Rabies Virus- An Overview

Structure of Rabies Virus

  • The virus is enveloped, rod shaped particles measuring 75 × 180 nm.
  • Mature virion appears either as bullet shaped particles with one rounded and one flattened end or as bacilliform particles.
  • The particles are surrounded by a membranous lipid envelope.
  • The particles have a buoyant density in CsCl of about 1.19 g/cm3.
  • The virion outer surface is covered with protruding spikes which is 10nm long.
  • The peplomers (spikes) are composed of trimers of the viral glycoprotein.
  • Inside the envelope is a ribonucleocapsid which encloses single-stranded, negative-sense RNA genome (12 kb; molecular weight 4.6 *10ˆ6).
  • The genome encode for five proteins designated as glycoprotein(G), nucleoprotein(N), phosphoprotein(P), matrix protein(M) and large polymerase protein(L).
Structure of Rabies Virus
Source: Davidson College

Genome of Rabies Virus

  • The rabies virus genome is composed of approximately 12000 nucleotides.
  • It is single-stranded RNA, linear, non-segmented, negative sense.
Genome of Rabies Virus
Source: CDC
  • The genomic RNA encodes for the five different viral proteins: nucleoprotein(N), phosphoprotein (P), matrix protein (M), glycoprotein (G) and the large polymerase protein (L).
  • The viral ribonucleoprotein (RNP) core consists of the viral RNA encapsidated by N proteins and associated with the P and L proteins.
  • The other viral proteins, M and G are involved in virion structure and attachment to cellular receptors, respectively.
  • The intergenic region (G-L) is approximately 450 nucleotides in length and does not appear to encode any polypeptides.

Epidemiology of Rabies Virus

  • Rabies infection in man is generally acquired from the bite of an infected animal.
  • The domestic dog (Canis familiaris) is the most important vector, although bat rabies continues to cause human infection across much of Central and South America.
Epidemiology of Rabies Virus
Source: WHO
  • The virus still remains endemic across much of the developing world, where the majority (99%) of human deaths due to rabies occur, mainly in Africa and Asia although extensive vaccination campaigns in dog and terrestrial wildlife populations have reduced the incidence across globe.
  • The World Health Organization (WHO) estimates an annual toll of 55 000 deaths following human infection with rabies virus, although this is likely to be a gross underestimate.

Transmission of Rabies Virus

  • Bite of infected rabid animal
  • Contact of saliva with broken skin or with mucous membrane
  • Corneal transplant

Replication of Rabies Virus

Replication of Rabies Virus
Source: NPTEL
  • Infection spreads through the bite of infected rabid animal.
  • A significant interaction of G protein and acetylcholine receptors of peripheral nervous system  provide evidence of virus attachment.
  • The virus then gains entry to central nervous system, entry mediated through mechanism called endocytosis.
  • Within the endosome, the pH lowers which bring about the conformational changes in the G protein that promotes the fusion of viral membrane to endosomal membrane resulting in release of viral nucleocapsid.
  • The single-stranded RNA genome is transcribed into positive sense mRNA by the virion-associated RNA polymerase.
  • The monocistronic mRNAs code for the five virion proteins: nucleocapsid (N), polymerase proteins (L, P), matrix (M), and glycoprotein (G).
  • 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 genome RNP is a template for complementary positive-sense RNA, which is responsible for the generation of negative-sense progeny RNA.
  • 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.
  • The viral matrix protein forms a layer on the inner side of the envelope, whereas the viral glycoprotein is on the outer layer and forms the spikes.

Pathogenesis of Rabies Virus

  • After inoculation of infectious saliva by bite, virus may persist and replicate in muscle tissue before progressing to the peripheral nervous tissue via neuromuscular junction.
  • Neurotropsim is a main feature associated with viral replication residing exclusively to neurons.
  • A significant interaction of G protein and acetylcholine receptor provide evidence of viral attachment.
  • After peripheral nerve entry, virus moves centripetally within axons to the CNS via transportation by retrograde axonal flow.

Pathogenesis of Rabies Virus

  • Incubation period is dependent on the distance between site of bite and CNS.
  • Apart from this, it also depends on age of host, immune status of host, viral strain involved and amount of inoculation.
  • In the CNS, the multiplication of the virus occurs in the grey matter and spreads in the endoneurium of Schwann cell.
  • Virus spread may be facilitated by movement across cell to cell junctions.
  • After period of multiplication, it disseminate into tissues and organs via efferent neurons.

Clinical manifestations of Rabies Virus

  • The disease is an acute, fulminant, fatal encephalitis.
  • The incubation period in humans is typically 1–3 months but may be as short as 1 week or more than a year.
  • The clinical spectrum can be divided into three phases: a short prodromal phase, an acute neurologic phase, and coma.

Clinical manifestations of Rabies Virus

  • The prodrome, lasting 2–10 days, may show any of the following nonspecific symptoms: malaise, anorexia, headache, photophobia, nausea and vomiting, sore throat, and fever.
  • During the acute neurologic phase, which lasts 2–7 days, patients show signs of nervous system dysfunction such as nervousness, apprehension, hallucinations, and bizarre behavior.
  • Beside these, general sympathetic overactivity is observed, including lacrimation, pupillary dilatation, and increased salivation and perspiration.
  • Hydrophobia (fear of water) or aerophobia (fear when feeling a breeze) is exhibited by number of patients.
  • The act of swallowing precipitates a painful spasm of the throat muscles.
  • Neurologic phase is followed by convulsive seizures or coma and death.
  • The major cause of death is cardiorespiratory arrest.
  • The disease course is slower, with some patients surviving 30 days.
  • However, recovery and survival are extremely rare.

Diagnosis of Rabies Virus

Specimen: saliva, corneal biopsy, brain tissue, neck skin biopsy

Histopathology

  • Detection of Negri bodies by Seller’s staining technique which comprises use of basic fuchsin and methylene blue.
Diagnosis of Rabies Virus
Source: CDC
  • Negri bodies are purplish pink, sharply demarcated, more or less spherical, and 2–10 μm in diameter, and they have a distinctive internal structure with basophilic granules in an eosinophilic matrix.

Antigen detection

  • Tissues infected with rabies virus are currently identified most rapidly and accurately by means of immunofluorescence or immunoperoxidase staining using antirabies monoclonal antibodies.

Antibody detection

  • Antibodies develop slowly in infected persons or animals during progression of the disease but promptly after vaccination with cell-derived vaccines.
  • Serum antibodies to rabies can be detected by immunofluorescence or neutralization tests.

Virus isolation

  • Available tissue is inoculated intracerebrally into suckling mice.
  • Infection in mice results in encephalitis and death.
  • The central nervous system of the inoculated animal is examined for Negri bodies and rabies antigen.
  • However, virus isolation takes too long to be useful in making a decision about whether to give vaccine.

Molecular method

  • Reverse transcription-polymerase chain reaction testing can be used to amplify parts of a rabies virus genome from fixed or unfixed brain tissue or saliva.
  • Sequencing of amplified products using Nucleic Acid Sequence Based Amplification can allow identification of the infecting virus strain.

Treatment of Rabies Virus

  • No successful treatment in clinical use.

Management, Prevention and Control of Rabies Virus

  • This include preexposure and post exposure prophylaxis.
  • Preexposure prophylaxis is given to individuals who are at risk that include veterians, animal handlers, laboratory workers.
  • Human diploid cell line vaccine (HDCV)  is given at two doses at 4 weeks interval.

Management, Prevention and Control of Rabies Virus

  • Post exposure prophylaxis includes
  • Animal examination for 10days for symptoms and are then killed.
  • Wound management by surgical debrigement and cleaning of wound with soap and water and quaternary ammonium compounds.
  • Passive immunization using Human Rabies Immune globulin (HRIG) collected from immunized persons and infiltrated at site of wound or administered intramuscularly as soon as possible after rabies exposure.
  • Active immunization with modern tissue culture vaccines consists of a series of four doses, all administered intramuscularly in the deltoid region, 1 mL each, over a 2-week period (days 0, 3, 7, and 14).
  • For persons with immunosuppression, the recommended postexposure prophylaxis series includes five doses of vaccine administered on days 0, 3, 7, 14, and 30.
  • Use of both active and passive immunization is strongly recommended for proper treatment.

About Author

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Sagar Aryal

Sagar Aryal is a microbiologist and a scientific blogger. He is doing his Ph.D. at the Central Department of Microbiology, Tribhuvan University, Kathmandu, Nepal. He was awarded the DAAD Research Grant to conduct part of his Ph.D. research work for two years (2019-2021) at Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Saarbrucken, Germany. Sagar is interested in research on actinobacteria, myxobacteria, and natural products. He is the Research Head of the Department of Natural Products, Kathmandu Research Institute for Biological Sciences (KRIBS), Lalitpur, Nepal. Sagar has more than ten years of experience in blogging, content writing, and SEO. Sagar was awarded the SfAM Communications Award 2015: Professional Communicator Category from the Society for Applied Microbiology (Now: Applied Microbiology International), Cambridge, United Kingdom (UK).

10 thoughts on “Rabies Virus- An Overview”

  1. Thanks for sharing. I have 2 comments :
    1- For some reasons, we can not receive the brain biopsy. We do real-time PCR on nuchal skin
    2- For post exposition vaccination, there’s the Zagreb protocol :
    2 J0 – 1 J7 – 1 J21

    Reply
  2. Thanks for sharing. I have 2 comments :
    1- We also do molecular diagnostic by real time PCR on skin biopsy. Sometimes it’s very difficult to get the brain biopsy.
    2- For post-exposition vaccination, there is the Zagreb protocole :
    2 shots J0 – 1 J7 and 1 J21.

    Reply

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