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The next step after entry is the [[Transcription (genetics)|transcription]] of the viral genome by the P-L polymerase (P is an essential cofactor for the L polymerase) in order to make new viral protein. The viral polymerase can only recognize [[ribonucleoprotein]] and cannot use free RNA as template. Transcription is regulated by [[Cis-regulatory element|''cis''-acting sequences]] on the virus genome and by protein M which is not only essential for virus budding but also regulates the fraction of mRNA production to replication.
The next step after entry is the [[Transcription (genetics)|transcription]] of the viral genome by the P-L polymerase (P is an essential cofactor for the L polymerase) in order to make new viral protein. The viral polymerase can only recognize [[ribonucleoprotein]] and cannot use free RNA as template. Transcription is regulated by [[Cis-regulatory element|''cis''-acting sequences]] on the virus genome and by protein M which is not only essential for virus budding but also regulates the fraction of mRNA production to replication.
Later in infection, the activity of the polymerase switches to replication in order to produce full-length positive-strand RNA copies. These complementary RNAs are used as templates to make new negative-strand RNA genomes. They are packaged together with protein N to form [[ribonucleoprotein]] which then can form new viruses.<ref name="pmid17938861"/>
Later in infection, the activity of the polymerase switches to replication in order to produce full-length positive-strand RNA copies. These complementary RNAs are used as templates to make new negative-strand RNA genomes. They are packaged together with protein N to form [[ribonucleoprotein]] which then can form new viruses.<ref name="pmid17938861"/>

==Replication==
When a human or animal is injected with infected saliva, the rabies virus replicates at the site of inoculation. Aided by the G protein, the viral envelope attaches and fuses with the host cell membrane (Figure 4, part 2). Invagination of the plasma membrane with clathrin-coated pits allows cytoplasmic absorption via pinocytosis. The virions aggregate with the large endosomes, and after fusion with their membranes, they initiate the uncoating and release of the viral RNP into the cytoplasm. Since the rabies virus has a linear –ssRNA genome, messenger RNAs are produced to permit virus replication using the host cell machinery. In particular, translation of the genome occurs on the free ribosomes in the cytoplasm, and some posttranslational processing occurs in the endoplasmic reticulum and Golgi apparatus.


==Infection==
==Infection==

Revision as of 23:29, 19 March 2012

This article is about the virus. For the disease, see Rabies. For other uses, see Rabies (disambiguation).

Wikipedia
Virus classification
Group:
Group V ((−)ssRNA)
Order:
Mononegavirales
Family:
Rhabdoviridae
Genus:
Lyssavirus
Species:
Rabies
TEM micrograph with numerous rabies virions (small dark-grey rod-like particles) and Negri bodies (the larger pathognomonic cellular inclusions of rabies infection)

The rabies virus is a neurotropic virus that causes fatal disease in human and animals. Rabies transmission can occur through the saliva of animals.

The rabies virus has a cylindrical morphology and is the type species of the Lyssavirus genus of the Rhabdoviridae family. These viruses are enveloped and have a single stranded RNA genome with negative-sense. The genetic information is packaged as a ribonucleoprotein complex in which RNA is tightly bound by the viral nucleoprotein. The RNA genome of the virus encodes five genes whose order is highly conserved. These genes code for nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G) and the viral RNA polymerase (L).[1]

All transcription and replication events take place in the cytoplasm inside a specialized “virus factory“, the Negri body (named after Adelchi Negri[2]). These are 2–10 µm in diameter and are typical for a rabies infection and thus have been used as definite histological proof of such infection.[3]

Structure

Lyssaviruses have helical symmetry, so their infectious particles are approximately cylindrical in shape. They are characterized by an extremely broad host spectrum ranging from plants to insects and mammals; human-infecting viruses more commonly have cubic symmetry and take shapes approximating regular polyhedra.

The virus has a bulletlike shape with a length of about 180 nm and a cross-sectional diameter of about 75 nm. One end is rounded or conical and the other end is planar or concave. The lipoprotein envelope carries knob-like spikes composed of Glycoprotein G. Spikes do not cover the planar end of the virion (virus particle). Beneath the envelope is the membrane or matrix (M) protein layer which may be invaginated at the planar end. The core of the virion consists of helically arranged ribonucleoprotein.

Life cycle

Template:Viral life cycle After receptor binding, rabies virus enters its host cells through the endosomal transport pathway. Inside the endosome, the low pH value induces the membrane fusion process, thus enabling the viral genome to reach the cytosol. Both processes, receptor binding and membrane fusion, are catalyzed by the glycoprotein G which plays a critical role in pathogenesis (mutant virus without G proteins cannot propagate).[1]

The next step after entry is the transcription of the viral genome by the P-L polymerase (P is an essential cofactor for the L polymerase) in order to make new viral protein. The viral polymerase can only recognize ribonucleoprotein and cannot use free RNA as template. Transcription is regulated by cis-acting sequences on the virus genome and by protein M which is not only essential for virus budding but also regulates the fraction of mRNA production to replication. Later in infection, the activity of the polymerase switches to replication in order to produce full-length positive-strand RNA copies. These complementary RNAs are used as templates to make new negative-strand RNA genomes. They are packaged together with protein N to form ribonucleoprotein which then can form new viruses.[3]

Replication

When a human or animal is injected with infected saliva, the rabies virus replicates at the site of inoculation. Aided by the G protein, the viral envelope attaches and fuses with the host cell membrane (Figure 4, part 2). Invagination of the plasma membrane with clathrin-coated pits allows cytoplasmic absorption via pinocytosis. The virions aggregate with the large endosomes, and after fusion with their membranes, they initiate the uncoating and release of the viral RNP into the cytoplasm. Since the rabies virus has a linear –ssRNA genome, messenger RNAs are produced to permit virus replication using the host cell machinery. In particular, translation of the genome occurs on the free ribosomes in the cytoplasm, and some posttranslational processing occurs in the endoplasmic reticulum and Golgi apparatus.

Infection

In September 1931, Dr. Poupe Charles Jones of Trinidad in the West Indies, a Government Bacteriologist, found Negri bodies in the brain of a bat with unusual habits. He said that a rabies virus was key to the curing of Lyssophobia. In 1932, Dr. Russ Pfister first discovered that infected vampire bats could transmit rabies to humans and other animals.[4][5]

From the wound of entry, the rabies virus travels quickly along the neural pathways of the peripheral nervous system. The retrograde axonal transport of the rabies virus to the CNS is the key step of pathogenesis during natural infection. The exact molecular mechanism of this transport is unknown although binding of the P protein from rabies virus to the dynein light chain protein DYNLL1 has been shown.[6] P also acts as an interferon antagonist, thus decreasing the immune response of the host.

From the CNS, the virus further spreads to other organs. The salivary glands located in the tissues of the mouth and cheeks receive high concentrations of the virus, thus allowing it to be further transmitted due to projectile salivation. Fatality can occur from two days to five years from the time of initial infection.[7] This however depends largely on the species of animal acting as a reservoir. Most infected mammals die within weeks, while strains of a species such as the African Yellow Mongoose (Cynictis penicillata) might survive an infection asymptomatically for years.[8]

Antigenicity

Upon viral entry into the body and also after vaccination, the body produces virus neutralizing antibodies which bind and inactivate the virus. Specific regions of the G protein have been shown to be most antigenic in leading to the production of virus neutralizing antibodies. These antigenic sites, or epitopes, are categorized into regions I-IV and minor site a. Previous work has demonstrated that antigenic sites II and III are most commonly targeted by natural neutralizing antibodies[9]. Additionally, a monoclonal antibody with neutralizing functionality has been demonstrated to target antigenic site I[10]. Other proteins, such as the nucleoprotein, have been shown to be unable to elicit production of virus neutralizing antibodies[11]. The epitopes which bind neutralizing antibodies are both linear and conformational[12].

Evolution

All extant rabies viruses appear to have evolved within the last 1500 years.[13]

There are seven genotypes of rabies virus. In Eurasia cases are due to three of these - genotype 1 (classical rabies) and to a lesser extent genotypes 5 and 6 (European bat lyssaviruses type-1 and -2).[14] Genotype 1 evolved in Europe in the 17th century and spread to Asia, Africa and the Americas as a result of European exploration and colonization.

References

  1. ^ a b Finke S, Conzelmann KK (2005). "Replication strategies of rabies virus". Virus Res. 111 (2): 120–131. doi:10.1016/j.virusres.2005.04.004. PMID 15885837. {{cite journal}}: Unknown parameter |month= ignored (help)
  2. ^ synd/2491 at Who Named It?
  3. ^ a b Albertini AA, Schoehn G, Weissenhorn W, Ruigrok RW (2008). "Structural aspects of rabies virus replication". Cell. Mol. Life Sci. 65 (2): 282–294. doi:10.1007/s00018-007-7298-1. PMID 17938861. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ Pawan(1936), pp. 137-156.
  5. ^ Pawan, J.L. (1936b). "Rabies in the Vampire Bat of Trinidad with Special Reference to the Clinical Course and the Latency of Infection." Annals of Tropical Medicine and Parisitology. Vol. 30, No. 4. December, 1936.
  6. ^ Raux H, Flamand A, Blondel D (2000). "Interaction of the rabies virus P protein with the LC8 dynein light chain". J. Virol. 74 (21): 10212–10216. doi:10.1128/JVI.74.21.10212-10216.2000. PMC 102061. PMID 11024151. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ "Rabies". University of Northern British Columbia. Retrieved 2008-10-10. {{cite web}}: Cite has empty unknown parameters: |month= and |coauthors= (help)
  8. ^ Taylor PJ (1993). "A systematic and population genetic approach to the rabies problem in the yellow mongoose (Cynictis penicillata)". Onderstepoort J. Vet. Res. 60 (4): 379–87. PMID 7777324. {{cite journal}}: Unknown parameter |month= ignored (help)
  9. ^ Benmansour A (1991). "Antigenicity of rabies virus glycoprotein". Journal of Virology. 65 (8): 4198–4203. PMID 1712859. {{cite journal}}: Cite has empty unknown parameter: |month= (help)
  10. ^ Marissen, WE.; Kramer, RA.; Rice, A.; Weldon, WC.; Niezgoda, M.; Faber, M.; Slootstra, JW.; Meloen, RH.; Clijsters-van der Horst, M. (2005). "Novel rabies virus-neutralizing epitope recognized by human monoclonal antibody: fine mapping and escape mutant analysis". J Virol. 79 (8): 4672–8. doi:10.1128/JVI.79.8.4672-4678.2005. PMID 15795253. {{cite journal}}: Unknown parameter |month= ignored (help)
  11. ^ Wiktor, TJ.; György, E.; Schlumberger, D.; Sokol, F.; Koprowski, H. (1973). "Antigenic properties of rabies virus components". J Immunol. 110 (1): 269–76. PMID 4568184. {{cite journal}}: Unknown parameter |month= ignored (help)
  12. ^ Bakker, AB.; Marissen, WE.; Kramer, RA.; Rice, AB.; Weldon, WC.; Niezgoda, M.; Hanlon, CA.; Thijsse, S.; Backus, HH. (2005). "Novel human monoclonal antibody combination effectively neutralizing natural rabies virus variants and individual in vitro escape mutants". J Virol. 79 (14): 9062–8. doi:10.1128/JVI.79.14.9062-9068.2005. PMID 15994800. {{cite journal}}: Unknown parameter |month= ignored (help)
  13. ^ Nadin-Davis SA, Real LA (2011) Molecular phylogenetics of the lyssaviruses--insights from a coalescent approach. Adv Virus Res 79:203-238
  14. ^ McElhinney LM, Marston DA, Stankov S, Tu C, Black C, Johnson N, Jiang Y, Tordo N, Müller T, Fooks AR (2008) Molecular epidemiology of lyssaviruses in Eurasia. Dev Biol (Basel) 131:125-131
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