Morphology:
Genetically, these viruses have non-segmented (-)sense RNA genome reminiscent of Paramyxoviruses. There are >200 Rhabdoviruses known (probably still an underestimate of the total), which infect man (Rabies - the only member of the group to do so 'naturally'), other mammals, fish, insects (some replicate in arthropods and were previously classified as Arboviruses) and plants - versatile! The family is split into 5 genera:
| Lyssavirus (Greek. 'frenzy'): |
Rabies virus; other mammalian viruses; some insect viruses |
|---|---|
| Vesiculovirus: | Vesicular Stomatitis Virus (VSV); mostly insect viruses |
| Ephemerovirus: | Bovine ephemeral fever virus (vertebrates) |
| Cytorhabdovirus: | Lettuce necrotic yellows virus (plants) |
| Nucleorhabdovirus: | Potato yellow dwarf virus (plants) |
Rabies is an 'ancient' disease, first shown to be of infectious origin in 1808, shown to be of viral etiology by Pasteur in the 1880's (when Pasteur and Koch were developing the germ theory of disease - prior to the firm modern definition of 'viruses' by Beijerinick (1898)). Over a decade, Pasteur carried out the serial passage of Rabies virus in rabbits, and eventually succeeded in isolating an attenuated preparation which was used to treat patients bitten by mad dogs (not without some risks).
Morphology:
Particles ca. 180 x 70nm with unique bullet-shaped appearance (all rather similar). Enveloped with prominent spikes on surface (G protein - haemagglutinates RBCs), but not very variable in appearance. The envelope is lined by the matrix protein and contains the nucleocapsid (RNA + N protein) wound helically inside the core. Two non-structural proteins, L and NS, are associated with the nucleocapsid and act in concert as the viral polymerase. As with most enveloped viruses, the particle is relatively labile.
Genome:
~11kb. ~50nt 'leader' region at the 3' end and ~60 non-translated region at the 5' end of the (-)sense vRNA. Similar to paramyxoviruses, there is a conserved polyadenylation signal at the end of each gene and a short intergenic region between each of the 5 genes. Most of our knowledge of Rhabdoviruses comes from Vesicular Stomatitis Virus (VSV) - very similar to Rabies, but the entire rabies genome has now been cloned, sequenced and expressed (see below).
Replication:
Transmission varies depending on virus/host, but most are transmitted by direct contact - e.g. rabies - animal bites or insect vector. There is a long incubation period in vivo, but this is not reflected in the kinetics of virus replication in culture. The G protein spikes bind to receptors on the surface of host cells and the viruses enters the cell by endocytosis and fusion with the membrane of the vesicle (as Paramyxoviruses), mediated by the G protein.
Receptor molecules for Rhabdoviruses are not known, but are believed to be phospholipids rather than specific proteins. Replication occurs in the cytoplasm - both the L and NS proteins are necessary for transcription - neither function alone. Five monocistronic mRNAs are produced, capped at the 5' end and polyadenylated at the 3' end and each containing the leader sequence from the 3' end of the vRNA at the 5' end of the message. These mRNAs are made by sequential transcription of the ORFs in the virus genome and it has been shown that the intergenic sequence is responsible for termination and re-initiation of transcription by the polymerase between each gene, thus producing separate transcripts.
Progeny vRNA is made from a (+)sense intermediate, but this step is not well understood. The genome is replicated by the L + P polymerase complex (as in transcription), but additional host cell factors (not known) are also required. It is characteristic of Rhabdoviruses that these events all occur in a portion of the cytoplasm which acts as a virus 'factory' and appears as a characteristic cytoplasmic inclusion body - e.g. Rabies - perinuclear Negri bodies (Negri, 1909).
Virions are assembled around the tightly coiled nucleoprotein core, and bud both from cytoplasmic membranes and the outer membrane of the cell (acquiring the M + G proteins as they do so).
Pathogenesis: Rabies:
Entry occurs by wound or abrasion of skin directly into bloodstream (animal bite - e.g. vampire bats in S. America). 1o replication occurs locally in muscle and connective tissue (no symptoms), but virus eventually infects peripheral nerves, then travels (passively?) along neuronal axons to CNS, where it produces severe and fatal encephalitis. Few cases escape these severe consequences. Viraemia and haematogenous spread of virus to CNS has not been shown. Incubation period varies from 3-8 weeks to 1 year depending on size and site of inoculation (e.g. head/face/neck vs. hands or feet).