What kind of virus causes rabies

Although RV pathogenicity is a multigenic trait involving several elements of the RV genome, the RV glycoprotein plays a major role in RV pathogenesis by controlling the rate of virus uptake and trans-synaptic virus spread, and by regulating the rate of virus replication. Pathogenic street RV strains differ significantly from tissue culture-adapted RV strains in their neuroinvasiveness.

Whereas street RV strains are highly neuroinvasive, most tissue culture-adapted RV strains have either no or only limited ability to invade the CNS from a peripheral site. The high neuroinvasiveness of pathogenic street RVs is, at least in part, due to their ability to evade immune responses and to conserve the structures of neurons. The finding that tissue culture-adapted RV strains replicate very fast and induce strong innate and adaptive immune responses opens new avenues for therapeutic intervention against rabies.

Rabies is a CNS disease that is almost invariably fatal. The causative agent is rabies virus RV , a negative-stranded RNA virus of the rhabdovirus family, which has a relatively simple, modular genome organization and encodes five structural proteins: a RNA-dependent RNA polymerase L , a nucleoprotein N , a phosphorylated protein P , a matrix protein M and an external surface glycoprotein G.

G is the only RV antigen capable of inducing the production of RV-neutralizing antibodies, which are the major immune effectors against a lethal RV infection. The RNP may play a significant role in the establishment of immunologic memory and long-lasting immunity [ 1 , 2 ]. RV has a broad host range and can infect almost all mammals.

Although there have been several routes of transmission reported for RV, natural infection most frequently occurs via a bite. In addition to bites, consumption of RV-infected carcasses might contribute to RV infection in arctic foxes [ 3 ], and contact of RV with mucous membranes was found to be another possible route of transmission [ 4 ]. In certain, unusual circumstances such as accidental release of aerosolized RV in the laboratory [ 5 , 6 ] or aerosolized RV in caves that are occupied by large numbers of bats [ 7 ], transmission via aerosol can occur.

Whether or not street RVs and mouse-adapted or tissue culture-adapted RV strains replicate at the inoculation site before they invade the CNS is still not clear.

While experimental intramuscular infection of young hamsters or raccoons with street RV revealed RV replication in striated muscle cells before the virus invaded the axons of motor neurons through neuromuscular junction [ 8 , 9 ], intramuscular infection of mice with the mouse-adapted CVS RV strain showed that RV migrates directly into the CNS without prior replication at the inoculation site [ 10 ].

After entering unmyelinated axon terminals, RV is retrogradely transported to the cell body. Recent findings indicate that hitchhiking axonal vesicle transport may represent a key strategy to move virions over long distances in axons [ 11 ]. The infection then spreads through a chain of neurons that are connected by synaptic junctions. However, the exact mechanism that facilitates the trans-synaptic spread is still unknown.

After infection of the brain, the virus spreads centrifugally to the peripheral and autonomic nervous system in many peripheral organs [ 13 ]. In the final stage of the infection cycle, RV migrates to the salivary glands; after replication in mucogenic acinar cells, it is shed into the saliva and is ready to be transmitted to the next host [ 14 ].

With respect to RV-induced pathology, apoptotic cell death has been proposed as a potential pathogenic mechanism in experimental rabies models of mice infected with a fixed RV strain [ 15 ]. However, infection of mice with the silver-haired bat-associated RV does not result in the induction of apoptosis [ 16 ].

Furthermore, RV infection causes only limited gross or histopathological lesions in the brains of human rabies patients despite the severe clinical neurological signs of rabies [ 13 ]. Unlike other acute viral infections of the CNS, hemorrhages or tissue necrosis is not commonly observed in the RV-infected brain [ 15 ]. The pathogenic mechanism that might contribute to the profound CNS dysfunction, characteristic of rabies, could be the impairment of neuronal functions.

It has been shown that expression of housekeeping genes is markedly decreased in RV-infected neurons, resulting in a generalized inhibition of protein synthesis [ 17 ], and several studies have shown defective neurotransmission following RV infection.

Tsiang demonstrated that the binding of acetylcholine receptor antagonist to infected rat brain homogenates was decreased when compared with controls [ 18 ]. RV-infected rat brain also exhibited impairment of both the release and binding of serotonin, a neurotransmitter involved in controlling the sleep cycle, pain perception and behavior [ 19 , 20 ]. In addition to the effects on neurotransmission, RV infection might have effects on ion channels as well. Infected mouse neuroblastoma cells show a reduction in functional expression of voltage-dependent sodium channels, which could prevent action potentials and ultimately result in functional impairment [ 21 ].

In addition to the lack of major pathological lesions in the CNS, no immune response is detectable in most cases of human rabies at 7—10 days after onset of clinical signs [ 22 ]. These profound differences, between the pathogenesis of rabies and that of most other viral or bacterial infections of the CNS, are further evidenced by the fact that immunosuppression either has no effect or is detrimental to the outcome of rabies [ 23 ].

The low level of immune response often seen in rabies victims is puzzling since it cannot be explained by a weak immunogenicity of RV antigens. In fact, RV G and the nucleocapsid protein are potent B- and T-cell antigens when administered parenterally [ 24 ]. A possible explanation for the low degree of immune responses against RV in human rabies patients or animals might be that RV infection of the CNS induces immune suppression [ 25 ] and it has been proposed that RV uses a subversive strategy including the prevention of apoptosis and the destruction of invading T cells [ 26 ].

Attenuated RV strains that have been adapted to non-neuronal cells differ significantly from pathogenic street RV strains in their neuroinvasiveness, which refers to their ability to invade the CNS from a peripheral site. In this regard, the tissue culture-adapted RV strains have either no or only limited ability to invade the CNS from a peripheral site, whereas street RV strains or mouse-adapted RV strains such as CVS are highly neuroinvasive [ 27 ].

The key factors involved in neuroinvasion by RV are virus uptake, axonal transport, trans-synaptic spread and the rate of virus replication. Until recently, our knowledge of RV pathogenesis was limited and largely based on descriptive studies with street RV strains or experimental infection with attenuated laboratory-adapted strains. The advent of reverse genetics technology made it possible to identify viral elements that determine the pathogenic phenotype of RV and to obtain a better insight into the mechanisms involved in the pathogenesis of rabies.

RV infection begins with viral attachment to a putative cellular receptor. Although several membrane surface molecules have been proposed as RV receptors, including nicotinic acetylcholine receptor [ 28 ], neural cell adhesion molecule [ 29 ] and low-affinity neurotropin receptor p75 NTR [ 30 ], it is still not clear whether these molecules actually play a role in the life cycle of RV.

After receptor binding, RV is internalized via adsorptive or receptor-mediated endocytosis [ 32 , 33 ]. Then, the low pH environment within the endosomal compartment causes a conformational change in RV G, which triggers the fusion of the viral membrane to the endosomal membrane, thereby releasing the RNP into the cytoplasm [ 34 ].

On the viral side, RV G plays a crucial role in virus uptake, most likely via the interaction with putative cellular receptors that facilitate fast uptake.

In this respect, it has been demonstrated that the pathogenicity of tissue culture-adapted RV strains e. Furthermore, experiments with chimeric RVs revealed that the time necessary for internalization of RV virions was significantly increased and the pathogenicity was strongly reduced after exchange of the G gene of the highly pathogenic RV strain SB, which was derived from a cDNA clone obtained from the silver-haired bat-associated RV strain [ 37 ], with that of a highly attenuated SN strain, which was rescued from a cDNA clone of the SAD B19 RV vaccine strain [ 38 ].

Together, these data support the notion that the kinetics of virus uptake, which is a function of RV G, is a major factor that determines the pathogenicity of RV. A unique property of RV is its ability to spread from cell-to-cell. The observation that the Gln ERA variant loses pH-dependent cell fusion activity in vitro [ 39 , 40 ] and exhibits a strongly reduced ability to spread from cell to cell [ 39 , 41 , 42 ] suggests that RV G also plays a pivotal role in cell-to-cell spread and thus viral transport, probably through its fusiogenic activity.

Transneuronal tracer studies of RV infection in rats [ 44 ] and rhesus monkeys [ 45 ] showed that RV migrates exclusively in the retrograde direction in axons.

Although several RV proteins have been implicated in neuronal transport mechanisms, RV G appears to play a predominant role in the transneuronal spread of a RV infection. For example, while peripheral infection with an equine infectious anemia virus EIAV pseudotyped with RV G results in viral transport to the spinal cord, the same EIAV pseudotyped with vesicular stomatitis virus G was unable to invade the nervous system [ 46 ].

The strongest evidence for an essential role of RV G in trans-synaptic transport, however, comes from intracranial infection of mice with a RV G-deficient recombinant virus, which showed that the infection remained restricted to neurons at the inoculation site without any signs of spread to secondary neurons [ 47 ]. However, it is likely that, in addition to RV G, RV M also plays a role in virus spread and thus in trans-synaptic transport.

Recent studies suggested that an interaction between RV P and the dynein light chain links the RV RNP to the host cell transport system, thereby facilitating retrograde axonal virus transport [ 50 , 51 ].

However, peripheral infection of adult mice showed that removal of the LC8 binding domain from RV P does not prevent virus entry into the CNS suggesting that the RV protein is not directly involved in the retrograde axonal spread of RV [ 52 ].

Unlike many other viruses, such as influenza virus, the pathogenicity of RVs correlates inversely with the rate of viral RNA synthesis and the production of infectious virus particles.

Comparison of the levels of viral mRNA and genomic RNA produced by different chimeric viruses suggests that viral RNA transcription and replication are regulated by several factors including RV M, which has been identified as a trans-acting factor that mediates the switch from initial high levels of mRNA synthesis to genomic RNA synthesis [ 53 ]. Furthermore, the M of all rhabdoviruses is able to shut down viral gene expression by binding to the RNP, resulting in a highly condensed skeleton-like structure that is unable to support RNA synthesis [ 49 ].

Phenotypic characterization of these wild-type and chimeric RVs in tissue culture revealed that the pathogenicity of a particular RV correlates inversely with its ability to replicate in neuronal cells. This conclusion is supported by data obtained with RV G variants that differ in a single amino acid in their G proteins [ 36 ].

Additional evidence for an inverse correlation between pathogenicity and the rate of viral RNA synthesis and virus particle production was obtained from mice infected with chimeric recombinant viruses in which the G and M genes of the attenuated SN strain were exchanged with those of the highly pathogenic SB strain [ 48 ]. These experiments revealed a significant increase in the pathogenicity of the SN parental strain bearing RV G from the pathogenic SB strain.

Replacement of G or M or both in SN with the corresponding genes from SB was associated with a significant decrease in the rate of production of virus particles as well as in the rate of viral RNA synthesis. These data indicate that both G and M play an important role in RV pathogenesis by regulating virus replication.

Certain nucleotide sequences within the RV G genes such as those including the codons for Arg and Lys have been identified as targets for cellular miRNAs. It has been shown that target recognition by cellular miRNAs can result in positive or negative regulation of virus replication [ 55 — 57 ].

The regulation of viral replication appears to be one of the important mechanisms involved in RV pathogenesis. To evade the immune response and to preserve integrity of the neuronal network, pathogenic RV strains, but not attenuated strains, can regulate their growth rate.

A lower replication level probably benefits the pathogenic RV strains by conserving the structure of neurons that are used by these viruses to reach the CNS. Another explanation for the lower replication rate of pathogenic RVs is that in order to evade early detection by the host immune system, the virus keeps the expression levels of its antigens at a minimum.

It is well known that street RV strains, which are considerably more pathogenic than tissue culture-adapted strains, express very limited levels of G and do not induce apoptosis until late in the infection cycle, suggesting that the pathogenicity of a particular virus strain correlates inversely with RV G expression and with the capacity to induce apoptosis [ 58 ].

Morphological studies with neuron cultures infected with this recombinant RV showed that cell death increased significantly in parallel with the overexpression of RV G and that apoptosis is the primary mechanism involved in RV G-mediated cell death. However, the mechanism by which the RV G gene mediates the apoptosis signaling process remains largely unknown. It has been speculated that RV G expression exceeding a certain threshold severely perturbs the cell membrane, resulting in the activation of proteins that trigger apoptosis cascades [ 59 ].

It is very likely that apoptotic cells are not rapidly cleared in the CNS and therefore undergo secondary necrosis [ 16 , 60 ]. Alternatively, RV infection and, in particular, the overexpression of the RV G protein might result in pyroptosis, a cell death pathway similar to apoptosis, which, in contrast to apoptosis, involves the activation of caspase 1 and thereby leading to necrosis [ 61 ].

The extent of necrosis or pyroptosis caused by an RV infection likely playes a decisive role in the induction of antiviral immunity. While apoptotic cells maintain their membrane integrity and do not stimulate innate immune responses, necrotic cells become permeable and release endogenous adjuvants that can trigger a robust innate immune response [ 62 ].

Consequently, the regulation of the expression of RV G is very likely an essential factor in the pathogenesis of rabies as it provides a means for pathogenic RV variants to survive and spread within the nervous system without causing overt neuronal damage and induce a protective immune response that would interfere with the infection.

It has been shown that the levels of RV G expressed by different chimeric RV variants are reflected by the rate of viral RNA synthesis, indicating that the differential regulation of RV G expression by these variants is the result of variations in the rates of transcription of viral mRNAs [ 48 ]. As is the case with the rate of viral RNA transcription, the amounts of RV G expressed by these variants inversely correlates with virus pathogenicity [ 48 ].

On the other hand, infection of primary neuron cultures with the less pathogenic RV variant CVS-B2c resulted in fourfold higher levels of G protein than infection with the highly pathogenic CVS-N2c variant despite the synthesis of comparable G mRNA levels in both infections [ 58 ].

The glycoprotein forms approximately trimeric spikes which are tightly arranged on the surface of the virus. The M protein is associated both with the envelope and the RNP and may be the central protein of rhabdovirus assembly.

The basic structure and composition of rabies virus is depicted in the longitudinal diagram below. Rabies is an RNA virus. The order and relative size of the genes in the genome are shown in the figure below. The arrangement of these proteins and the RNA genome determine the structure of the rabies virus. The fusion of the rabies virus envelope to the host cell membrane adsorption initiates the infection process. The interaction of the G protein and specific cell surface receptors may be involved.

After adsorption, the virus penetrates the host cell and enters the cytoplasm. The virions aggregate in the large endosomes cytoplasmic vesicles. The viral membranes fuse to the endosomal membranes, causing the release of viral RNP into the cytoplasm uncoating.

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 endoplamsic reticulum ER and Golgi apparatus.

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 synthesis of full-length copies postive strands of the viral genome. These positive strands of rabies RNA serve as templates for synthesis of full-length negative strands of the viral genome.

For instance, a bat that flies into your room while you're sleeping may bite you without waking you. If you awake to find a bat in your room, assume you've been bitten. Also, if you find a bat near a person who can't report a bite, such as a small child or a person with a disability, assume that person has been bitten.

Rabies infection is caused by the rabies virus. The virus is spread through the saliva of infected animals. Infected animals can spread the virus by biting another animal or a person.

In rare cases, rabies can be spread when infected saliva gets into an open wound or the mucous membranes, such as the mouth or eyes. This could occur if an infected animal were to lick an open cut on your skin. Any mammal an animal that suckles its young can transmit the rabies virus. The animals most likely to transmit the rabies virus to people include:.

In rare cases, the virus has been transmitted to tissue and organ transplant recipients from an infected organ. Consider the rabies vaccine if you're traveling. If you're traveling to a country where rabies is common and you'll be there for an extended period of time, ask your doctor whether you should receive the rabies vaccine.

Mayo Clinic does not endorse companies or products. Advertising revenue supports our not-for-profit mission. This content does not have an English version. This content does not have an Arabic version. Overview Rabies is a deadly virus spread to people from the saliva of infected animals.

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