Rabies is a preventable viral disease most often transmitted through the bite of a rabid animal. The rabies virus infects the central nervous system of mammals, ultimately causing disease in the brain and death. The vast majority of rabies cases reported to the Centers for Disease Control and Prevention (CDC) each year occur in wild animals like bats, raccoons, skunks, and foxes, although any mammal can get rabies.
Rabies virus belongs to the order Mononegavirales, viruses with a nonsegmented, negative-stranded RNA genome. Within this group, viruses with a distinct “bullet” shape are classified in the Rhabdoviridae family, which includes at least three genera of animal viruses, Lyssavirus, Ephemerovirus, and Vesiculovirus. The genus Lyssavirus includes rabies virus, Lagos bat, Mokola virus, Duvenhage virus, European bat virus 1 & 2 and Australian bat virus.
Structure
Rhabdoviruses are approximately 180 nm long and 75 nm wide. The rabies genome encodes five proteins: nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G) and polymerase (L). All rhabdoviruses have two major structural components: a helical ribonucleoprotein core (RNP) and a surrounding envelope. In the RNP, genomic RNA is tightly encased by the nucleoprotein. Two other viral proteins, the phosphoprotein and the large protein (L-protein or polymerase) are associated with the RNP.
The glycoprotein forms approximately 400 trimeric spikes which are tightly arranged on the surface of the virus. The M protein is associated both with the envelope and the RNP and maybe the central protein of rhabdovirus assembly. The basic structure and composition of the rabies virus are depicted in the longitudinal diagram below.
Rabies is an RNA virus. The genome encodes 5 proteins designated as N, P, M, G, and L. The order and relative size of the genes in the genome are shown in the figure below. The arrangement of these proteins and the RNA genome determine the structure of the rabies virus.
Replication
The fusion of the rabies virus envelope to the host cell membrane (adsorption) initiates the infection process. The interaction of the G protein and specific cell surface receptors may be involved.
After adsorption, the virus penetrates the host cell and enters the cytoplasm by pinocytosis (via clathrin-coated pits). The virions aggregate in the large endosomes (cytoplasmic vesicles). The viral membranes fuse to the endosomal membranes, causing the release of viral RNP into the cytoplasm (uncoating). Because lyssaviruses have a linear single-negative-stranded ribonucleic acid (RNA) genome, messenger RNAs (mRNAs) must be transcribed to permit virus replication.
A viral-encoded polymerase (L gene) transcribes the genomic strand of rabies RNA into leader RNA and five capped and polyadenylated mRNAs, which are translated into proteins. Translation, which involves the synthesis of the N, P, M, G and L proteins, occurs on free ribosomes in the cytoplasm. Although G protein synthesis is initiated on free ribosomes, completion of synthesis and glycosylation (processing of the glycoprotein), occurs in the endoplasmic reticulum (ER) and Golgi apparatus. The intracellular ratio of leader RNA to N protein regulates the switch from transcription to replication. When this switch is activated, replication of the viral genome begins. The first step in viral replication is the synthesis of full-length copies (positive strands) of the viral genome. When the switch to replication occurs, RNA transcription becomes “non-stop” and stop codons are ignored. The viral polymerase enters a single site on the 3’ end of the genome and proceeds to synthesize full-length copies of the genome. These positive strands of rabies RNA serve as templates for the synthesis of full-length negative strands of the viral genome.
During the assembly process, the N-P-L complex encapsulates negative-stranded genomic RNA to form the RNP core, and the M protein forms a capsule, or matrix, around the RNP. The RNP-M complex migrates to an area of the plasma membrane containing glycoprotein inserts, and the M-protein initiates coiling. The M-RNP complex binds with the glycoprotein and the completed virus buds from the plasma membrane. Within the central nervous system (CNS), there is preferential viral budding from plasma membranes. Conversely, virus in the salivary glands buds primarily from the cell membrane into the acinar lumen. Viral budding into the salivary gland and virus-induced aggressive biting-behavior in the host animal maximize the chances of viral infection of a new host.
Vertebrate host, arthropod vector
Genus Curiovirus. Curioviruses have been isolated from midges, sandflies, and mosquitoes. Vertebrate hosts are largely unknown but there is evidence of infection of birds. The genome features one or more genes located between the M and G genes, and one or more genes located between the G and L genes, including a gene encoding a viroporin-like protein.
Genus Ephemerovirus. Viruses assigned to the genus have been isolated primarily from livestock, mosquitoes or midges. Some cause an acute febrile illness in bovines that is seldom fatal. The genome of ephemeroviruses features multiple genes between the G and L genes encoding accessory proteins including a non-structural class I transmembrane glycoprotein (GNS) and a viroporin (α1).
Genus Hapavirus. This genus comprises viruses that have been isolated from mosquitoes or midges and that infect birds and mammals. The genome of hepaciviruses is large and complex, featuring multiple accessory genes between P and M genes, and between G and L genes, usually including a gene encoding a viroporin-like protein.
Genus Ledantevirus. Ledanteviruses infect mammals; many have been isolated from bats or rodents and some (or all) may be transmitted by arthropods. Some have been associated with disease in humans or livestock. The genome is relatively simple but some viruses feature an additional gene between the G and L genes encoding a small protein of unknown function.
Genus Sripuvirus. Viruses assigned to this genus have been isolated from either sandflies or lizards. The genome of scrip viruses features a small protein encoded in a consecutive ORF in the M gene and a small transmembrane protein encoded in an alternative ORF at the start of the G gene.
Genus Tibrovirus. Some tibroviruses infect cattle and water buffalo and are transmitted by midges; several other tibroviruses have been detected in humans but their role in human disease is currently unclear. The genome features two accessory genes between the M and G genes, and a gene encoding a viroporin-like protein between the G and L genes.
Genus Vesiculovirus. Vesiculoviruses infect a wide range of vertebrate hosts and are transmitted by insects; some may also be transmitted amongst vertebrates by direct contact. Several vesiculoviruses cause vesicular stomatitis in livestock and/or have been associated with influenza-like illness and occasional encephalitis in humans. The genome is relatively simple, containing the five structural protein genes and short intergenic regions, but may also include alternative ORFs in the P gene and use of alternative initiation codons in the M gene.
Invertebrate host
Genus Almendravirus. The viruses assigned to this genus were isolated from mosquitoes and appear to be poorly adapted (or not adapted) to replication in vertebrates. The genome of almendraviruses features an additional gene located between the G and L genes, encoding a small viroporin-like protein.
Genus Alphanemrhavirus. This genus comprises viruses that have been detected by high-throughput sequencing in parasitic nematodes (roundworms of the phylum Nematoda). The genome of alphanemrhaviruses is relatively simple, containing the five structural protein genes, but may include an additional small ORF in the M gene (Mx) overlapping the end of the M ORF. No alphanemrhaviruses have yet been isolated.
Genus Caligrhavirus. Caligrhaviruses have been detected in sea lice (crustaceans in the family Caligidae) in which they appear to cause active infections. The caligrhavirus genome is relatively simple, containing the five structural protein genes, but may include an additional gene (U1) between the G and L genes. No caligrhaviruses have yet been isolated but virions have been observed by electron microscopy.
Genus Sigma virus. Sigmaviruses are transmitted vertically, each virus infecting a fly of a single species in the families Drosophilidae or Muscidae. Infection results in paralysis or death of flies upon exposure to carbon dioxide. The genome may feature an additional gene (X) located between the M and G genes, encoding a protein of unknown function.
Plant host
Genus Cytorhabdovirus. Viruses assigned to this genus infect a wide range of plants and are transmitted by arthropod vectors (aphids, planthoppers, and leafhoppers) in which they replicate. In plant cells, cytorhabdoviruses replicate in the cytoplasm. Cytorhabdoviruses have an unsegmented genome featuring an additional gene located between the P gene and M gene, encoding a movement protein; some may also encode a viroporin-like protein.
Genus Dichorhavirus. Dichorhaviruses infect plants and are transmitted by Brevipalpus mites. They cause localized lesions on leaves, stems, and fruits of economically important plants such as citrus, coffee, and orchids. The genome of picornaviruses is bi-segmented: RNA1 contains the N, P, M and G genes, and an additional gene located between the P gene and M gene encoding a putative movement protein; RNA2 contains the L gene. Virions formed in plant cells may lack envelopes.
Genus Nucleorhabdovirus. Nucleorhabdoviruses infect a wide range of plants and are transmitted by arthropod vectors (aphids, planthoppers, leafhoppers) in which they replicate. Nucleorhabdoviruses replicate in the nucleus of infected plant cells. Nucleorhabdoviruses cluster phylogenetically with the bi-segmented dichorhaviruses. They feature an additional gene between the P gene and the M gene encoding a movement protein.
Genus Varicosavirus. Varicosaviruses occur naturally in two families of plants (Compositae and Solanaceae) and are transmitted in soil and zoospores of a chytrid fungus, Olpidium brassicas. The genome is bi-segmented: RNA1 contains an ORF encoding a small protein followed by the L gene; RNA2 contains 5 ORFs including the coat protein gene. Virions observed in plant cells are non-enveloped rods resembling intracellular nucleocapsids of other rhabdoviruses.