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Micrograph of bullet shaped structures.
Virions of the rabies virus have a characteristic bullet-like shape. (credit: modification of work by the Centers for Disease Control and Prevention)

OpenStax Microbiology

Rabies is a deadly zoonotic disease that has been known since antiquity. The disease is caused by rabies virus (RV), a member of the family Rhabdoviridae, and is primarily transmitted through the bite of an infected mammal. Rhabdoviridae are enveloped RNA viruses that have a distinctive bullet shape; they were first studied by Louis Pasteur, who obtained rabies virus from rabid dogs and cultivated the virus in rabbits. He successfully prepared a rabies vaccine using dried nerve tissues from infected animals. This vaccine was used to first treat an infected human in 1885.

The most common reservoirs in the United States are wild animals such as raccoons (30.2% of all animal cases during 2014), bats (29.1%), skunks (26.3%), and foxes (4.1%); collectively, these animals were responsible for a total of 92.6% of animal rabies cases in the United States in 2014. The remaining 7.4% of cases that year were in domesticated animals such as dogs, cats, horses, mules, sheep, goats, and llamas. While there are typically only one or two human cases per year in the United States, rabies still causes tens of thousands of human deaths per year worldwide, primarily in Asia and Africa.

The low incidence of rabies in the United States is primarily a result of the widespread vaccination of dogs and cats. An oral vaccine is also used to protect wild animals, such as raccoons and foxes, from infection. Oral vaccine programs tend to focus on geographic areas where rabies is endemic. The oral vaccine is usually delivered in a package of bait that is dropped by airplane, although baiting in urban areas is done by hand to maximize safety. Many countries require a quarantine or proof of rabies vaccination for domestic pets being brought into the country. These procedures are especially strict in island nations where rabies is not yet present, such as Australia.

The incubation period for rabies can be lengthy, ranging from several weeks or months to over a year. As the virus replicates, it moves from the site of the bite into motor and sensory axons of peripheral nerves and spreads from nerve to nerve using a process called retrograde transport, eventually making its way to the CNS through the spinal ganglia. Once rabies virus reaches the brain, the infection leads to encephalitis caused by the disruption of normal neurotransmitter function, resulting in the symptoms associated with rabies. The virions act in the synaptic spaces as competitors with a variety of neurotransmitters for acetylcholine, GABA, and glycine receptors. Thus, the action of rabies virus is neurotoxic rather than cytotoxic. After the rabies virus infects the brain, it can continue to spread through other neuronal pathways, traveling out of the CNS to tissues such as the salivary glands, where the virus can be released. As a result, as the disease progresses the virus can be found in many other tissues, including the salivary glands, taste buds, nasal cavity, and tears.

The early symptoms of rabies include discomfort at the site of the bite, fever, and headache. Once the virus reaches the brain and later symptoms appear, the disease is always fatal. Terminal rabies cases can end in one of two ways: either furious or paralytic rabies. Individuals with furious rabies become very agitated and hyperactive. Hydrophobia (a fear of water) is common in patients with furious rabies, which is caused by muscular spasms in the throat when swallowing or thinking about water. Excess salivation and a desire to bite can lead to foaming of the mouth. These behaviors serve to enhance the likelihood of viral transmission, although contact with infected secretions like saliva or tears alone is sufficient for infection. The disease culminates after just a few days with terror and confusion, followed by cardiovascular and respiratory arrest. In contrast, individuals with paralytic rabies generally follow a longer course of disease. The muscles at the site of infection become paralyzed. Over a period of time, the paralysis slowly spreads throughout the body. This paralytic form of disease culminates in coma and death.

Before present-day diagnostic methods were available, rabies diagnosis was made using a clinical case history and histopathological examination of biopsy or autopsy tissues, looking for the presence of Negri bodies. We now know these histologic changes cannot be used to confirm a rabies diagnosis. There are no tests that can detect rabies virus in humans at the time of the bite or shortly thereafter. Once the virus has begun to replicate (but before clinical symptoms occur), the virus can be detected using an immunofluorescence test on cutaneous nerves found at the base of hair follicles. Saliva can also be tested for viral genetic material by reverse transcription followed by polymerase chain reaction (RT-PCR). Even when these tests are performed, most suspected infections are treated as positive in the absence of contravening evidence. It is better that patients undergo unnecessary therapy because of a false-positive result, rather than die as the result of a false-negative result.

Human rabies infections are treated by immunization with multiple doses of an attenuated vaccine to develop active immunity in the patient. Vaccination of an already-infected individual has the potential to work because of the slow progress of the disease, which allows time for the patient’s immune system to develop antibodies against the virus. Patients may also be treated with human rabies immune globulin (antibodies to the rabies virus) to encourage passive immunity. These antibodies will neutralize any free viral particles. Although the rabies infection progresses slowly in peripheral tissues, patients are not normally able to mount a protective immune response on their own.


Parker, N., Schneegurt, M., Thi Tu, A.-H., Forster, B. M., & Lister, P. (n.d.). Microbiology. Houston, Texas: OpenStax. Access for free at: https://openstax.org/details/books/microbiology