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Summary

[RABIES] Among the diseases of viral origin, rabies is unique in its distribution and range of victims since it can afflict all warm-blooded animals. The interaction between the virus and the host population has facilitated the survival of the disease. The rabies virus (RV) has not changed in any si...

Description

[RABIES] Among the diseases of viral origin, rabies is unique in its distribution and range of victims since it can afflict all warm-blooded animals. The interaction between the virus and the host population has facilitated the survival of the disease. The rabies virus (RV) has not changed in any significant way and has been capable of taking advantage of conditions suited to the continuance of rabies. Infection by RV is invariably lethal in the absence of protective immune response which, however, can contribute to the pathogenesis of rabies. Proinflammatory cytokines might affect, directly or indirectly, the levels of neurotrophins, growth factors, neurotransmitters and neurotoxins in the brain by activating glia, neurons, and vascular and immune cells.

Index History (3) Virus structure (4) Genome (5) Life cycle (5) Immune response (6) Pathogenesis (7) Symptoms (8) Diagnosis (9) Treatment (10) Prevention and control (10) Literature reference (12)

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History No documents attesting to the existence of animal or human rabies in Germany and Austria seem to have existed prior to the Middle Ages. In the 12th Century, Hildegarde of Bingen proposed a remedy (plaster of flour) for the bite of a rabid animal and Albert the Great, Bishop of Regensburg, reported cases of rabies in horses. In 1535, an inn-keeper from the Duchy of Wurtemberg offered his customers meat from a pig that had died from rabies: they died from rabies after having bitten each other. In 1578, Fettich reported a large number of cases of vulpine rabies in the same region and Bauhin reported that in 1580, near Frankfurt, foxes had unearthed and eaten the carcass of a rabid pig. Bauhin gives interesting details about the epidemic and the means used for controlling it: ‘the (infected) foxes attacked and bit the other foxes to such an extent that a large number of foxes fell to the disease. In the end, the latter bit first the cattle and the mares, and then people who, after they were bitten, succumbed to a sort of hydrophobia... and several of them died wretchedly. As a result, when the magistrate had been told of this misery, he gave everyone permission to go fox-hunting, wiping out the foxes altogether: we have seen nothing of the sort since.’ Outbreaks of canine rabies were reported in Austria in 1556. In the early 17th Century, Fabian of Hilden asserted that saliva, even when dry, could remain virulent, citing the case of a person who had become infected after having broken off with his teeth the thread that had been used to mend a garment torn by a rabid dog. From 1725 to 1726, rabies affected dogs, as well as wolves and other wild animals in Saxony and Silesia. Urban rabies, which was enzootic throughout the 18th Century, was overcome by slaughtering dogs that were rabid or suspected of being so. T o o refers to the controversy that arose concerning an anti-rabies treatment, based on crushed cantharides, recommended by King Frederic II of Prussia in 1777, who suggested to his French friend, D’Alembert, ‘to have it administered to the English Parliament, because it would appear that some rabid dog has bitten it’! In 1786, Vandesmonde reported the case of a person from Regensburg who had apparently contracted rabies two months after having been bitten by a dog presenting no signs of rabies on the day it bit. Zincke, in Jena, succeeded, in 1804, in transmitting rabies to experimental animals: dogs, cats, rabbits and even chickens, by inoculating them with saliva from a rabid dog. Between 1805 and 1807, an epizootic of vulpine rabies raged in Baden-Wü

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and reappeared in 1828, with

secondary cases among martens. In the same region, several cases of rabies were reported among martens between 1810 and 1813. Between 1804 and 1840, a major epizootic of vulpine rabies held sway in southern Germany and Switzerland. From 1838 to 1843, Vienna was invaded by a severe dog epizootic. From 1843 to 1844, an unusual outbreak of cattle rabies occurred in the district of Heyden (Rhine-land) and spread among animals with no evidence of dog bite. Between 1866 and 1872, a serious rabies epizootic hit foxes in Carinthia, leading to their virtual extinctionand the contamination of numerous domestic animals. In Bavaria, the number of cases of canine rabies rose alarmingly between 1871 and 1875, and many people died of rabies: 15 in 1873, 29 in 1874 and 23 in 1875. A law passed on 2 June 1876 then imposed a tax ondogs, making their identification compulsory, and rabies disappeared five years later.

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Virus structure RABV and the non-RABV lyssaviruses belong to the class of RNA viruses that contain a linear, single-strand, negativesense (noninfectious) RNA genome that is approximately 12 kb or 12 000 nucleotides (nts) in length (Mr 4.2_106). The viral genome (2–3% of the virion weight) forms the backbone of the tightly coiled helical RNP (ribonucleoprotein/RNA plus protein) core, which extends along the longitudinal axis of the bullet-shaped virus particles.

The RNA genome contains five genes that code for the five structural proteins of the virion, which are designated N (nucleoprotein), P (phosphoprotein), M(matrix protein), G (glycoprotein), and L (RNA transcriptase/polymerase or large protein). The five genes are organized in the genome in order, starting at the 3

end, N, P, M, G, and L. The first four

genes are separated by short (di- or penta-) intergenic nt stretches (N–P, P–M, and M–G) and a longer 19–28-nt sequence between the last L gene and the G gene. The full nucleotide sequence of the RNA genome includes a noncoding leader (Le) sequence at the 3

terminus and a noncoding trailer (Tr) sequence at the 5

provide specific cis-acting signals (a specific nucleotide sequence

acting within

end. These short (58–70 nt) sequences the genome RNA) to initiate specific

functions in genome RNA transcription and replication.

The five structural proteins of RABV (as well as non-RABV lyssaviruses) comprise 67–74% of the virion by weight. The three viral proteins associated with the viral RNP core include the N (the most abundant protein in the RNP core) and the noncatalytic polymerase-associated P and the catalytic L components of the RNA polymerase complex. All three proteins are involved in the RNA polymerase activity of the virion, which generates monocistronic mRNA transcripts of each of the viral protein genes and a full-length complementary (plus-sense) transcript of the viral genome that serves as a template to produce a progeny (negativesense) RNA genome. The remaining two structural proteins of RABV, G and M, are associated with the lipid bilayer envelope that surrounds the RNP core.Mis a small-size nonglycosylated protein that lines the viral envelope forming an inner leaflet between the envelope and the RNP core. G is the only glycoprotein. It forms the trimeric spikes on the outer surface of the viral envelope. The mature viral G is glycosylated with branched-chain oligosaccharides, which account for 10–12% of the total mass of the protein. RABV particles or virions are best described as bacilliform or bullet-shaped with one end rounded (hemispherical) and the other end flattened (planar). The physical appearance of this rigid rod-like, bullet-shaped virion was first described from 4

images seen using the electron microscope. The average length of standard-size, infectious virions is 180 nm (130–250 nm) and the average diameter is 75 nm.

genome The linear single-strand negative-sense RNA (vRNA) of lyssavrus genomes of about 12 kb in length includes the 5 genes that appear in a strictly conserved order 3 L-5`

flanked by the short 3

- and 5

-N-P-M-G-

- terminal regulatory

extragenic regions known as leader (Le) and trailer (Tr) regions. These two extragenic regions are terminated by unmodified 3 (5

-hydroxyl (3

-OH) and 5

-triphosphate

-PPP) ends, respectively. The Le region, acting as a

genetic promoter (GP), initiates transcription of five monocistronic mRNAs from the genes of the vRNA genome as well as the synthesis of full-length antigenome RNA. During transcription and replication of the viral genome RNA, the tight clamping of the N-vRNA interaction opens exclusively and transiently to allow the polymerase complex access to the vRNA.

Life cycle The rabies virus life cycle can be divided into three main phases; the first is attachment to the host cell, the second is the synthesis of the viral genome within the host cell, and the final stage is the assembly and departing of the virus from the host cell. In the first phase, either the virus enters using endocytosis in which the viral membrane fuses with the membrane of the host cell via certain receptors (the details of which are still under scrutiny) or the virus enters through the use of the cell s vesicles. The second stage of the RABV lifecycle begins when the ribonucleicprotein core of the virus is ejected into the cytoplasm of the host cell. The rabies virus only replicates en the cell areas where ribosomes do exist (soma of neurons). When the nucleocapsid reaches the cytoplasm, the genome immediately starts to transcribe via viral transcriptase (L protein). During this process RNAm is generated for each cistron. It is important to note that the activities of genome replication of the virus are independent of the host cell s. Once the RNAm belonging to the G protein is translated in the rough endoplasmic reticulum, the protein glycosylates in the Golgi apparatus. This protein inserts in the endoplasmic reticulums membrane. This part of membrane, which contains the G protein, is inserted in the cytoplasmatic membrane as a process of membrane renewal. This is used as a signal for M protein, once traduced, to couple the 5

cytoplasmic domain of the G protein. After, the RNA depending RNA polymerase (L protein), produces thousands of copies of the virus genome after, what is called, the antigenome. Once the transcription, replication and translation are finished, the molding of the nucleocapsits is spontaneous. The almost ready virions travel to the G an M protein region, were the virions are ensambled, by mutual survey of the aminoacids sequences of the N, G and M proteins. The newly formatted virions emerge of the cell and are ready to infect other cells.

Immune response Because RABV is strictly neuroinvasive and little viral antigen is present in tissue in the early stages of the disease, the humoral response to viral antigens in the infected host is negligible until later in the course of infection, usually after clinical signs appear, and remains low until the terminal phase of the disease. High levels of antibody appear in serum and in CSF only at death and in cases where illness is naturally or artificially prolonged. In the rare cases of chronic and abortive RABV infections, virus-specific antibodies have been detected in the serum and CSF, and in the brain of animals. VNA is produced in response to the massive amount of viral antigen (G in particular) that is generated through widespread infection of the CNS and made accessible to the host

s reticuloendothelial system.

The critically important cell-mediated immune response to RABV infection is perhaps the most puzzling of the host s total immune response to RABV infection. T-helper lymphocytes, which play an essential role in supporting B-cell production of antibodies, and cytotoxic lymphocytes (CTLs), which function independently in cell-mediated viral clearance, are both key responses in the cell-mediated immunity derived from viral antigens. However, in spite of their importance in viral clearance, T-lymphocytes appear to be suppressed in animals infected by pathogenic

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viruses. As a result of virus-

induced immunosuppression, the disease increases in severity and mortality rises. Unlike the response to virulent RABV infection, immunization with attenuated live and inactivated RABV vaccines induces humoral and cellmediated immune responses that develop to functional levels in 7–10 days and persist for a year or more. Vaccine-induced antibody and T-cellmediated responses in animals and humans, known as adaptive immune responses, are regarded as key and are of paramount importance in the prophylatic protection of animals and humans. Also, acute infections caused by live virulent RABV strains, as well as the less virulent strains, injected into a peripheral site (e.g., the hind leg of an animal), that progress to and within the spinal cord and the brain are accompanied by the production of the inflammatory cytokines IL-1, TNF-a, INF-b, and IL-6, as well as chemokines such as CCL-5 and CXCL-10. This indicates that the nervous system can sense RABV entry and mount a reactive innate, as well as an adaptive immune response. An adaptive innate immune response is helpful in PEP and PET if, as proposed, chemokines and inflammatory cytokines attract lymphocytes that are activated in the periphery. It is to be emphasized that even with a relatively rapid adaptive immune response of 7–10 days, the requirement in PET for the administration of RIG is critical. RIG is the fraction of anti-rabies serum produced in immunized humans (HRIG) or equines (ERIG), which provides immediate passive immunity. It is administered with proven effectiveness over the initial few days and even weeks after RABV exposure in humans. RIG must be administered to humans exposed to RABV as a passive immune treatment in order to provide immediate access to VNAs until the patient s immune system can begin to produce its own antibody. The importance of antibodies in controlling the spread of RABV infections is clear when one considers that antibodies are capable of effectively neutralizing virus that is present in intercellular spaces or in body fluids. Antibodies may bind to virus

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expressed on thecell surface, allowing complement- or antibody-dependent cellular cytotoxicity to mediate killing of infected cells. Antibodies, however, are also implicated in an immunopathologic role in regard to the early death phenomenon, which is associated with rabies in animals and possibly humans. If animals have low levels of virus- or vaccine-induced rabiesspecific antibody at the time they are challenged with RABV, they frequently die earlier than those without antibodies. In an analogous situation, where humans appear to develop clinical rabies with shorter incubation periods as a result of postexposure immunization, compared with individuals who were exposed to rabies but not immunized, the early death phenomenon may also apply. Inasmuch as the mechanism of early death may resemble the immune cytolysis observed in RABV-infected cells treated with antiserum and complement in vitro, the immunopathologic effect of antibody would be to accelerate the pathogenesis of the virus. The efficacy of postexposure immunization and long-term effects of vaccine-induced prophylaxis against rabies seems also to be linked to the stimulation of a strong CTL response. Induction of CTLs and other effector T-cells during infection with live attenuated RABV vaccine strains and in response to immunization with inactivated virus is consistent with the observation that T-lymphocytes, and CTLs in particular, are essential for protection against a lethal dose of RABV. There is no evidence that early death is associated with rabies-specific T-cells or does any other form of immunopathology appear to be mediated through rabies immune T-cells.

Pathogenesis The pathogenetic process of rabies usually begins with the introduction of virus-laden saliva into a bite or scratch wound inflicted by a rabid animal. The incubation period after the bite can be extremely variable depending on the relative susceptibility of the species, the location of the wound (to the head vs. extremities), and the depth and location of virus deposit in the wound. Other routes of infection have included intranasal (in animals that sniff) and oral routes (among bats that spray in high-density cave dwellings) as well as corneal transplants (in human cases). Virus migration from peripheral sites on the body to the brain is suspected to occur passively in the axoplasm of peripheral motor and perhaps sensory nerves (centripetal passage to the brain) at the estimated rate of retrograde axoplasmic transport -1 -1 (3 mm h or between 50 and 100 mm day ) in peripheral nerves.

Inflammatory lesions caused by perivascular infiltration of lymphocytes, macrophage, and occasionally polymorphonuclear cells are the most common and frequently noted histological signs of change in the spinal cord and brainstem of animals and humans infected with RABV. The morphologically distinct lesions that are significant in rabies diagnosis are the specific eosinophilic inclusion bodies (Negri bodies) found within neurons of peripheral and basal ganglia of the spinal cord, in the pons and medulla of the brainstem, in the cerebral cortex and thalamus and Purkinje cells of cerebellum, and in ganglion cells of Ammon s horn of the hippocampus. Signs of active transport of virus in the brain include replication in the neurons, budding from the plasma membrane, and release into tissue interstitial spaces. The virus appears to infect susceptible cells by viropexis or direct cell-to-cell transmission. Once 7

delivered in the extracellular spaces of the brain, the virus can presumably spread by passive transport over relatively long distances through intercellular spaces large enough to pass virus by interstitial fluid movement. Virus that is transmitted directly from one nerve cell to a contiguous nerve cell could also spread and result in the same long-distance movement because of the many long, intertwined neuronal processes that connect in the brain.

* Approximate date. † Indirect fluorescent antibody. The figure above shows the timeline of course for a patient with presumptive abortive human rabies in Texas in 2009.

Once the virus begins to spread from the brain in the final phase of rabies infection, the tropism of infectious virus changes and the virus is delivered to a variety of extraneural and nonneural tissues. The centrifugal (outward) spread of virus generally occurs via the same axoplasmic transport routes that were used for the centripetal (inward) passage of virus inward to the CNS. Among the most heavily infected tissues following propagation of virus in the CNS are the end organs in oral and nasal cavities, and the head and neck. To take a skin biopsy from the nape of the neck is one of the best diagnostic methods of confirming an antemortem diagnosis of rabies in humans. The fact that rabies antigen is occasionally detectable in skin biopsy and in corneal impressions is evidence of its nerve-mediated dissemination. Infection of the salivary glands by dissemination of virus from the CNS is extremely important in the life cycle of the virus because it is required for effective transmission of disease. Virus titers in the salivary glands often exceed those in the brain. Histopathology in peripheral nerves as virus spreads through the peripheral nervous system (PNS) is associated with inflammatory, reactive, and degenerative changes in structural components of the PNS. Changes in sensory and autonomic ganglia as well as a neuronopathy (degeneration and loss of sensory and autonomic neurons) leading to degeneration of spinal and peripheral nerve fibers and routes have particular diagnostic utility.

Symptoms The incubation period (the length of time between exposure to virus and development of clinical signs) is usually 1 to 2 months, but because it can vary from less than a week to several years, rabies is one of the most variable of infectious diseases. The length of the incubation period may depend on the bite site and relative proximity to the CNS, severity of the bite, type and quantity of virus introduced, host age, and immune status. 8

Development of clinical...