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Classification
Rabies virus belongs to the order Mononegavirales, viruses with
a nonsegmented, negative-stranded RNA genomes. 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 are 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 phospoprotein 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 may be
the central protein of rhabdovirus assembly. The basic structure and composition
of rabies virus is depicted in the longitudinal diagram below.
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Rabies
virions are bullet-shaped with 10-nm spike-like glycoprotein
peplomers covering the surface. The ribonucleoprotein
is composed of RNA encased in nucleoprotein -(), phosphorylated
or phosphoprotein - ,
and polymerase - . |
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The
cross-sectional diagram below demonstrates the concentric layers: envelope
membrane bilayer, M protein, and tightly coiled encased genomic RNA.
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.
The
rabies virus genome is single-stranded, antisense, nonsegmented, RNA of
approximately 12 kb. There is a leader-sequence (LDR) of approximately
50 nucleotides, followed by N, P, M, G, and L genes.
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 endoplamsic
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 synthesis of full-length copies
(postive 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 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 chances of viral
infection of a new host.
For
more detailed information on rhabdovirus structure, see:
1. Wunner W.H. (1991). The chemical composition and molecular structure
of rabies viruses. In G. M. Baer (Ed.), The Natural
History of Rabies. (pp. 31-67). Boca Raton, FL: CRC
Press.
2.
Conzelmann K.K. (1998). Nonsegmented negative-stranded RNA viruses:
Genetics and manipulation of viral genomes. Ann. Rev. Genet.32:123-162.
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