Rabies Virusby

Tanyaradzwa R Ngara

Introduction

× Rabies was called lyssa or lytta, which means frenzy or madness.

× They named human rabies hydrophobia

× Rabies is a zoonotic (transmitted from animals to human) viral infectious disease.

Rabies Virus

× A group V virus

× carry their genetic material in the form of negative-sense single stranded RNA

× of the order Mononegavirales

× Rhabdovirus, Lyssavirus genus

× The family Rhabdoviridae consists of more than 185 different viruses isolated from both plants and animals

× Susceptible to disinfectants

× Inactivated by drying

Virion properties

× Contain linear, single stranded and negative sense RNA genome.

× Virions are 45-100nm in diameter, 100-430nm long.

× virion has a cylindrical nucleocapsid surrounded by an envelope with large glycoprotein spikes.

× encode for their own RNA polymerase (RNA dependent RNA polymerase).

Genome features

× The genome encodes for 5 genes in the following order.

× 3’ –N-P-M-G-L- 5’ N-

× Nucleocapsid protein

× P- Phosphoprotein- cofactor of the viral polymerase

× M- Inner virion protein/ helps in budding of the virion.

× G- Glycoprotein that assists in making virion spikes

× L- Large protein that represents RNA dependent RNA polymerase and helps in transcription and replication

Genome features

× Linear non-segmented negative sense RNA genome

× Organization of genome- 3'-Leader-Virion core- Surface proteins-Polymerase-Trailer 5'.

× Helical nucleocapsid contains the RNA dependent RNA polymerase.

× The leader RNA is neither capped nor polyadenylated and is not functional as mRNA.

Genome features

× Replication occurs when the polymerase complex ignores the transcription stop signals at the 3’ end of each gene and a full-length positive-sense anti-genome is synthesized.

× Transcription at the gene-start site is not perfect, which leads to a gradient of mRNA abundance that decreases according to the distance from the 3’ end of the genome.

Rabies virus Structure

Viral Life Cycle

Viral Life Cycle

× After receptor binding, rabies virus enters its host cells through the endosomal transport pathway.

× the low pH value induces the membrane fusion process, thus enabling the viral genome to reach the cytosol.

× Both processes of receptor binding and membrane fusion, are catalyzed by the glycoprotein G

× The first step of replication involves mRNA transcription from genomic RNA using RDRP.

Viral life cycle cont..

× For successful replication a large amount of nucleoprotein (N) and phosphoprotein (P) should be expressed.

× Switching of transcription to positive sense antigenomeoccurs after a threshold amount of N and P, which are then further used as a template for synthesis of negative stranded genomic RNA.

Viral life cycle…

× There is a single promoter site at the 3’ end of the viral genome where the polymerase attaches to the genomic RNA template and moves along the viral RNA.

× While moving it hits with start – stop signals at both the ends of the viral genes.

× Due to this only a small fraction undergoes continuous transcription process and hence this phenomenon is also known as attenuated transcription

Viral life cycle cont…

× more mRNA is produced towards the genes that are located at the 3’ end

× *hence producing a gradient of mRNA in the order of N>P>M>G>L.

× As a result of the mRNA gradient, large amount of structural protein such as nucleocapsid protein is produced as compared to L protein

Viral life cycle cont….

× Assembly and Maturation

× Nucleus

× Cytoplasm

× At membrane

Pathogenesis

× mode of transmission of rabies in man is by bite of a rabid animal or the contamination of scratch wounds by virus infected saliva.

× Replicates at site during the incubation period× Moves to nerve root endings× Replicates again× Spreads to the CNS× Vital nerve centers infected - irritable/aggressive× Direct transmission of virus occurs from cell to cell across

synaptic junctions.× Centrifugal spread to salivary glands, skin, etc.× Secreted with saliva communicable× Fatality can occur from two days to five years from the time of

initial infection.

General Symptoms

× Fever

× Headache

× Weakness

× Discomfort

× * Usually exhibited for 2-10 days

More Severe Symptoms

× Insomnia

× Anxiety

× Confusion

× Slight or Partial Paralysis

× Hallucinations

More Severe Symptoms

× Excitation

× Agitation

× Hypersalivation

× Difficulty Swallowing

× Hydrophobia

× * Death usually occurs within days of the onset of the more severe symptoms

Rabies in Animals

Rabid Animals By Frequency

× Dogs

× Raccoons

× Skunks

× Bats

× Foxes

× Rodents & Lagomorphs

Types of Exposure

× Bites

× Non-bites exposure: contamination of open wounds, abrasions, mucous membranes or, theoretically, scratches (potentially contaminated with infectious material from a rabid animal)

× Human to Human Transmission

Epidemiology Global Distribution of lyssaviruses

Epidemiology cont…

× Most of the developing countries in Asia are the victims of rabies.

× 55 000 deaths in Africa and Asia yearly (WHO, 2011)

× One Asian dies every 15 minutes where 15% are likely to be the children under 15 years

× in Bangladesh also where nearly 100,000 people being bitten by dogs in 2009 and 3,000 died of rabies

× In India, about 15 million people are bitten by dogs every year

Epidemiology cont…

Rabies in Africa

× Rabies causes at least 24,000 deaths per year in Africa (WHO, 2013)

× The major cause of spread of rabies in this region is urbanization

× In Rwanda an estimation of 127 Human dog bites was reported (Ministry of Health)

× Most southern African countries like; Angola, Namibia, Mozambique, Zimbabwe are also considered as high risk areas.

Treatment

• After Exposure

× Post exposure treatment consists of

× Local treatment of the wound

× Adminstration of rabies immunoglobins

× Immediate vaccination

Treatment..

× Local Treatment of the wound

• Wash wounds immediately with soap & water

This is the most effective way to decrease the chance of infection

Treatment…

× Patient with confirmed cases of rabies should be

× isolated,

× sedated and transferred to appropriate medical facility

Treatment

Primary Vaccinations

Treatment cont…..

Primary Vaccinations

× Three 1.0-mL injections of HDCV or PCEC vaccine should be administered intramuscularly (deltoid area) -- one injection per day on days 0, 7, and 21 or 28

Treatment

Passive Immunization

× Horse Anti Rabies serum

× Human Rabies immunoglobin (HRIG)

× Booster doses are essential whenever anti rabies serum is given with the vaccine

Prevention

• Eliminating rabies in dogs

× eliminating rabies in dogs through vaccination

× This has reduced the number of human rabies cases in most Latin America

× However recent increases in human rabies deaths suggest that rabies is emerging as a serious public health issue

Prevention cont..

× prevention of human rabies through control of domestic dog rabies is a realistic goal

• Preventive immunization in people

× Safe, effective vaccines also exist for human use

× Pre-exposure immunization in people (Travellers to high-risk areas in rabies affected countries, animals handlers, veterinarians in rabies affected areas

Prevention cont…

• Epidemiological surveillance× Dog bites must be notifiable within national surveillance system

on weekly basis× Collected data should be processed and disseminated rapidly

between different administrative levels

• Steps to be taken after reporting a dog bite× Dog movement: stray or restricted dog?× Circumstances around the bite: is the dog provoked or not?× Dog vaccination status× The offending dog should be contained and observed for 14

days

Applications in Gene Therapy

Neuronal gene transfer

× To treat cardiovascular regions of CNS tissue

× Spinal cord regeneration

Thank You