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51237950292001610830 – 1606590 – 1607246
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centercenterKing Abdulaziz University
Rabies
Dr.Sanaa Alattas
Ghaida Almatari – Raghad Alabih – Sultana Zabarmawi
100000100000King Abdulaziz University
Rabies
Dr.Sanaa Alattas
Ghaida Almatari – Raghad Alabih – Sultana Zabarmawi
Content:
Introduction………………………………………………………2
History of viruses………………………………………………3
Structure……………………………………………………………6
Replication…………………………………………………………8
Taxonomy…………………………………………………………10
Infection………………………………………………………………16
Symptoms……………………………………………………………21
Diagnosis Of Rabies……………………………………..…………………………..21
Treatment …………………………………………………………………………………………22
Introduction:
Rabies is a fatal disease caused by a viral infection transfers by bite from animals or humans that are infected. The virus moves from peripheral nerves to the brain causing inflammation of the brain tissues humans and mammals. The family of this virus called Rhabdoviridae, it comprises 100 or more of single-stranded, negative-sense, nonsegmented viruses that has several wide variety of host, such as vertebrates, invertebrates, and plants.
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There are some charactarestic that is Common to all members of the family is a distinctive bullet or rod shaped morphology. the family includes at least three genera of animal viruses, Lyssavirus, Ephemerovirus, and Vesiculovirus. medically the most significant member of this genus is Lyssavirus that includes rabies virus, Lagos bat, Mokola virus, Duvenhage virus, European bat virus 1 & 2 and Australian bat virus. dogs’ bites are the most common source of rabies infections in humans as well as bats bite.
1- History of the virus:
Etymology:
The term rabies is derived from the Latin which means, “madness”, The Greeks derived the word lyssa from Lyssavirus has used in the genus name of the rabies virus from lud or “violent”.
Rabies, drives from the Latin word “to rage,”
it has been recognised for over 4 millenniums, the virus causes thousands of deaths each year in over hundreds of countries, over 59,000 people die of rabies infection every year. 95% of human rabies cases occur in africa and asia, mostly impacting children. 99% of cases, due to dog bites. it is a neglected disease found inpopulations who often have limited access to vaccines. In the 16th century, specifically in 1548 the physician Girolamo Fracastoro finds out that rabies was a fatal disease has a huge affection to humans as well as animals, after studing the dieases Fracastoro called it “an incurable wound”. In1804, Georg Gottfried Zinke first injected rabies1 from an infected dog to a normal one, and from dog to a rabbit and a hen(chicken), by injection of rabid animal saliva, proving that the disease was infectious.1884 Louis Pasteur ; Emile Roux (figure 1.1) (figure 1.2) described rabies is found in the brain and the spinal cord. The next year Joseph Meister, nine years old, was brought to him from Alsace having been bitten by a rabid dog. With some reluctance, Pasteur was persuaded by Dr.s Vulpian and Grancher to give Dr. Grancher the emulsifier of a rabbit had died of rabies cord, and had been kept in dry air for about15 days. The boy was given portions of further inoculations within10 days, until after three months he states that the child’s life was now safe and his health appeared to be excellent, therefore Joseph Meister, was the first human tested this vaccine and fully cured. Pasteur successfully treated another patient infected by a mad dog six days earlier. By 1886, he had treated 350 patients all over Europe, Russia, and America.In1936 Leslie Webster & Anna Clow Stained the rabies virus & demonstrate the characteristic bullet like shape.1967 human diploid cell vaccine Attenuated virus is grown in human cell cultures.1930 The first ever written record of rabies is in Mesopotamian Codex of Eshnunna, which instruct that the owner of a dog showing symptoms of rabies must take preventive measure against bites. If another person were bitten by a rabid dog and later died, the owner was heavily mulct. And one of the last ancient discoveries was in1932 by Russ Pfster he discovered that the only 3 species of bats that feed on blood (Desmodus rotundus, Diphylla ecaudata, and Diaemus youngi) are found specificly in Latin America. Rabies outbreaks caused by D. rotundus vampire bats have resulted in human deaths in Latin America.
Rabies was considered an epidamic for its wide dispersal in the19th century. In France where Saint Hubert was revered, the “St Hubert’s Key” was heated and applied to wounds. By an implementation of magical thinking. It was common for a person that had bitten by a dog even if it not infected distrustful by his of being rabid, to commit suicide or in the worst cases to be killed by other people. This gave Louis Pasteur immense opportunity to test post-exposure treatments from In ancient times, the attachment of the tongue (the lingual frenulum, a mucous membrane) was cut and removed as this was where rabies was thought to be originated. This unproductive practice ceased right after with the discovery of the actual cause of rabies.
Now countries are responding to achieve the target of zero human deaths by 2030 by scaling up their response to consign rabies to the history books.
2- Structure:
The virus has recorded to be negative-sense and non-segmentedwith only 1 stranded RNA virus or ssRNA.
2.1 Basic Shape:
measures approximately 60 nm wide and 180 nm long. composed of an internal protein core or nucleocapsid, that contains the nucleic acid, and envelope on the outer surface, a lipid-containing bilayer covered with transmembrane glycoprotein spikes, as shown below (figure 2.1)
2.2 Genome :
Rabies virus contains one copy of a single-stranded, negative (noncoding) RNA of approximately 12,000 nucleotides.
The virus genome encodes five proteins in the order of
3′-N-P-M-G-L-5′ and they associated with either the ribonucleoprotein (RNP) complex or the viral envelope, and four intergenic regions (Figure 2.2)
The virus envelope contains 5 strucural protines
(L) large transcriptase protein RNA depandant RNA polymarase
(M) The matrix protein located on the inner surface of the virus envelope, and it is associated with the envelope and the RNP and might be the central protein of rhabdovirus assembly,
(G) glycoprotein forms around 400 trimeric spikes that are tightly arranged together on the surface of the virus.
(N) nucleoprotein tightly binds the viral RNA to form the nucleocapsid core, (P) phosphorylated protein (L), and (N) are the rabies virus nucleocapsid (RNP) (Figure 2.3)
3- Replication
Replication of a lot of rhabdoviruses occurs in the cytoplasm, although many of the plant-infecting viruses replicate in the nucleus. The process of Viral replication can be is called cytoplasmic. The replication of rabies virus is believed to be similar to that of other negative-stranded RNA viruses. And the replication process takes certain steps:
3-1_ Adsorption: Entry into the host cell is achieved by attachment of the viral G glycoproteins to host receptors, which mediates clathrin-mediated endocytosis. The fusion of the rabies virus envelope to the host cell membrane initiates the infection process. The interaction of the G protein and specific cell surface receptors may be involved.
3-2_ Penetration: After adsorption, penetrates the cytoplasm by fusion or pinocytosis (via clathrin-coated pits).
3-3_ Uncoating: It strips off the protein surrounding the genetic material and The viral membranes fuse to the endosomal membranes, causing the release of viral RNP into the cytoplasm (uncoating).
3-4_Transcrption: Using staining polymerization is the method of transcription ? The initiates primary transcription of the five complementary monocistronic messenger RNAs by using the virion-associated RNA-dependent RNA polymerase? In the order for replication, both the P and L protein must be expressed to regulate transcription. The L protein has a numerous of enzymatic activities such as RNA replication capping mRNAs phosphorylation of P. L protein gives specialty in about replication in cytoplasm. Transcription results in five monocistronic mRNAs being produced because the intergenic sequences act as both termination and promoter sequences for adjacent genes. This type of transcription mechanism is explained by the stop-start model( stuttering transcription). Owing to the stop-start model, the large amounts of the structural proteins are produced. According to this model, the virus-associated RNA polymerase starts firstly the synthesis of leader RNA and then the five mRNA which will produce N, P, M, G, L proteins, respectively. After the leader RNA was produced, the polymerase enzyme reinitiates virion transcription on N gene and proceeds its synthesis until it ends 3? end of the chain.Then, the synthesis of P mRNAs is made by the same enzyme with new starter signal. These steps continue until the enzyme arrives the end of the L gene. During the transcription process, the polymerase enzyme may leave the template at any point and then bound just at the 3? end of the genome RNA to start mRNA synthesis again. This process will results concentration gradient of the amount of mRNA based on its place and its range from the 3? end. In the circumstances, the amounts of mRNA species change and will be produced N>P>M>G>L proteins.9 During their synthesis, the mRNAs are processed to introduce a 5′ cap and a 3′ polyadenylated tail to each of the molecules.This structure is homologous to cellular mRNAs and can thus be translated by cellular ribosomes to produce both structural and non-structural proteins.
3-5_Translation: Each RNA is then translated into an individual viral protein. 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 endoplasmic reticulum (ER) and Golgi apparatus.
3-6_Processing: This process is the making of the protein envelope for rabies virus
3-7_Replication: virus After viral proteins have been synthesized, replication of the genomic RNA continues with the synthesis of full length, positive-stranded RNA, which acts as a template for the production of progeny negative-stranded RNA. 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 a synthesis of full-length copies (positive 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.
3-8_Assembly: 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).
3-9_Budding: there is preferential viral budding from plasma membranes. Conversely, the 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. The virus exits the host cell by budding and tubule-guided viral movement. Transmission routes are zoonosis and bite.
4_Taxonomy
Family Rhabdoviridae: genera, species, and their viruses :
Virus (Abbreviation)SpeciesGenusalfalfa dwarf virus (ADV)Alfalfa dwarf cytorhabdovirusCytorhabdovirusbarley yellow striate mosaic virus (BYSMV)Barley yellow striate mosaic cytorhabdovirusbroccoli necrotic yellows virus (BNYV)Broccoli necrotic yellows cytorhabdovirusfestuca leaf streak virus (FLSV)Festuca leaf streak cytorhabdoviruslettuce necrotic yellows virus (LNYV)Lettuce necrotic yellows cytorhabdovirus* lettuce yellow mottle virus (LYMoV)Lettuce yellow mottle cytorhabdovirusnorthern cereal mosaic virus (NCMV)Northern cereal mosaic cytorhabdovirussonchus virus (SonV)Sonchus cytorhabdovirusstrawberry crinkle virus (SCV)Strawberry crinkle cytorhabdoviruswheat American striate mosaic virus (WASMV)Wheat American striate mosaic cytorhabdoviruscoffee ringspot virus (CoRSV)Coffee ringspot dichorhavirusDichorhavirusorchid fleck virus (OFV)Orchid fleck dichorhavirus* Adelaide River virus (ARV)Adelaide River ephemerovirusEphemerovirusBerrimah virus (BRMV)Berrimah ephemerovirusbovine ephemeral fever virus (BEFV)Bovine fever ephemerovirus* kotonkan virus (KOTV)Kotonkan ephemerovirusObodhiang virus (OBOV)Obodhiang ephemerovirusAravan virus (ARAV)Aravan lyssavirusLyssavirusAustralian bat lyssavirus (ABLV)Australian bat lyssavirusBokeloh bat lyssavirus (BBLV)Bokeloh bat lyssavirusDuvenhage virus (DUVV)Duvenhage lyssavirusEuropean bat lyssavirus 1 (EBLV-1)European bat 1 lyssavirusEuropean bat lyssavirus 2 (EBLV-2)European bat 2 lyssavirusIkoma lyssavirus (IKOV)Ikoma lyssavirusIrkut virus (IRKV)Irkut lyssavirusKhujand virus (KHUV)Khujand lyssavirusLagos bat virus (LBV)Lagos bat lyssavirusMokola virus (MOKV)Mokola lyssavirusrabies virus (RABV)Rabies lyssavirus* Shimoni bat virus (SHIBV)Shimoni bat lyssavirusWest Caucasian bat virus (WCBV)West Caucasian bat lyssavirusHirame rhabdovirus (HIRV)Hirame novirhabdovirusNovirhabdovirusinfectious hematopoietic necrosis virus (IHNV)Oncorhynchus 1 novirhabdovirus* viral hemorrhagic septicemia virus (VHSV)Oncorhynchus 2 novirhabdovirussnakehead rhabdovirus (SHRV)Snakehead novirhabdovirusdatura yellow vein virus (DYVV)Datura yellow vein nucleorhabdovirusNucleorhabdoviruseggplant mottled dwarf virus (EMDV)Eggplant mottled dwarf nucleorhabdovirusmaize fine streak virus (MSFV)Maize fine streak nucleorhabdovirusmaize Iranian mosaic virus (MIMV)Maize Iranian mosaic nucleorhabdovirusmaize mosaic virus (MMV)Maize mosaic nucleorhabdoviruspotato yellow dwarf virus (PYDV)Potato yellow dwarf nucleorhabdovirus* rice yellow stunt virus (RYSV)Rice yellow stunt nucleorhabdovirusrice transitory yellowing virus (RTYV)sonchus yellow net virus (SYNV)Sonchus yellow net nucleorhabdovirussowthistle yellow vein virus (SYVV)Sowthistle yellow vein nucleorhabdovirustaro vein chlorosis virus (TaVCV)Taro vein chlorosis nucleorhabdoviruseel virus European X (EVEX)Anguillid perhabdovirusPerhabdovirusperch rhabdovirus (PRV)Perch perhabdovirus* lake trout rhabdovirus (LTRV)Sea trout perhabdovirusDrosophila affinis sigmavirus (DAffSV)Drosophila affinis sigmavirusSigmavirusDrosophila ananassae sigmavirus (DAnaSV)Drosophila ananassae sigmavirusDrosophila immigrans sigmavirus (DImmSV)Drosophila immigrans sigmavirusDrosophila melanogaster sigmavirus (DMelSV)Drosophila melanogaster sigmavirus* Drosophila obscura sigmavirus (DObsSV)Drosophila obscura sigmavirusDrosophila tristis sigmavirus (DTriSV)Drosophila tristis sigmavirusMuscina stabulans sigmavirus (MStaSV)Muscina stabulans sigmavirusspring viremia of carp virus (SVCV)Carp sprivivirus* Sprivivirusgrass carp rhabdovirus (GrCRV)Pike fry spriviviruspike fry rhabdovirus (PFRV)Tench rhabdovirus (TenRV)Coastal Plains virus (CPV)Coastal Plains tibrovirusTibrovirusBivens Arm virus (BAV)Tibrogargan tibrovirus* Tibrogargan virus (TIBV)Durham virus (DURV)Durham tupavirus* Tupavirustupaia virus (TUPV)Tupaia tupaviruslettuce big-vein associated virus (LBVaV)Lettuce big-vein associated varicosavirus* Varicosavirusvesicular stomatitis Alagoas virus (VSAV)Alagoas vesiculovirusVesiculovirusCarajás virus (CJSV)Carajas vesiculovirusChandipura virus (CHPV)Chandipura vesiculovirusCocal virus (COCV)Cocal vesiculovirusvesicular stomatitis Indiana virus (VSIV)Indiana vesiculovirus* Isfahan virus (ISFV)Isfahan vesiculovirusMaraba virus (MARAV)Maraba vesiculovirusvesicular stomatitis New Jersey virus (VSNJV)New Jersey vesiculovirusPiry virus (PIRYV)Piry vesiculovirusFlanders virus (FLAV) Flanders virus Unassigned
Ngaingan virus (NGAV) Ngaingan virus Wongabel virus (WONV) Wongabel virus 5_Infection
A person is usually infected after having been bitten or deeply scratched by a rabid animal. Infection from rabies dogs accounts for 99% of cases. Africa and Asia bear the largest burden of rabies in humans and account for 95% of global rabies deaths. In the Americas, bats are now the leading cause of death from human rabies, with most of the dog-borne infections in this region being halted. Bats’ disease is also an emerging threat to public health in Australia and Western Europe. It is very rare to record human deaths from exposure to foxes, raccoons, gazelles, jackals, emeralds and other wild host species. There are no known cases of rabies infestation transmitted by rodent bites. In September 1931, Joseph Lennox Pawan of Trinidad in the West Indies, a Government Bacteriologist, found Negri bodies in the brain of a bat with unusual habits. In 1932, Pawan first discovered that infected vampire bats could transmit rabies to humans and other animals. Infection can also occur when a contaminated substance is mixed. Saliva is usually directly related to the human mucosa or modern skin lesions. The transmission of infection between people by biting is theoretically possible but has never been confirmed. One rarely gets rabies by inhaling the virus-containing droplets or transplanting infected organs. Rabies infection has never been confirmed through the consumption of raw meat or animal tissue in humans. discoveries rabies starts 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 (Central Nervous System) 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.11 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.12 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.
Replication (Figer 3 )
infection (figer 5)
6_ Symptoms
The initial onset of rabies begins with flu-like symptoms, including:
Fever.
Muscle weakness.
Tingling.
You may also feel burning at the bite site.
As the virus continues to attack the central nervous system.
There are two different types of the disease that can develop:
6-1_ Furious Rabies
Infected people who develop furious rabies will be hyperactive and excitable and may display erratic behavior.
Other symptoms include:
1- wakefulness
2-anxiety
3-hallucinations
4-excess salivation
5-problems swallowing
6-2_ Paralytic Rabies
This form of rabies takes longer to set in, but the effects are just as severe. Infected people slowly become paralyzed, will at last slip into a coma, and die. According to the World Health Organization, 30 percent of rabies cases are paralytic.
7_Diagnosis of rabies virus
Rabies can be difficult to diagnose, in its early stages, and It can be confused with other infectious diseases.
7-1_Diagnosis in animals
That can be made by taking any part from the affected brain, and the test should be included tissues from two locations in brain, from the brainstem and cerebellum. There are much diagnosis method for detection of rabies in animals like: direct fluorescent antibody, tissue culture infection technique, and polymerase chain reaction. All these techniques are recommended by World Health Organization (WHO).
7-2_Clinical diagnosis in human
Clinical diagnosis of rabies split to three stages; prodromal, excitement (furious) and paralytic. The first symptom is neuropathic pain in the site of infection consequent to viral replication. After a prodromal phase either or both the excitement or paralytic forms of the disease may be observed and In some cases, no signs are observed. Rabies virus has been set as the case of sudden death and diagnosis can only be definite by a laboratory tests conduct after mortem on central nervous system tissue isolated from cranium. Tests are also conducted on the samples of saliva, serum, and skin biopsies of hair follicles at the nape of the neck.
8_Prevention and treatment
can be prevented before the symptoms of rabies appear, it is about giving a person an injection: immune globulin and of rabies vaccine on the bite zone promptly because it offense the virus and retard or stop viral advancement through the nerves.
An active rabies treatment regime that gives the protection from the disease is developed. The treatment regime are; Post-exposure prophylaxis and Pre-exposure prophylaxis.
8-1_Post-exposure prophylaxis
if any person has bitten by an animal, the injury must be washed with soap and water.
Post-exposure prophylaxis is about: one dosage of rabies immunoglobulin and five dosage of rabies vaccine during 28 days. . Rabies immune globulin contains antibodies from blood donors who were given rabies vaccine. The rabies vaccine works by stimulating a person’s immune system to produce antibodies that neutralize the virus.
8-2_Pre-exposure prophylaxis
The people who need pre-exposure prophylaxis. Who are exposed to a high risk like; a veterinarian, and laboratory workers. All these people should be treated with rabies vaccines to avoid the chances of sudden infection.
-4058706174175figure 1.2
Louis Pasteur (/?lu?i pæ?st??r/, French: lwi pastœ?; December 27, 1822 – September 28, 1895) was a French biologist, microbiologist and chemist renowned for his discoveries of the principles of vaccination, microbial fermentation and pasteurization. He is remembered for his remarkable breakthroughs in the causes and prevention of diseases, and his discoveries have saved many lives ever since. He reduced mortality from puerperal fever, and created the first vaccines for rabies and anthrax. His medical discoveries provided direct support for the germ theory of disease and its application in clinical medicine.
0figure 1.2
Louis Pasteur (/?lu?i pæ?st??r/, French: lwi pastœ?; December 27, 1822 – September 28, 1895) was a French biologist, microbiologist and chemist renowned for his discoveries of the principles of vaccination, microbial fermentation and pasteurization. He is remembered for his remarkable breakthroughs in the causes and prevention of diseases, and his discoveries have saved many lives ever since. He reduced mortality from puerperal fever, and created the first vaccines for rabies and anthrax. His medical discoveries provided direct support for the germ theory of disease and its application in clinical medicine.
450856290945Figure 1.2
Pierre Paul Émile Roux FRS1 (17 December 1853, Confolens, Charente – 3 November 1933, Paris) was a French physician, bacteriologist and immunologist. Roux was one of the closest collaborators of Louis Pasteur (1822–1895), a co-founder of the Pasteur Institute, and responsible for the Institute’s production of the anti-diphtheria serum, the first effective therapy for this disease
0Figure 1.2
Pierre Paul Émile Roux FRS1 (17 December 1853, Confolens, Charente – 3 November 1933, Paris) was a French physician, bacteriologist and immunologist. Roux was one of the closest collaborators of Louis Pasteur (1822–1895), a co-founder of the Pasteur Institute, and responsible for the Institute’s production of the anti-diphtheria serum, the first effective therapy for this disease
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Figure 2.1
The basic shape of capsid for Rhabdovridae family
-1771655607050Figure 2.2
The viral genome encodes five proteins in the order of
3′-N-P-M-G-L-5′
0Figure 2.2
The viral genome encodes five proteins in the order of
3′-N-P-M-G-L-5′
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