Rhabdoviruses

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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:

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.

Hogenhout SA, et al. Plant and animal rhabdovirus host range: a bug's view. Trends in Microbiol. 2003 11: 264-271.

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). Primary 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).

The pathogenicity of rabies viruses seems to depend in part on the presence of an arginine or a lysine residue at the position 333 of the glycoprotein. Avirulent rabies virus mutants do not contain these amino-acid residues at this position and two genotypes of lyssavirus, Mokola and Lagos bat, which carry neither arginine nor lysine at position 333 of the glycoprotein are not pathogenic in mice after intramuscular injection.

Epidemiology:

Man is a dead-end infection for the virus, normal hosts are foxes, dogs, cats, bats, skunks, etc. Pattern is endemic rather than epidemic. Cattle rabies is a serious economic disease in countries where rabies is endemic, particularly S. America.

European Bat Lyssavirus:
This virus is widespread in European bats and like other bat Lyssaviruses found worldwide, is similar to but antigenically distinct from classical rabies, meaning that rabies vaccines may be relatively ineffective against infection. European Bat Lyssaviruses show much less variation than rabies virus, which might indicate a close adaptation to their host. It has been suggested that EBL came to Europe from two different directions, North Africa and from the East. These viruses have been responsible for a few deaths when transmitted to humans. Casual contact with bats or bat droppings does not appear to transmit the infection, being bitten or scratched seems to be required.

Treatment:

• Inactivated - as pioneered by Pasteur in the 1880's - used until the 1950's (material from infected animals containing up to 5% nervous tissue - provoked severe immune reactions in recipients, but saved lives). This type of vaccine was then produced by growing the virus in embryonated duck eggs - better, but still produced severe encephalitis in some recipients. Inactivated vaccine is now produced by growing the virus in diploid human fibroblasts - effective and safe but expensive, therefore duck egg-produced material still used in third world.
• Live attenuated - has been used to vaccinate domestic animals and livestock. Effective, but not considered sufficiently safe for human use.
• Recombinant - recently developed recombinant vaccinia virus / G protein vaccine is being used to eradicate rabies in foxes in Europe (Brochier et al, Nature 354: 520 (1991): Raboral V-RG

However, this is a difficult disease to control, and during the last decade, rabies has reemerged in many regions of the USA:

USDA Rabies Wildlife Vaccination Program

Protection against other lyssaviruses:
With classical rabies vaccines, cross-protection correlates to genetic and antigenic distance between the vaccine strain and the challenge strain. The vaccines available today are produced from "fixed strains", all of which belong to genotype 1. They show different degrees of cross-protection towards other genotypes. EBL2 seems to be immunologically close to and very well protected by a vaccine of genotype 1. The African viruses are very distant and are not covered by classical vaccine. The cross- reactivity with EBL1 varies according to the vaccine virus strain.

UK Department of Health current vaccination guidelines

Vesicular Stomatitis Virus (VSV):

VSV normally causes an epidemic, self-limited disease of cattle which is of some economic importance in countries where it is endemic, e.g. N. America, however it has also been described in France and in South Africa. Epidemics occur annually or at intervals of 2 to 3 years in tropical and subtropical countries and at intervals of 5 to 10 years in temperate zones. The disease is similar in appearance to foot & mouth disease! The virus can also infect humans, causing a relatively mild febrile illness.

Conzelmann, K.K. (1998) Nonsegmented Negative-Strand RNA Viruses: Genetics and Manipulation of Viral Genomes. Ann. Rev. Genet. 32: 123-162

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