The rabies virus virion(Nat Rev Microbiol. 2010 Jan)

Rabies is a viral encephalomyelitis of humans or other warm-blooded animals. It can be naturally infected and spread among domestic animals and wild animals. Once clinical symptoms appear after infection, the fatality rate is almost 100%. The causative agent is Rabies virus (RABV) belonging to the Rhabdoviridae family. RABV is a negative-strand RNA virus with a typical bullet shape and a genome of about 12 knt in length. From the 3' end to the 5' end, there are five structural genes encode five structural proteins N(Nucleoprotein), P(Phosphprotein), M (Matrixprotein),G(Glycoprotein)and L(RNA-dependent RNA polymerase)respectively . Non-overlapping and the lengths are 1424, 991, 805 and 1675nt. The rabies virus genome is negative-strand RNA, and the viral RNA cannot act as mRNA. It needs to first synthesize five corresponding mRNAs under the action of viral RNA polymerase, and then translate them into viral proteins. Among them, the combination of G protein and M protein forms a lipoprotein double-layer envelope wrapped virion shell, which wraps the viral genome RNA, N protein, P protein and L protein.

In 2005, Willoughby used Milwaukee therapy to successfully save an unvaccinated rabies patient. The patient received sedative drugs and antiviral drugs to maintain the sedation of the body and prolong the survival time. Neutralizing antibodies induced by the autoimmune system. Finally, the clearance of RABV in vivo and the rescue of the patient were achieved. There is currently no effective treatment for rabies, and neutralizing antibodies are still the only way to clear RABV from the body.

Nucleoprotein (P16285)

Encapsidates the genome in a ratio of one protein N per nine ribonucleotides, protecting it from nucleases. If expressed without protein P it binds non-specifically RNA and therefore can bind it's own mRNA. Interaction with protein P abolishes any non-specific RNA binding, and prevents phosphorylation. The soluble N-P complex encapsidates specifically the genomic RNA, with protein N protecting the genome like a pearl necklace. The encapsidated genomic RNA is termed the nucleocapsid (NC) and serves as template for viral transcription and replication. Protein N binds protein P in the NC through a different interaction, and can be phosphorylated. Subsequent viral replication is dependent on intracellular concentration of newly synthesized protein N. During replication, encapsidation by protein N is coupled to RNA synthesis and all replicative products are resistant to nucleases.

Phosphoprotein(P22363)

Non catalytic polymerase cofactor and regulatory protein that plays a role in viral transcription and replication. Stabilizes the RNA polymerase L to the N-RNA template and binds the soluble protein N, preventing it from encapsidating non-genomic RNA. Also inhibits host IFN-alpha and IFN-beta signaling by binding and retaining phosphorylated STAT1 in the cytoplasm or by inhibiting the DNA binding of STAT1 in the nucleus. Might be involved, through interaction with host dynein, in intracellular microtubule-dependent virus transport of incoming virus from the synapse toward the cell body.

Matrix protein(P16287)

Plays a major role in assembly, budding and uncoating of virion after membrane fusion.

Completely covers the ribonucleoprotein coil and keep it in condensed bullet-shaped form. Inhibits viral transcription and stimulates replication. Plays a major role in early induction of TRAIL-mediated apoptosis in infected neurons

Glycoprotein(P03524)

Attaches the virus to host cellular receptor, inducing endocytosis of the virion. In the endosome, the acidic pH induces conformational changes in the glycoprotein trimer, which trigger fusion between virus and cell membrane. There is convincing in vitro evidence that the muscular form of the nicotinic acetylcholine receptor (nAChR), the neuronal cell adhesion molecule (NCAM), and the p75 neurotrophin receptor (p75NTR) bind glycoprotein and thereby facilitate rabies virus entry into cells.

Large structural protein(P16289)

RNA-directed RNA polymerase that catalyzes the transcription of viral mRNAs, their capping and polyadenylation. The template is composed of the viral RNA tightly encapsidated by the nucleoprotein (N). The viral polymerase binds to the genomic RNA at the 3' leader promoter, and transcribes subsequently all viral mRNAs with a decreasing efficiency. The first gene is the most transcribed, and the last the least transcribed. The viral phosphoprotein acts as a processivity factor. Capping is concommitant with initiation of mRNA transcription. Indeed, a GDP polyribonucleotidyl transferase (PRNTase) adds the cap structure when the nascent RNA chain length has reached few nucleotides. Ribose 2'-O methylation of viral mRNA cap precedes and facilitates subsequent guanine-N-7 methylation, both acticities being carried by the viral polymerase. Polyadenylation of mRNAs occur by a stuttering mechanism at a slipery stop site present at the end viral genes. After finishing transcription of a mRNA, the polymerase can resume transcription of the downstream gene.

References

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