Rhabdoviridae

Genus: Vesiculovirus


Genus: Vesiculovirus

Distinguishing features

Viruses assigned to the genus Vesiculovirus form a distinct monophyletic group based on well-supported Maximum Likelihood trees inferred from complete L sequences. Vesiculoviruses are transmitted by insects and infect mammals, birds and reptiles. Some vesiculoviruses can also be transmitted by direct contact. The vesiculovirus clade is part of a larger phylogenetic group of rhabdoviruses with relatively simple genomes that includes spriviviruses and perhabdoviruses infecting fish. Vesiculovirus genomes contain only five structural protein genes (3′ N-P-M-G-L 5′) and short intergenic regions. Some members of the genus also encode two small highly basic proteins (C and C') in an alternative ORF within the P gene. 

Virion

Morphology

Vesiculovirus virions are enveloped and bullet-shaped, approximately 190 nm in length and 85 nm in diameter. The three-dimensional structure of vesicular stomatitis Indiana virus (VSIV) has been determined utilizing cryo-electron microscopy (Figure 1.Vesiculovirus) (Ge et al., 2010). The nucleocapsid forms a conical-shaped tip and a helical structure in the trunk. Each virion contains an outer helix of matrix protein (M) and an inner helix of nucleoprotein (N) and RNA. M has a hub domain with four contact sites which link to neighboring M and N subunits, providing rigidity by clamping adjacent turns of the RNP. Interactions among N and M provide scaffolding and stability to the complex and are critical in maintaining the bullet shape. Two layers of lipids obtained from the host cell membrane with embedded trimers of the envelope glycoprotein (G) form the outer layers of the virion and mediate the interaction with cellular receptor(s).

Figure 1.Vesiculovirus. Architecture of the vesicular stomatitis Indiana virus particle. Montage model of the tip and cryo-electron-microscopy map of the trunk. N is green, M is blue, and the inner (2) and outer (1) leaflets of the membrane are violet and pink. (Inset) illustration of the base region of the virion. X marks the absence of a turn of M helix below the lowest turn of the N helix (from: Ge et al., 2010. Reproduced with permission from AAAS).

Nucleic acid

Viruses contain a single molecule of linear, negative-sense, single-stranded RNA of approximately 10.7–11.3 kb (Walker et al., 2015). Defective-interfering RNAs are usually significantly shorter than full-length RNA and can be found packaged into small virions known as defective interfering (DI) particles (Huang et al., 1966).

Proteins

Vesiculoviruses have five structural proteins (designated N, P, M, G and L) that are common to all rhabdoviruses. For VSIV, the numbers of molecules per infectious virus particle have been estimated as: L (20–50); G (500–1,500); N (1,000–2,000); P (100–500); and M (1,500–4,000) (Cartwright et al., 1972, Thomas et al., 1985). Several vesiculoviruses (VSIV, vesicular stomatitis New Jersey virus (VSNJV), Jurona virus (JURV), Cocal virus (COCV) and Chandipura virus (CHPV) also have two small, highly basic proteins encoded in a second ORF within the P gene (Walker et al., 2015). In VSIV, an alternative ORF is expressed from alternative initiation codons as two proteins of 65 and 55 amino acids (C and C', respectively) (Spiropoulou and Nichol 1993, Peluso et al., 1996). The role of the nonstructural C and C' proteins is unclear. Engineered viruses that do not express C proteins are indistinguishable from wild type virus in protein synthesis, virus production and host-protein synthesis shut-off in tissue culture cells (Kretzschmar et al., 1996).

Genome organisation and replication

Total genomic RNA lengths range from approximately 10,700 bases in Carajas virus (CARV) to 11,336 bases in field isolates of VSIV (Walker et al., 2015, Rodriguez et al., 2002) (Figure 2.Vesiculovirus). The VSIV genome organisation consists of a 47 nt leader sequence followed by the five structural protein genes in the order 3′ N-P-M-G-L-5′ and a 57–59 nt trailer sequence at the 5′ end. Most differences in length are found in non-translated regions, particularly in the M and G mRNAs (Rodriguez et al., 2002). Despite variability in lengths of the five mRNAs of VSIV, COCV and vesicular stomatitis Alagoas virus (VSAV) (all assigned to the Indiana serotype), four of the five predicted structural proteins (N, M, G and L) vary in length by only one amino acid residue. 

Vesiculovirus replication is well studied and has served as model for replication of the rhabdoviruses (Banerjee 1987, Banerjee and Barik 1992). Transcription begins at a single entry site at the 3′ end of the genome with each gene expressed as a capped and polyadenylated monocistronic mRNA. The first transcript is the 3′ leader, which is neither capped nor polyadenylated. It is transported to the nucleus where it inhibits host cell transcription. The leader transcript is followed by the N mRNA, which is capped during synthesis by the virion polymerase complex (composed of N, P and L). The intergenic sequence (5′ AGUUUUUUUCAUA 3′) signals polyadenylation, termination and re-initiation of transcription in decreasing amounts as the polymerase complex moves away from the single entry site. Therefore, the gene order (3′ N>P>M>G>L 5′) provides an efficient way of regulating gene expression, by which proteins necessary in larger amounts (such as N) are located near the 3′ end and are transcribed in larger amounts and those needed in smaller amounts are located towards the 5′ end and are transcribed less frequently. Following translation of the mRNAs to yield the viral proteins, genome replication starts. In the replication process, the RdRP initiates at the 3′ end of the genome, ignores all the signals for stop and polyadenylation of individual mRNAs and instead synthesises a full-length complementary anti-genome. This in turn serves as template for synthesis of a 45-nt minus sense leader RNA and for synthesis of full-length progeny genomes. Full-length genomes can either serve as templates for secondary transcription, or can be assembled into infectious particles. Factors determining the RdRP functions in transcription or replication modes are not fully understood but the proportion of N and available RNP templates are thought to be critical for determining these functions (Arnheiter et al., 1985). Following replication, further rounds of transcription (secondary transcription), translation and replication ensue.

Figure 2.Vesiculovirus. Schematic representation of vesiculovirus genome organisations. N, P, M, G and L represent ORFs encoding the structural proteins. Alternative ORFs (turquoise) in the P gene of some vesiculoviruses are highlighted. In vesicular stomatitis Indiana virus, the alternative ORF in the P gene encodes two small basic proteins (C and C′) that are expressed in infected cells.

Antigenicity

Vesiculoviruses have been classified into serotypes based on their neutralisation pattern which is determined by epitopes located in the viral G (Tesh et al., 1977, Kelley et al., 1972, Lefrancois and Lyles 1982). G also determines protection in animals vaccinated either with inactivated whole virus or with subunit vaccines (Yilma et al., 1985, Mackett et al., 1985, Gearhart et al., 1987). Furthermore, recombinant viruses containing G of VSNJV, but all other proteins from VSIV, induced protective immune responses against challenge with VSNJV (Martinez et al., 2004). N is a cross-reactive antigen used in complement fixation tests that help define members of the genus (Kang and Prevec 1970). Weak serological cross-reactions may occur between viruses of different genera (Calisher et al., 1989, Tesh et al., 1983). One of the criteria used for vesiculovirus classification is cross-reactivity by complement fixation (Tesh et al., 1977).

In the case of vesicular stomatitis viruses, there are two major serotypes: New Jersey and Indiana. The Indiana serotype has been subdivided into four distinct serological complexes (Federer et al., 1967, Pauszek et al., 2008). Indiana 1 comprises the classical Indiana virus (VSIV) found from northern South America to southern USA. The Indiana 2 subtype has COCV as the prototype virus which was originally isolated from mites collected from rice rats in Trinidad in 1961. Indiana 2 viruses cause disease in cattle and horses in Brazil and Argentina. The Indiana 3 subtype is represented by vesicular stomatitis Alagoas virus (VSAV) which was first isolated from a mule in Alagoas, Brazil, in 1964. This subtype is the most common cause of vesicular stomatitis in livestock in Brazil. The Indiana 4 subtype was originally identified as VSAV but was subsequently shown to be genetically distinct and named Morreton virus (MORV) after the location in north-east Colombia from which it was first isolated from phlebotomine sandflies in 1986 (Tesh et al., 1987). MORV antibodies have been detected in animals and humans in Colombia but a direct association with disease has not yet been demonstrated (Tesh et al., 1987). There are other vesiculoviruses that infect mammals, including humans, (e.g., Piry virus (PIRYV), Isfahan virus (ISFV) and CHPV, and some have been isolated from blood sucking insects (e.g., Maraba virus (MARV), CARV and Radi virus (RADV) (de Souza et al., 2016).

Biology

Vesiculoviruses infect mammals and are transmitted by insects and, therefore, are considered arboviruses (Rodriguez and Pauszek 2012). The natural cycle of vesiculoviruses infecting mammals remains largely unknown but these viruses are commonly found in insects of several species and serological evidence suggests they are capable of infecting wild mammals, birds and reptiles in endemic areas. This wide range of hosts might explain the ability of vesiculoviruses to infect and replicate in a very diverse range of vertebrate and invertebrate cells in vitro. Vesiculoviruses can be transmitted both by insects and by contact. Vesicular stomatitis viruses (VSIV, VSNJV, VSAV) are transmitted to cattle, horses and pigs by various blood-sucking insects found to be infected during epidemics, including sandflies, blackflies and biting midges, but also can be transmitted between mammals by direct contact (Rodriguez and Pauszek 2012). Experimental mechanical transmission also has been achieved by feeding vesiculovirus laboratory-infected grasshoppers to cattle. However, grasshoppers have never been shown to carry vesiculoviruses in nature. Vesiculoviruses are transmitted not only transovarially but also horizontally between infected and non-infected black-flies while co-feeding on mammalian hosts (Tesh et al., 2016). The latter means of transmission might explain the noticeable absence of viremic mammalian hosts for vesiculoviruses, an unusual feature for an arbovirus.

Vesicular stomatitis New Jersey (VSNJV) and Indiana subtypes 1, 2 and 3 (VSIV, COCV and VSAV) are primarily veterinary pathogens, causing epizootics in cattle, pigs and horses in the Americas (Rodriguez and Pauszek 2012). Infected animals usually develop 3-5 days of fever with vesicular lesions on the tongue, buccal mucosa, teats, and coronary bands of the feet. The illness in bovine and swine clinically resembles foot-and-mouth disease, which presents an urgent diagnostic problem. Complications of infection in these animals include weight loss, dehydration, reduced milk production and mastitis in cows, and lameness. Clinical infection also occurs in humans and is usually characterised by a 3-4 day flu-like illness. Most reported cases have occurred in veterinarians and animal handlers in contact with sick animals. ISFV, CHPV and PIRYV have also been reported to cause a flu-like illness in humans (Tesh et al., 1977, Rodriguez and Pauszek 2012). Reports that CHPV also causes fatal encephalitis in humans have been questioned (Manghani et al., 1986, Sejvar 2006).

Species demarcation criteria

Vesiculovirus species have been defined primarily by serological means coupled with phylogenetic analysis of the genomes. Biological characteristics such as host range and mechanisms of transmission are also used to distinguish viral species within the genus. 

Viruses assigned to different species within the genus Vesiculovirus have several of the following characteristics: A) minimum amino acid sequence divergence of 20% in L; B) minimum amino acid sequence divergence of 10% in N; C) minimum amino acid sequence divergence of 15% in G; D) can be distinguished in serological tests; and E) occupy different ecological niches as evidenced by differences in hosts and or arthropod vectors.

Member Species

SpeciesVirus name(s)Exemplar isolateExemplar accession numberExemplar RefSeq numberAvailable sequenceOther isolatesOther isolate accession numbersVirus Abbreviation(s)
Alagoas vesiculovirusvesicular stomatitis Alagoas virus Indiana 3EU373658NC_025353Complete genomeVSAV
American bat vesiculovirusAmerican bat vesiculovirusTFFN-2013JX569193NC_022755Complete coding genomeABVV
Carajas vesiculovirusCarajas virus BeAr 411391KM205015Complete coding genomeCARV
Chandipura vesiculovirusChandipura virus CIN0451GU212856NC_020805Complete coding genomeCHPV
Cocal vesiculovirusCocal virus TRVL40233EU373657NC_028255Complete genomeCOCV
Indiana vesiculovirusvesicular stomatitis Indiana virus 98COE AF473864Complete genomeVSIV
Isfahan vesiculovirusIsfahan virus 91026-167AJ810084NC_020806Complete genomeISFV
Jurona vesiculovirusJurona virusBeAr 40578KM204996Complete coding genomeJURV
Malpais Spring vesiculovirusMalpais Spring virus85-488NMKC412247NC_025364Complete genomeMSPV
Maraba vesiculovirusMaraba virus BeAr 411459HQ660076NC_025255Complete genomeMARV
Morreton vesiculovirusMorreton virusCoAr 191048KM205007NC_034508Complete coding genomeMORV
New Jersey vesiculovirusvesicular stomatitis New Jersey virus NJ89GASJX121110Complete genomeVSNJV
Perinet vesiculovirusPerinet virusDAkAr Mg802HM566195NC_025394Complete coding genomePERV
Piry vesiculovirusPiry virus BeAn 2423KU178986Complete coding genomePIRYV
Radi vesiculovirusRadi virusPh1-166KM205024Complete coding genomeRADV
Yug Bogdanovac vesiculovirusYug Bogdanovac virusYU4-76JF911700NC_025378Complete coding genomeYBV

Virus names, the choice of exemplar isolates, and virus abbreviations, are not official ICTV designations.
Download GenBank/EMBL query for sequences listed in the table here.

Derivation of names

The genus name is derived from vesicular stomatitis and the associated lesions that can occur in the mouth and on hooves and udders of animals infected with some vesiculoviruses. 

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