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Rabies

Introduction

Pathogenesis

Epidemiology

Diagnosis/Treatment

References

 


 

Introduction

    Rabies is a fatal central nervous system (CNS) disease responsible for approximately 60,000 annual deaths worldwide, making it the tenth most common lethal infectious disease (Dietzschold et al. 2005). The causative agent is a neurotropic virus consisting of nonsegmented, negative-stranded RNA contained within a bullet-shaped envelope. Rabies virus (RV) is 1 of 7 serotypes belonging to the genus Lyssavirus and the family Rhabdoviridae (Plotkin 2000). The most common site of RV entry in humans is the skin or mucous membrane, where the virus is delivered into the muscle and subcutaneous tissue through biting, licking or scratching by an RV-infected animal (Warrell et al. 2004). Disease can present with one of two clinical forms. In the majority of rabies cases, the pathologic manifestation in the CNS is acute encephalomyelitis. This form is known as classic or encephalitic (furious) rabies and comprises 80-85% of rabies cases. It is distinguished by neurotropism, neuroinvasiveness and impaired neuronal functions (Jackson 2002). The ssymptoms of classic rabies include hydrophobia, pharyngeal spasms, and hyperactivity leading to paralysis, coma and death (Hankins et al. 2004). Paralytic rabies is a less common clinical form characterized by the development of prominent and flaccid muscle weakness (Jackson 2002). Death in both clinical and paralytic rabies ultimately results from neuronal dysfunction due to the dramatically inhibited synthesis of proteins required for maintaining neuronal functions (Dietzschold et al. 2005).

   Rabies progresses through 5 clinical stages that can vary depending on the extent of the bites, the amount of secretion, and the proximity to the CNS, with disease transmitted through bites close to the brain progressing more rapidly than disease transmitted through bites on the lower extremities (Hankins et al. 2004). The incubation stage ranges from 10 days to 1 year, with the average lying somewhere between 20-60 days. The prodrome stage occurs 2 to 10 days after exposure and can last from 1 day to 2 weeks. This stage is characterized by nonspecific flu-like symptoms such as fever, malaise, headache and nausea (Jackson 2002). Acute neurologic syndrome occurs 7-10 days after the onset of prodrome and includes dysarthia, dysphagia, excessive salivation, vertigo, agitation, visual and auditory hallucinations, hydrophobia secondary to painful contractions of pharyngeal muscles, and polyneuritis. Coma occurs 7-10 days after the onset of acute neurologic syndrome. This stage includes hydrophobia, prolonged apnea, generalized flaccid paralysis, seizures and coma with acute respiratory collapse. Death may follow 2-3 days after the onset of paralysis (Hankins et al. 2004).

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Pathogenesis

    The viral particle is comprised of a membrane made of host lipids and two proteins, G and M, surrounding a helical nucleocapsid (Thoulouse et al. 1998). As shown in figure 1, the helical coil of the ribonucleoprotein(RNP) complex core is formed by the rabies genome, a single non-segmented strand of negative-sense RNA, a nucleoprotein, a phosphoprotein, and an RNA-dependent RNA polymerase. The RNP core is covered by a layer of matrix protein, which is in turn covered by a host-derived lipoprotein envelope studded with rabies glycoprotein (Warrell et al. 2004). The trimeric G protein exposed on the surface of the virion is responsible for the attachment to the target cell by interaction with several cell membrane components. In particular, the nicotinic acetylcholine receptor (nAChR) acts as a receptor for RV. Binding of RV to nAChRs localizes and concentrates the virus on postsynaptic cells, which in turn facilitates subsequent uptake and transfer of the virus to peripheral motor nerves (Jackson 2002). In neurons that do not express nAChRs, it has been shown that other molecules such as phospholipids, gangliosides, neuronal cell adhesion molecule and the nerve growth factor receptor can serve as an RV receptors (Dietzschold et al. 2005). Following attachment to the G protein to the cell membrane, RV enters the cell by endocytosis and then resides in an early endosomal compartment. The acidic environment of the endosome causes fusion of the viral membrane with the endosomal membrane (Jackson 2002). This allows for the nucleocapsid to escape into the cytosol, where transcription and replication occur (Thoulouse et al. 1998).

Figure 1. The internal ribonucleoprotein (RNP) core of the rabies virion consists of a negative-sense genome RNA encapsidated by nucleoprotein, polymerase cofactor phosphoprotein, and the virion-associated RNA polymerase. The RNP core is covered in matrix protein and surrounded by a lipid-bilayer envelope (Warrell et al. 2004). Permission to use figure pending.  


   Although RV can infect a variety of cell types, it primarily targets neurons. The cycle of viral infection is depicted in figure 2. The virus spreads by retrograde axonal transport from the peripheral nerves to the neuronal cell body, possibly by cytoplasmic dynein (Wang et al. 2005). After replication in the cell body of the primary neuron, infection proceeds via retrograde axonal transport and transsynaptic spread through several neurons, as illustrated by figure 3. Transsynaptic spread is the ability of the virus to use synaptic junctions to propagate within the CNS (Dietzschold et al. 2005). Neuronal infection by RV causes abnormalities in the function of neurotransmitters affecting serotonin, GABA and muscarinic acetylcholine transmission (Warrell et al. 2004). Acinar cells are infected next, which in turn shed the virus into the oral cavity. This accounts for the presence of the virus in saliva (Dietzschold et al. 2005).

Figure 2. The cycle of rabies infection begins with viral entry at a peripheral site and proceeds through retrograde axonal transport. Viral replication occurs in the cell body of the primary neuron. Infection proceeds by transsynaptic spread through several neurons before spreading to the acinar cells, which then shed the virus into the saliva (Dietzschold et al. 2005). Permission to use figure pending.

 

Figure 3. The neuroinvasiveness of the virus results from its ability to migrate to the central nervous system (CNS) through retrograde axonal transport and transynaptic spread. Rabies virus spreads from the postsynaptic site to the presynaptic site via receptor-mediated endocytosis. In retrograde axonal transport, the ribonucleoprotein complexes of the virus are carried by direct attachment to a dynein motor or by encapsulation in vessicles attached to a dynein motor (Dietzschold et al. 2005). Permission to use figure pending.

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Epidemiology

  Because animal bite is the primary route of RV transmission to humans, the epidemiology of human rabies is a direct reflection of the regional animal reservoir for rabies virus and the opportunity for human-animal interaction (Childs 2002). Worldwide, canid species are the main vector in the transmission of rabies to humans, particularly in developing countries where canine rabies is endemic (Krebs 1995). In countries where canine rabies persists, the age and sex distribution of human rabies deaths generally mirrors the distribution of dog bit victims. The Indian subcontinent, Southeast Asia and most of Africa are the major foci of rabies today, with more than 30,000 cases each year in India alone (Plotkin 2000). Crowded urban centers with inadequate public health infrastructures are prone to transmission of rabies virus. In developed countries where canine rabies has retreated, the transmission of rabies by wild mammals accounts for 90% of human exposures (Hankins et al. 2004). Rabid bats, especially silver-haired bats, are the most prevalent source of human rabies in the United States. Between 25,000 and 40,000 people in the US are treated annually for exposure to rabid or potentially rabid animals (Hankins et al. 2004). Other rare routes of rabies transmission include handling of infected carcasses, consumption of raw, infected meat and inhalation of aerosolized rabies in caves inhabited by millions of bats. At least eight cases of human-to-human transmission of rabies have resulted from the transplantation of infected corneas (Jackson 2002).

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Diagnosis/Treatment

   Diagnosing rabies can be difficult if no history of exposure reported, and it is often misdiagnosed as Guillain-Barre syndrome, poliomyelitis and other viral encephalitides, or laryngeal disorder (Plotkin 2000). A conclusive rabies diagnosis can be made in humans before death by observing virus-specific fluorescent material in skin biopsy specimens, isolating the virus from patient saliva, or detecting the presence of antirabies antibodies in the serum or cerebrospinal fluid of patients who have not been immunized (Hankins et al. 2004). The basic principles behind rabies prophylaxis are the removal of free virus from the body by both washing and neutralization, followed by the induction of a rabies virus-specific immune response in the exposed individual before rabies virus can replicate in the CNS. This requires the administration of both passive and active vaccination. In passive vaccination, rabies immune globulin (RIG) from adults who have been immunized with rabies vaccine is administered to previously unimmunized people so as to passively impart antibodies. There are three primary types of active rabies vaccinations currently administered to humans throughout the world: nerve tissue-derived vaccines (NTVs), high-quality cell culture vaccines produced under stringent quality control and lower-quality cell culture vaccines that do not adhere to FDA regulations of national pharmacopeia standards in industrialized countries (Briggs et al. 2002). NTVs are produced from brain tissue of animals infected with a fixed strain of rabies virus. After the brain tissue is harvested, the virus is inactivated and then diluted to a concentration of 2-5% of brain tissue. NTVs are extremely painful, however, and can cause severe neurologic adverse reactions due to the presence of myelinated tissue in the vaccine (Briggs et al. 2002). Unfortunately, nerve tissue vaccines are still the most widely used prophylaxis for rabies. The optimal rabies vaccine today is human diploid cell vaccine (HDCV), which is a type of cell-culture vaccine produced in human fibroblasts. Unfortunately, treatment is generally unsuccessful when administered after the patient becomes symptomatic. Therefore, efforts must be focused on disease-preventing measures (Vanniasinkam et al. 2004).

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References

Childs, JE. (2002). Epidemiology. In: Rabies (eds. AC Jackson and WH Wunner). Academic Press, 493.

Dietzschold, B, M Schnell, H Koprowski. (2005). Pathogenesis of Rabies. Current Topics in Microbiology and Immunology. 292: 45-56.

Hankins, DG. (2004). Overview, prevention, and treatment of rabies. Mayo Clinic Proceedings. 79(5): 671-6.

Jackson, AC. (2002). Human disease. In: Rabies (eds. AC Jackson and WH Wunner). Academic Press, 493.

Janeway, A.C, P. Travers, M. Walport., J.M. Shlomchik.2005. Immunobiology: The Immune System  in Health and Disease. 6th ed. New  York, NY: Garland Publishing. pp  196,  416-417.

Krebs, JW, ML Wilson, JE Childs. (1995). Rabies: epidemiology, prevention and future research. Journal of Mammalogy. 76(3): 681-94.

Plotkin, SA. (2000). Rabies. Clinical Infectious Diseases. 30(1): 4-11.

Thoulouse, MA, M Lafage, M Schachner, U Hartmann, H Cremer, M Lafon. (1998). The Neural Cell Adhesion Molecule Is a Receptor for Rabies Virus. Journal of Virology. 72(9): 7181-7190.

Vanniasinkam, T and HCJ Ertl. (2004). Rabies vaccines: the third generation. Letters in Drug Design and Discovery. 1: 289-292.

Wang, ZW, L Sarmento, Y Wang, X Li, V Dhingra, T Tseggai, B Jiang, ZF Fu. (2005). Attenuated rabies virus activates, while pathogenic rabies virus evades, the host innate immune responses in the crentral nervous system. Journal of Virology. 79(19): 12554-12565.

Warrell, MJ and DA Warrell. (2004). Rabies and other lyssavirus diseases. The Lancet. 363(9413): 959-69.

 

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