Nichol et al., 1995; Schutze et al., 1995; Chiou, 1996; Kurath et al., 1997). The NV amino acid identity/ similarity values between IHNV and VHSV or HIRRV indicate that this protein is highly conserved, with identity/similarity values of 23.3%/47.6% and 16.5%/ 40.4%, respectively (Kurath et al., 1997). There are sufficient differences in the NV genes among the different IHNV isolates for ribonuclease (RNAse) protection assays to have been used to distinguish the isolates (Kurath et al., 1995).
Characterizing the expression of the NV protein in infected cells has been problematic. In the original report by Kurath and Leong (1985), the NV protein was clearly observed in autoradiograms of SDS-PAGE gels containing lysates of infected cells labelled with 35S-methionine or the in vitro translation products of mRNA from infected cells. Subsequent reports have shown that the expression of NV is very low or below detection limits for IHNV by radiolabelling (Chiou, 1996), VHSV (Basurco and Benmansour, 1995) and HIRRV (Nishizawa et al., 1991a, b). More recently, NV protein expression was detected in cells infected by either IHNV or VHSV by immunofluorescence and Western immunoblot (Schutze et al., 1996).
Although there has been much speculation concerning the function of NV (Kurath and Leong, 1985; Nichol et al., 1995; Chiou, 1996), the role NV plays in the replication of the virus remains unknown. No functional motifs have been identified in the protein sequence and no significant homology to other protein sequences in the GenBank database has been uncovered (Basurco and Benmansour, 1995; Nichol et al., 1995). NV in Novirhabdoviruses has been found to be essential in IHNV replication (Thoulouze et al., 2004) and nonessential in the replication of the warm water novirhabdovirus, Snakehead Rhabdovirus (Alonso et al., 2004; Johnson et al., 2000). The difference in findings is dramatic and it is not clear whether the difference is due to host cell line characteristics and/or temperature.
Polymerase. The L gene (nt 5016 to nt 10,976) of IHNV encodes a protein of 1986 amino acids with an estimated molecular mass of 225.2 kDa (Bjorklund et al., 1995; Morzunov et al., 1995; Schutze et al., 1995). The IHNV polymerase is similar to the VSV polymerase, which has been shown to be solely responsible for all transcriptional activities. Thus, the IHNV polymerase should also be capable of RNA-dependent RNA polymerization, cap methylation and poly-A polymerization. The deduced amino acid sequence contains the six conserved blocks of amino acids identified as conserved sequences in negative stranded RNA polymerases (Poch et al., 1990). Any dissection of polymerase function will require the isolation of a functional polymerase cDNA clone, a feat that has not yet been accomplished.
Serotype analysis and strain characterization
Early work on the characterization of different isolates of IHNV with polyclonal antisera indicated that there was only one serotype of the virus and thus there was no means of distinguishing the different viral isolates (McCain et al., 1971). It was not until the work of Hsu et al. (1985, 1986) that a means of distinguishing the different isolates was developed. Based on the migration patterns of the IHN viral proteins on SDS-polyacrylamide gels, IHNV typing resulted in the identification of five electropherotypes. This provided the first evidence that the viral type was geographically defined and all host species in the area would carry the same viral type.
Further verification that there was only one serotype of IHNV was carried out with antisera to the viral glycoprotein. The IHNV glycoprotein had been shown to be the only viral protein capable of eliciting a neutralizing antibody response in rabbits and providing protective immunity in young fish (Engelking and Leong, 1989a,b). Purified glycoprotein from IHNV-RB-1 protected the fish against challenge with a potentially lethal IHNV infection (Engelking and Leong, 1989a). The work was extended to show that the purified glycoprotein from IHNV-RB-1 also induced protective immunity against the five IHNV electropherotypes by immersion vaccination (Engelking and Leong, 1989b). These findings suggested that there was only one serotype of IHNV. A comparison of the neutralization indices with ten different isolates of IHNV representing all five electropherotypes against anti-IHNV-RB-1, anti-IHNV-CO-2, anti-G protein of IHNV-RB-1, and anti-G protein of IHNV-CO-2 sera indicated that there was only serotype. However, the four antisera did define two groups: a group of readily neutralized IHNV isolates, including RB-1 (type 1), CO-2 (type 4), Elk River (ER) (type 3), CD-2 (type 5), HA-1 (type 2) and TA-1 (type 1), and a group of less readily neutralized virus isolates, including DW-2 (type 3), DW-3 (type 3), LE (type 2) and NS (type 3).
Monoclonal antibodies have replaced electropherotyping for characterizing isolates of IHNV. Winton et al. (1988) separated 12 IHNV strains into four groups, using three MAbs. Further characterization of 12 different IHNV isolates with seven MAbs produced ten different reactivity patterns (Nichol et al., 1995). The atypical IHNV isolate, HO-7, was not neutralized by any of the seven MAbs. S. Ristow’s group at Washington State University examined 17 isolates of IHNV with a bank of five glycoprotein-reactive MAbs (Ristow and Arnzen-de Avila, 1991). Twelve of the 17 isolates were neutralized by two MAbs (3GH127B and 3GH92A) and, of the 12, one was the only isolate neutralized by a single MAb (1GH131A). Five isolates were not neutralized by any of the MAbs. Two MAbs did not neutralize any of the virus isolates (3GH135L and 2GH5F). When the same 17 isolates were examined with a bank of 15 MAbs reactive with either the N or G proteins, 15 distinct reaction patterns were observed. All of these studies supported the conclusion that strains of IHNV were endemic to a geographic region and the introduction of new strains into the region could be monitored by electropherotype, antigenic characteristics, and sequence analysis (Kurath et al., 2003).
Kurath and her colleagues are now utilizing RNAse protection assays to evaluate the differences in strains of IHNV (Kurath et al., 1995). Oshima et al. (1995) used two-dimensional oligonucleotide patterns to assess genetic diversity among different IHNV isolates. All of these techniques have confirmed the finding that IHNV strains are geographically confined and the appearance of a new strain in an area might indicate the introduction of IHNV-infected fish or eggs. More recently, Kurath et al., have used direct sequence analyses of the middle region of the glycoprotein gene for 323 different field isolates of IHNV and identified genogroups in the Pacific Northwest (Kurath et al., 2003).
Host AnimalsTop of page
|Animal name||Context||Life stage||System|
|Acipenser transmontanus (white sturgeon)||Experimental settings|
|Dicentrarchus labrax (European seabass)||Experimental settings|
|Oncorhynchus gorbuscha (pink salmon)||Experimental settings|
|Oncorhynchus keta (chum salmon)||Experimental settings, Wild host||Aquatic: Larval|Aquatic/Fry|
|Oncorhynchus kisutch (coho salmon)||Experimental settings|
|Oncorhynchus masou macrostomus|
|Oncorhynchus masou masou (cherry salmon)||Domesticated host|
|Oncorhynchus masou rhodurus||Domesticated host|
|Oncorhynchus mykiss (rainbow trout)||Domesticated host, Wild host|
|Oncorhynchus nerka (sockeye salmon)||Domesticated host, Experimental settings, Wild host||Aquatic: Adult|Aquatic/Egg|Aquatic/Larval|Aquatic/Fry|
|Oncorhynchus tshawytscha (chinook salmon)||Domesticated host, Experimental settings, Wild host||Aquatic: Adult|Aquatic/Egg|Aquatic/Larval|Aquatic/Fry|
|Piscicola salmositica||Experimental settings, Wild host|
|Prosopium williamsoni||Experimental settings|
|Psetta maxima (turbot)||Experimental settings|
|Salmo salar (Atlantic salmon)||Domesticated host, Wild host|
|Salmo trutta (sea trout)||Domesticated host, Wild host|
|Salvelinus alpinus (Arctic charr)||Experimental settings|
|Salvelinus fontinalis (brook trout)||Domesticated host, Wild host|
|Salvelinus namaycush (lake trout)||Experimental settings|
|Sparus aurata (gilthead seabream)||Experimental settings|
|Stenodus leucichthys||Experimental settings|
|Thymallus arcticus (arctic grayling)||Experimental settings|
Vectors and Intermediate HostsTop of page
ReferencesTop of page
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ContributorsTop of page
Center for Salmon Disease Research, Oregon State University, Corvallis, Oregon 97331-3804, USA
Distribution MapsTop of page
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