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Jack Wardale

Medical Microbiology BL 222 01

Rabies Emerging Infectious Diseases Research Paper
December 5th 2016

Despite the common misconception that rabies is no longer a contemporary threat, the rabies
virus (RABV) contributes to more than 55,000 deaths every year, mainly people living in Africa
and Asia (CDC 2011). It is such a pressing issue globally that September 28th each year marks
rabies awareness day (Zhou et al. 2016). It has a negative-stranded RNA genome, characterized
as part of the Rhabdoviridae family by the distinct bullet looking shape (CDC 2011).
Rabies is one of the oldest documented diseases in the world, documented as early as 2300
B.C. by the Egyptians (New Jersey Department of Health [date unknown]). Rabies is a viral
infection caused by the saliva, brain or nervous tissues and the usual method of transmission is in
the form of a bite from an infected host (CDC 2011). It has also been documented, although rare,
that a patient can acquire the virus through an organ transplant (Zhou et al. 2016). Although the
origin of the disease in the United States is unclear, domestically the most common way of
contracting the virus is by the direct transmission of a wild raccoon bite (CDC 2011). On the
other hand, globally dogs are responsible for 99% of all human infections (WHO 2016).
Although dogs cause the vast majority of cases, any mammal can be affected by rabies and act as
a vector species although the most common reservoirs for the disease in the United States are
skunks, bats, foxes and coyotes (New Jersey Department of Health [date unknown]). The disease
is therefore considered to have a broad host range. Despite the disease being normally associated
with wild animals, domestic animals can also be common reservoirs (CDC 2011). The earliest
documented case of bat rabies in the United States was in 1960, and the first cases of rabid
raccoons were identified in West Virginia in 1977 (New Jersey Department of Health [date
Globally, the origin for rabies is also unknown but the virus is most prevalent in Asia and
Africa due to stray dogs (WHO 2016). Although there have been no specific geographical

climates that necessarily favor the virus, unlike malaria, it was found in Brazil that high-risk
areas were where highways met (Andrade et al. 2016). A study was conducted on travellers to
determine who was most at risk for the rabies disease. It was found that most of the travellers
who were exposed to rabid animals were in Southeast Asia, where the disease is assumed to be
endemic in such countries as Indonesia, Nepal, China and India (Gautret et al. 2015). The virus
spreads over large distances by free roaming animals that become rabid and bite other animals,
eventually coming into contact with humans (Putra et al. 2013).
The geographical spread and the consequent suppression of the disease is dictated to
primarily by the economical state of the country. In the United States, a more economically
developed country, the amount of cases in 2014 for human rabies was one (CDC 2011). This is
due to two factors: vaccinations and education. On the other hand, less economically developed
countries, particularly in rural areas of Southeast Asia, do not receive the necessary education or
cannot afford the vaccines to protect them from the virus. Medicinally, arguably the most pivotal
point in the history of rabies was the vaccination discovered by Louis Pasteur in 1885 (Smith
2012). Pasteur administered the first vaccine for rabies by growing the virus in a rabbit and then
injecting a weakened form in a boy, Joseph Meister, who had been bitten by a dog (Smith 2012).
Politically, if the government makes no effort to implement a prevention strategy for rabies, it
will ultimately dictate how the country copes with the virus. An example of a country that has
used politics to suppress RABV is England, part of Great Britain, which has been rabies-free
since 1922, due to the strict regulations pertaining to incoming animals (Jones et al. 2005). They
require the animals to be vaccinated and quarantined for six months upon entry (Jones et al.
2005). On the other hand, many countries in the Southeast Asia have little to no policy regarding
rabies and as a result are more susceptible to an epidemic. It is therefore up to the government as

much as anyone to control outbreaks of rabies. The government also influences the education of
the country and if they educate their citizens with preventative measures, then they are less likely
to engage in situations with animals that are suspected to have rabies. This lack of education is
why children are often the most susceptible to the disease, accounting for more than half of those
contracting rabies (CDC 2011).
Once infected with the virus, if the person infected has been vaccinated, the bodys
immune response is generated by T-helper cells in concomitance with a neutralizing antibody as
opposed to cytotoxic T-cells in non-vaccinated patients that may even prove damaging to the host
(Johnson et al. 2010). Without the vaccine however, a poor immunological response is generated
due to the stealthy nature of the virus itself (Johnson et al. 2010). Often patients do not have the
required amount of neutralizing antibodies presented until the symptoms of the disease become
more severe and this is often too late. It is believed that this is because the virus suppresses cellmediated immunity due to the suppression of interferon production (Johnson et al. 2010).
Moreover, the antibodies are rarely witnessed in the central nervous system, the location that
requires them the most as the virus spreads to the brain. (Johnson et al. 2010.) Further research is
being conducted in order to understand how the antigens are presented and consequently how
future vaccinations or anti-viral medicine can prevent neuroinvasion (Johnson et al. 2010). It is
understood however that RABV contains virulence factors that are necessary for the spread of
infection. One known virulence factor is the viral glycoprotein in order for the virus to attach to
the host cell (Schnell et al. 2009). Although some strains of the virus do not contain this
glycoprotein due to a deletion of the gene, the virus can still invade cells but cannot spread from
the chosen infected cell (Schnell et al. 2009). The viral glycoprotein is thought to assume this
function because it holds structural features similar to class I and II fusion proteins, as found in

the related vesicular stomatitis virus (VSV). Another pivotal virulence factor is the G protein,
which can induce apoptosis (Scott and Nel 2016). The final major virulence factor is the one that
is thought to contribute to neuronal dysfunction; the P protein is responsible for causing
mitochondrial dysfunction, which leads to neuronal damage as a byproduct of limited ATP
availability (Scott and Nel 2016). Unlike many other neuropathogenic viruses, RABV does not
always induce apoptosis, despite preconceived ideas about apoptosis holding a pivotal role in the
spread of the virus (Schnell et al. 2009). The non-pathogenic strain, ERA, appears to cause
apoptosis in host cells however the pathogenic strain CVS does not (Schnell et al. 2009). This is
thought to be again due to preventing a humoral immune response from materializing. It could be
argued that a lot of the success of the virus is due to the immune system evasion. It is thought
that RABV induces the expression of the programmed death-1 (PD-1) inhibitory molecule (Scott
and Nel 2016), thus preventing apoptosis. The rabies virus encourages the expression of the B7
homolog 1 ligand, one of two ligands of PD-1, which inhibits cytokine production and inhibits Tcell proliferation (Scott and Nel 2016).
In order to check for the onset of virulence factors, the virus is diagnosed in humans after a
variety of tests in order to quantify the presence of the rabies antigen. Samples are taken from
saliva and spinal fluid and skin biopsies are necessary to test for the appropriate antibodies.
Coupling reverse transcription and the polymerase chain reaction (RT-qPCR), lab technicians can
isolate and amplify the virus, while skin biopsies may also be used to examine the rabies
antigens in the cutaneous nerve (CDC 2011). Animals infected on the other hand are subject to
the direct florescent antibody (dFA) test by testing for RABV antigens present in their tissues
(CDC 2011). In less economically developed countries however, a new diagnostic tool is being
tested to replace the florescent test in order to help screen for the disease (Lchenne et al. 2016).

The new method suggested is a rapid immunodiagnostic test (RIDT), which was valued as a
reliable method by the supporting RT-qPCR results (Duong et al. 2016). The RIDT involves an
immunochromatographic assay that contains monoclonal antibodies that targets rabies antigens
in the serum of the patient (Duong et al. 2016). Like the influenza RIDT, if antibody-antigen
complexes are formed, a color will appear indicating a positive test. The positives of this test are
that it is a quick, low cost and very user friendly (Lchenne et al. 2016). The results are reliable
enough to become a viable method in developing countries. The speed and low cost of this test
allows greater awareness and earlier diagnostic opportunities for members of deprived
communities in order to alleviate the spread of the disease where possible. The only drawbacks
may be the false negatives that are associated with the influenza RIDT. Incorrect prep and testing
immediately after infection may yield a false negative which may cause misdiagnosis, so it is
paramount that those administering the tests are aware of the limitations and reliability issues.
This low cost method, despite the potential limitations, provides at least a foundation for those
countries that currently have no affordable alternative to dFA or RT-qPCR.
The common signs and symptoms of rabies that may lead someone to require a diagnostic test
are usually likened to flu initially, including a fever, headache, weakness and moderate
discomfort, which may last for a prolonged period of time (CDC 2011). The clinical presentation
of a bite or a scratch is a major indicator, along with the patient feeling an itching sensation at the
site of the bite. As the signs and symptoms worsen however, the patient may experience
delirium, abnormal behavior, hallucinations and insomnia (CDC 2011). Infection with RABV is
known to cause encephalitis and thus has a very high fatality rate (Johnson et al. 2010). The
acute period of the disease typically lasts between two to ten days. Once the clinical signs of
rabies appear, the disease is nearly always fatal; only ten cases of survival have been recorded,

only two of which were not vaccinated prior to exposure (CDC 2011). The virus is not typically
associated with being opportunistic, since it usually infects a healthy individual. The virus itself
has diverged into three different genera, Lyssavirus, Ephemerovirus, and Vesiculovirus (CDC
2011). There are several factors that can influence the infected persons immune response, such
as age, time of infection and sex (Scott and Nel 2016). As with many other infections, rabies is
more likely to infect the young or the very old, depending on the method of infection (Scott and
Nel 206). The sex of the person has also been found to be a factor, with men being more
susceptible to an infection due to lower levels of the hormone estrogen, which plays a role in the
immune-endocrine relationship (Scott and Nel 2016). Moreover, the time of infection can be
crucial, with people who are exposed to rabies closer to their vaccination having a higher chance
of viral infection due to the lower antibodies available to alleviate the initial infection (Scott and
Nel 2016).
With regards to viral entry, it is thought that the virus infects muscle tissue upon being
transmitted via a bite and uses the nerves to end up at the penultimate destination of the brain,
before it infects the salivary glands in order to be spread to another healthy host (CDC 2011).
The virus has been found to enter the cell using a clathrin-mediated endocytic pathway that
requires actin to induce pinocytosis, instigated by the viral glycoprotein (Weir et al. 2014.) Once
the virus fuses with the envelope, the infectious particles enter the cytoplasm in a vesicle, and
amass in the large endosomes before uncoating into the cytoplasm (CDC 2011). In the central
nervous system, there is preferential budding however in the salivary glands the virus buds into
the acinar lumen (CDC 2011). The entry of RABV into the axon does not initially provide the
correct chemical environment; RABV must migrate to the neuronal cell body in order to
replicate and transcribe the viral mRNA (Schnell et al. 2009). So far, there have been two

proposed methods for how this transportation occurs: transport of just the viral capsid or the
whole virion (Schnell et al. 2009). If it were just the viral capsid, uncoating would occur coupled
with the ribonucleoprotein (RNP) binding to cellular transport machinery (Schnell et al. 2009). It
was initially believed by an interaction observed between RABV phosphoprotein and dynein
light chain 8 (LC8) that the virus used the cytoplasmic dynein motor complex for intracellular
transport (Schnell et al. 2009). The deletion of the LC8-binding site in the phosphoprotein
however does not alter the viruss ability to reach the central nervous system and therefore it may
only indirectly affect the transportation of the virus (Schnell et al. 2009). In recent research
however, it has been observed that the virus is likely to be transported to the cell body using an
endosomal vesicle (Schnell et al. 2009).
With regards to replication, transcription and protein expression, it is important to note that the
genetic makeup of the virus is a single stranded, negative sense RNA, and thus needs to be
transcribed by a viral-encoded polymerase (CDC 2011). Rabies is not typical of other
rhabdoviruses by prioritizing the production of as much viral RNA in the least amount of time.
Instead, RABV is very conservative for two main reasons: if the neural cells are compromised
this could stop viral transport, and the production of large amounts of virulence factors would
generate a large humoral immune response which would prevent the viral replication from
occurring (Schnell et al. 2009). Therefore, RABV has evolved over time to mediate replication
that is too low to be detected by the host but high enough where viral production is successful
(Schnell et al. 2009). Although the exact method of primary transcription is not known, LC8
serves as an important factor. The virally-encoded polymerase, found in the RABV capsid,
transcribes the genomic strand of RNA resulting in an uncapped and unpolyadenylated leader
RNA followed by five capped and polyadenylated mRNAs that encode the viral proteins

(Schnell et al. 2009). The accepted mechanism for rabies transcription is known as the stop-start
model, where the polymerase stops transcription at a conserved signal sequence, skips an
intergenic region, and then restarts transcription at a start signal sequence (Schnell et al. 2009).
The incubation time of the disease can often last for weeks to months (CDC 2011). The synthesis
of the glycoprotein occurs in the golgi apparatus (CDC 2011). The ratio between the leader RNA
and a certain protein, known as the N protein, dictates whether to transcribe or replicate the viral
genome (CDC 2011). When a certain ratio is met, the viral replication begins by making fulllength positive strands of the viral genome (CDC 2011). The viral polymerase enters a single site
on the 3 end of the genome, initiating full copies of the genome to be made (CDC 2011). The
positive strands that are created then serve as a template strand for negative strands of the viral
genome to be made (CDC 2011). Once replication has finished, the assembly process starts; the
N-P-L complex encases the viral genome and an M protein forms the capsule around the RNP
core (CDC 2011). This complex then migrates to the part of the membrane where the
glycoprotein inserts, inducing M-protein coiling (CDC 2011). Upon binding to the glycoprotein,
the virus buds from the plasma membrane and is released into the extracellular space in order to
infect neighboring cells (CDC 2011).
Although a cure does not currently exist for rabies, the current technique is dependent on
whether the patient has contracted the virus or not. Any vaccination before potential exposure to
the pathogen is known as a pre-exposure prophalyaxis (PEP) vaccination, which offers
substantial protection from the virus. There are currently three vaccines available in the United
States: Human Diploid Cell Vaccine (HDVC), Purified Chick Embryo Cell Vaccine (PCEC), and
Human Rabies Immune Globin (CDC 2011). A rabies post-exposure prophalyaxis vaccination
however is used to treat the infection after a patient has been suspected of exposure to RABV in

order to prevent the onset of the infection. This contains a dose of human rabies immune
globulin, which are passive antibodies followed by a HDCV or PCECV vaccination on the day
of exposure is possible, then again at days 3, 7 and 14 (CDC 2011). If they have been previously
vaccinated however, a HDCV or PCECV vaccine will be administered on the day of exposure
and at day 3 (CDC 2011). This vaccination however may prove far too expensive for many that
live in less economically developed countries. Alternatives are being researched to the traditional
methods of post-exposure prophylaxis in order to provide a more inexpensive and readily
available treatment. One such example is looking at a Nanobodies vaccine to improve production
against the disease with a smaller budget (Terryn et al. 2016). There are currently no known drug
resistant strains of RABV since the disease is entirely preventable by a PEP vaccination. A study
was conducted on the HDCV vaccine between 1990 and 2015 to observe if the vaccine had any
adverse effects. Over the 25-year period, no adverse side effects were found (Moro et al. 2016).
Where these vaccinations are simply not affordable, countries are at a much higher risk of a
RABV endemic. A notable epidemic concerning rabies was recorded in Bali, Indonesia between
2008 and 2011, one of the highest risk areas for contracting the virus. The first case was
confirmed in the Bukit Peninsula and was thought to be brought by fishermen from the island of
Sulawesi but soon spread despite efforts to try and contain the virus between 2008 and 2009
(Putra et al. 2016). In total, more than 130 people died from RABV, largely due to the lack of
post-exposure prophylaxis. The drug was however administered to over 130,000 people, and cost
upwards of 17 million dollars (Putra et al. 2016). Before the outbreak, the island had no
preventative strategy in place, including no diagnostic tools or vaccinations and little funding,
and a large free roaming population of dogs enabled the disease to spread (Putra et al. 2016).
Help came in the form of the Indonesian government who provided PEP vaccines and began the

culling of unconfined dogs, despite objections by certain populations, and the Australian
government who provided dFA tests. The epidemic was eventually nullified due to herd
immunity, 70% of the island eventually becoming vaccinated (Putra et al. 2016).
To emphasize the stark contrast between strategies in more economically developed countries
and less economically developed countries, a RABV outbreak in Flagstaff, Arizona was used to
act as a comparison. After a small outbreak in 2009, a thorough outbreak control and education
campaign took place, reducing the number of rabid bat cases to four (McCollum et al. 2012).
Surveys conducted during the outbreak showed that local residents knew the relevant precautions
(McCollum et al. 2012). The county also provided traps for the residents to catch the infected
animals and the outbreak was soon eliminated before any people became infected (McCollum et
al. 2012). These preventative measures, both in terms of education and traps, meant that the
people of Flagstaff were able to avoid contracting the virus.
As it stands right now, the most high-risk areas are still all of Africa and the majority of
Asia. Northern and central South America is also an emerging threat for RABV exposure
(Chiodin and Boyne 2003). Moderate risks are in the south of South America, Greenland and
Eastern Europe (Chiodin and Boyne 2003). Low risk areas include all of the geographical areas
not mentioned, as there is no area that is devoid of potential viral exposure, particularly with
advances in air travel (Chiodin and Boyne 2003). There is a definite correlation between the
countries at risk and the economy of that country. There are currently no known emerging strands
that are of particular concern, the primary concern is instead the education and funding for
vaccines in the poorer economically developed countries. As time goes on, unless a mutation is
found that the current vaccinations cannot protect, it is likely to see a decrease of cases in the
future. This is because nations will continue to develop, providing better medicinal infrastructure

allowing better access for vaccinations. Moreover, accessibility will be coupled with a better
education system, teaching future generations both the clinical signs of the disease but also how
to prevent the disease. The World Health Organization (WHO) is currently working on at least
five key requirements that countries need to fulfill in order to control and prevent human rabies:
availability of vaccinations, an increase in public education, dog control programs, political
support and improved surveillance.
Another example of surveillance is a prospective approach in Ethiopia, a less
economically developed country, called the Stepwise Approach towards Rabies Elimination
(SARE) tool, ran by the Food Agriculture Organization (FAO) and the United Nations and the
Global Alliance for Rabies Control (GARC) (Coetzer et al. 2016). The program is used in order
for countries to self-assess their progression towards becoming rabies free. By implementing the
SARE, key weaknesses were identified in the Ethiopian rabies strategy, such as the lack of dog
vaccinations, which were inhibiting the countries progress towards eliminating the virus by 2030.
The useful information that the SARE gave Ethiopia will perhaps lead the way for other
countries in a similar economic and rabies prevalent state to adopt the method in order to
replicate its success (Coetzer et al. 2016).
Catholic Social Teaching is a fundamental element of the Catholic Churchs faith, and is
rooted in tradition by promoting a society that is reflective of the values taught in the Bible
(United States Conference of Catholic Bishops 2005). It includes seven key themes that each
represents a certain lesson that can be applied to a lot of contemporary issues, such as disease
control. The catholic social teaching that is most relevant to this disease is the option for the poor
and vulnerable (United States Conference of Catholic Bishop 2005). This theme was chosen

because this disease is not a matter of anyone being of equal risk; the members of more
economically developed countries are much less at risk than those who live in less economically
developed countries. It is the citizens of the more economically developed countries
responsibility in the eyes of the Catholic faith to help support those in the less economically
developed countries by offering aid to support vaccinations and better preventative strategies.
Until the countries become more economically developed, Catholics should feel it is part of
their responsibility as stewards of the earth to enable these communities to grow and become
educated, allowing them to at least have an option to be vaccinated against RABV. It may not
seem like a pressing issue, however just a small donation could make the difference to someones
life in an area where rabies are still prevalent.
An example of this social Catholic teaching in action would be the charitable organization
Mission Rabies. Luke Gamble, a veterinary graduate from Bristol University in England, created
Mission Rabies, which hopes to end the rabies virus indefinitely (Mission Rabies 2016). Gamble
hopes to achieve this by creating projects in less economically developed countries, such as
India, by vaccinating dogs in order to prevent the spread of the virus (Mission Rabies 2016). This
way, both dogs and humans can be spared from RABV by stopping the initial transmission to
dogs. This is a reflection of option for the poor and vulnerable Catholic social teaching because
in Gambles native country, England, there are no cases of rabies (Jones et al. 2005). Gamble
therefore does not need to be concerned about rabies, but has rather taken the initiative to try and
prevent rabies in poorer countries where the need is greater and the funding is limited. More
people in more economically developed countries need to not just be educated about preventative
measures in their own country but also need to be educated about the prevalence of the virus in
other countries and what they can do to help.

To conclude, rabies is certainly still an issue globally, however it is much more of an issue in
less economically developed countries, due to poor education, lack of vaccinations and poor
government prevention strategies in place, as evidenced by the epidemic in Indonesia. Since
there is no cure once there is an onset of symptoms, yet it is entirely preventable by pre-exposure
prophylaxis, it is even more important for vaccinations to be available in poorer countries. As the
world moves forward, from a Catholic teaching perspective, it is important for more
economically developed countries to assist in being an option for the poor and vulnerable, such
as the work performed by Mission Rabies. Eventually, with the right education and prevention
strategies, rabies will become a virus of the past, with everyone having the choice to be
vaccinated or not. As science moves forward, as witnessed by the RIDT tested, lower cost and
easier methods will become available for poorer countries in order to help prevent the spread of
rabies. Moreover, the more the virus transportation pathway and virulence is understood, the
more likely targets will be established for antiviral treatment to become available to treat rabies,
perhaps even making this a curable disease in the future.

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