Rabies

Rabies is a viral disease that causes inflammation of the brain in humans and
other mammals. Early symptoms can include fever and tingling at the site of exposure. These
symptoms are followed by one or more of the following symptoms: violent movements, uncontrolled
excitement, fear of water, an inability to move parts of the body, confusion, and loss of
consciousness. Once symptoms appear, the result is nearly always death. The time period between
contracting the disease and the start of symptoms is usually one to three months; however, this time
period can vary from less than one week to more than one year. The time is dependent on the
distance the virus must travel to reach the central nervous system.

Rabies is caused by lyssaviruses, including the rabies virus and Australian bat lyssavirus. Rabies
is spread when an infected animal scratches or bites another animal or human. Saliva from an
infected animal can also transmit rabies if the saliva comes into contact with the eyes, mouth, or
nose. Globally, dogs are the most common animal involved. More than 99% of rabies cases in
countries where dogs commonly have the disease are caused by dog bites. In
the Americas, bat bites are the most common source of rabies infections in humans, and less than
5% of cases are from dogs. Rodents are very rarely infected with rabies. The rabies virus travels to
the brain by following the peripheral nerves. The disease can only be diagnosed after the start of
symptoms.

Animal control and vaccination programs have decreased the risk of rabies from dogs in a number
of regions of the world. Immunizing people before they are exposed is recommended for those who
are at high risk. The high-risk group includes people who work with bats or who spend prolonged
periods in areas of the world where rabies is common. In people who have been exposed to rabies,
the rabies vaccine and sometimes rabies immunoglobulin are effective in preventing the disease if
the person receives the treatment before the start of rabies symptoms. Washing bites and scratches
for 15 minutes with soap and water, povidone iodine, or detergent may reduce the number of viral
particles and may be somewhat effective at preventing transmission. Only five people have survived
a rabies infection after showing symptoms, and this was with extensive treatment known as
the Milwaukee protocol.

Rabies caused about 17,400 deaths worldwide in 2015. More than 95% of human deaths caused
by rabies occur in Africa and Asia. About 40% of deaths occur in children under the age of 15.
Rabies is present in more than 150 countries and on all continents but Antarctica. More than 3 billion
people live in regions of the world where rabies occurs. A number of countries, including Australia
and Japan, as well as much of Western Europe, do not have rabies among dogs. Many small island
nations do not have rabies at all. It is classified as a neglected tropical disease.

Sings and symptoms

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headache. As rabies progresses and causes inflammation of the brain and/or meninges, signs and
symptoms can include slight or partial paralysis, anxiety, insomnia, confusion, agitation, abnormal
behavior, paranoia, terror, and hallucinations, progressing to delirium, and coma. The person may
also have hydrophobia. Death usually occurs 2 to 10 days after first symptoms. Survival is rare once
symptoms have presented, even with the administration of proper and intensive care. Jeanna Giese,
who in 2004 was the first patient treated with the Milwaukee protocol, became the first person ever
recorded to have survived rabies without receiving successful post-exposure prophylaxis.
An intention-to-treat analysis has since found this protocol has a survival rate of about 8%.

Cause
Rabies is caused by a number of lyssaviruses including the rabies virus and Australian bat
lyssavirus.

The rabies virus is the type species of the Lyssavirus genus, in the family Rhabdoviridae,
order Mononegavirales. Lyssavirions have helical symmetry, with a length of about 180 nm and a
cross-section of about 75 nm. These virions are enveloped and have a single-
stranded RNA genome with negative sense. The genetic information is packed as
a ribonucleoprotein complex in which RNA is tightly bound by the viral nucleoprotein. The RNA
genome of the virus encodes five genes whose order is highly conserved: nucleoprotein (N),
phosphoprotein (P), matrix protein (M), glycoprotein (G), and the viral RNA polymerase (L).

Once within a muscle or nerve cell, the virus undergoes replication. The trimeric spikes on the
exterior of the membrane of the virus interact with a specific cell receptor, the most likely one being
the acetylcholine receptor. The cellular membrane pinches in a procession known as pinocytosis and
allows entry of the virus into the cell by way of an endosome. The virus then uses the acidic
environment, which is necessary, of that endosome and binds to its membrane simultaneously,
releasing its five proteins and single strand RNA into the cytoplasm.

The L protein then transcribes five mRNA strands and a positive strand of RNA all from the original
negative strand RNA using free nucleotides in the cytoplasm. These five mRNA strands are then
translated into their corresponding proteins (P, L, N, G and M proteins) at free ribosomes in the
cytoplasm. Some proteins require post-translative modifications. For example, the G protein travels
through the rough endoplasmic reticulum, where it undergoes further folding, and is then transported
to the Golgi apparatus, where a sugar group is added to it (glycosylation).

Where there are enough proteins, the viral polymerase will begin to synthesize new negative
strands of RNA from the template of the positive strand RNA. These negative strands will then form
complexes with the N, P, L and M proteins and then travel to the inner membrane of the cell, where a
G protein has embedded itself in the membrane. The G protein then coils around the N-P-L-M
complex of proteins taking some of the host cell membrane with it, which will form the new outer
envelope of the virus particle. The virus then buds from the cell.

From the point of entry, the virus is neurotropic, traveling quickly along the neural pathways into
the central nervous system. The virus usually first infects muscle cells close to the site of infection,
where they are able to replicate without being 'noticed' by the host's immune system. Once enough
virus has been replicated, they begin to bind to acetylcholine receptors (p75NR) at the

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neuromuscular junction. The virus then travels through the nerve cell axon via retrograde transport,
as its P protein interacts with dynein, a protein present in the cytoplasm of nerve cells. Once the
virus reaches the cell body it travels rapidly to the Central Nervous System (CNS), replicating in
motor neurons and eventually reaching the brain. After the brain is infected, the virus travels
centrifugally to the peripheral and autonomic nervous systems, eventually migrating to the salivary
glands, where it is ready to be transmitted to the next host.

Transmission
All warm-blooded species, including humans, may become infected with the rabies virus and
develop symptoms. Birds were first artificially infected with rabies in 1884; however, infected birds
are largely, if not wholly, asymptomatic, and recover. Other bird species have been known to develop
rabies antibodies, a sign of infection, after feeding on rabies-infected mammals.

The virus has also adapted to grow in cells of cold-blooded vertebrates. Most animals can be
infected by the virus and can transmit the disease to humans.
Infected bats, monkeys, raccoons, foxes, skunks, cattle, wolves, coyotes, dogs, mongooses (normall
y the yellow mongoose) and cats present the greatest risk to humans.

Rabies may also spread through exposure to infected bears, domestic farm
animals, groundhogs, weasels, and other wild carnivorans. Lagomorphs, such as hares and rabbits,
and small rodents such as chipmunks, gerbils, guinea pigs, hamsters, mice, rats, and squirrels, are
almost never found to be infected with rabies and are not known to transmit rabies to humans. Bites
from mice, rats, or squirrels rarely require rabies prevention because these rodents are typically
killed by any encounter with a larger, rabid animal, and would, therefore, not be carriers. The Virginia
opossum is resistant but not immune to rabies.

The virus is usually present in the nerves and saliva of a symptomatic rabid animal. The route
of infection is usually, but not always, by a bite. In many cases, the infected animal is exceptionally
aggressive, may attack without provocation, and exhibits otherwise uncharacteristic behavior. This is
an example of a viral pathogen modifying the behavior of its host to facilitate its transmission to other
hosts.

Transmission between humans is extremely rare. A few cases have been recorded
through transplant surgery.] The only well-documented cases of rabies caused by human-to-human
transmission occurred among eight recipients of transplanted corneas and among three recipients of
solid organs. In addition to transmission from cornea and organ transplants, bite and non-bite
exposures inflicted by infected humans could theoretically transmit rabies, but no such cases have
been documented, since infected humans are usually hospitalized and necessary precautions taken.
Casual contact, such as touching a person with rabies or contact with non-infectious fluid or tissue
(urine, blood, feces) does not constitute an exposure and does not require post-exposure
prophylaxis. Additionally, as the virus is present in sperm or vaginal secretions, spread through sex
may be possible.

After a typical human infection by bite, the virus enters the peripheral nervous system. It then
travels along the afferent nerves toward the central nervous system. During this phase, the virus
cannot be easily detected within the host, and vaccination may still confer cell-mediated immunity to

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prevent symptomatic rabies. When the virus reaches the brain, it rapidly causes encephalitis, the
prodromal phase, which is the beginning of the symptoms. Once the patient becomes symptomatic,
treatment is almost never effective and mortality is over 99%. Rabies may also inflame the spinal
cord, producing transverse myelitis.

Diagnosis
Rabies can be difficult to diagnose, because, in the early stages, it is easily confused with other
diseases or with aggressiveness. The reference method for diagnosing rabies is the fluorescent
antibody test (FAT), an immunohistochemistry procedure, which is recommended by the World
Health Organization (WHO). The FAT relies on the ability of a detector molecule (usually fluorescein
isothiocyanate) coupled with a rabies-specific antibody, forming a conjugate, to bind to and allow the
visualisation of rabies antigen using fluorescent microscopy techniques. Microscopic analysis of
samples is the only direct method that allows for the identification of rabies virus-specific antigen in a
short time and at a reduced cost, irrespective of geographical origin and status of the host. It has to
be regarded as the first step in diagnostic procedures for all laboratories. Autolysed samples can,
however, reduce the sensitivity and specificity of the FAT. The RT PCR assays proved to be a
sensitive and specific tool for routine diagnostic purposes, particularly in decomposed samples or
archival specimens. The diagnosis can be reliably made from brain samples taken after death. The
diagnosis can also be made from saliva, urine, and cerebrospinal fluid samples, but this is not
as sensitive and reliable as brain samples. Cerebral inclusion bodies called Negri bodies are 100%
diagnostic for rabies infection but are found in only about 80% of cases. If possible, the animal from
which the bite was received should also be examined for rabies.

Some light microscopy techniques may also be used to diagnose rabies at a tenth of the cost of
traditional fluorescence microscopy techniques, allowing identification of the disease in less-
developed countries.