Zika Virus And Its Potential To Treat Brain Cancer

Introduction
Until now, viruses have been seen as nothing but damaging, dangerous and detrimental to our
health. Since their discovery in 1892 they have been perceived as a global health threat; not a
remedy or possible treatment for one of the leading causes of mortality worldwide. However,
recent scientific studies have shown that a specific strain, known as the zika virus, could
potentially treat aggressive brain cancers such as glioblastomas. Due to the virus's teratogenic
traits, it has been linked to an increase in foetuses developing neural abnormalities as it infects
and eventually kills cells vital in neurological development. Correctly reengineering it could lead
to the pathogen selectively targeting cancerous stem cells in the brain that are responsible for
tumours; if successful, this breakthrough could completely reform brain cancer treatment and
consequently transform oncology.
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The following essay will discuss a number of factors that will contribute to explaining whether
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the virus could be used as a medicinal drug. The initial paragraphs will explain what Zika is; it's
history, structure, pathogenesis and symptoms. Following this, the essay will explore Zika as a
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teratogen explaining how exactly it affects the developing brain and generates various
abnormalities. Thirdly, the essay will enquire into brain cancer and how the zika virus can
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challenge aggressive tumours. Finally, it will conclude evaluating whether using the virus as a
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cure would be more successful than the already available treatments and if its production as a
medicinal drug would be viable i.e. financially as well as ethically.
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History
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In order to come to a conclusion on whether or not the zika virus could potentially be re-
engineered and used as a treatment for brain cancer, it is crucial to first understand what it
actually is. The characteristics must be understood in order to decipher its pathogenesis and to
come to an educated decision on whether harnessing the ability to infect the developing brain
could revolutionise modern medicine. Zika’s name is inherited from where it was first isolated;
the Ziika forest of Uganda in 1947. Initial identification was in the sentinel rhesus macaque
monkey and the virus was first diagnosed in a human in 1952. Despite being discovered 70
years ago; the first outbreak of the disease was only a decade ago in the Island of Yap. Since
then, there have been several countries experiencing outbreaks, which has ignited the scientific
community’s interest into the pathogen.

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Taxonomy and Structure
Zika is classed as a flavivirus and is, therefore, a part of the ssRNA (+) taxonomic group. The
structure of the virus is important in understanding how it behaves. The genome is arranged
linearly, which means that unlike circular RNA, it has a beginning and an end. This is paired with
a monopartite genomic segmentation; Zika's genetic material only consists of a single strand of
positive RNA, that is very similar to our own human mRNA. This feature is essential in the
replication of the virus in our body. The capsid has a T=pseudo3 Icosahedral-like structure, like
all other flaviviruses, that consists of 12 pentameric and 20 hexametric capsomeres that
surround the virus' genetic material. It is then further surrounded by an E-dimer and M protein
which make up the envelope and attachment protein. The structure of the virus is crucial for
scientists to understand how exactly it utilises its components to cause damage to the human
body.

Infection
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Infection is caused via certain arthropods, specifically mosquitoes, making Zika an arbovirus.
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Additionally, other methods of transmission include sexual contact and blood transfusions. The
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types that are involved in the infection and transmission of Zika come from the Aedes group;
usually either Aedes Aegypti or Aedes Albopictus. When the Aedes mosquito lands on the skin,
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it pierces the outer most layer, the epidermis, using its proboscis. This then continues to pierce
through skin and into the second layer, the dermis, that has its own blood supply, and
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consequently the nutrients that the female mosquitos need to feed on to make and mature their
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eggs. As the proboscis goes through the epidermal and dermal layer, the cells in both of those
layers become susceptible to Zika. Due to this, permissive cells become infected; for a cell to be
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permissive to Zika it must have receptors that bind to the attachment protein from the virus. This
then leads to the merging of the virus and the host cell, initiating replication.
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Replication
Once the virus has entered the host cell, it begins the replication process which is how the virus
causes harm in our bodies and leads to detrimental effects on unborn babies. This is arguably
the most important part of the process that scientists must understand in order to be able to
observe what the virus would do if targeted at cancerous tumours. When the pathogen gets
close enough to a human cell that is permissive to the virus, its attachment proteins bind to the
host cell’s receptors. The binding that happens between the host cell and the virus triggers a
process called ‘clathrin-mediated endocytosis’; the virus is absorbed by the inward budding of
the plasma membrane vesicles. These vesicles contain proteins with receptor sites specific to
the molecules being absorbed. Once endocytosis has occurred, the virus successfully infiltrates

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the cell and begins to replicate. It does this by hijacking the cell’s ‘protein-making system’ and
therefore leads to the synthesis of its own viral proteins. This is done successfully as the virus’
genome greatly mimics the human one, meaning that it can exploit the host's cellular apparatus.
The cell continues to produce viral proteins until it eventually dies, releasing the virus’ which
then proceed to infect other cells. This process will continue as the infection spreads.2
However, regardless of the virus' ability to destroy our cells, the effect and symptoms within
adults are usually minimal, most commonly inducing mild fever and skin rash and more rarely
headaches and conjunctivitis.

Zika Virus as a Teratogen

The real danger of Zika is exposed when contracted by pregnant women as this can
consequently lead to babies being born with congenital Zika syndrome; a unique pattern of birth
defects found amongst foetuses and babies infected with Zika virus during pregnancy.
Congenital Zika virus comes with five main features, one of which is related specifically to the
brain and has inspired scientists to consider the possibility of re-engineering the virus as a
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medicinal drug; microcephaly. Other than this specific condition, the virus has also been linked
to brain-related complications in babies; these abnormalities include brain atrophy and
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asymmetry, abnormally formed or absent brain structures, hydrocephalus, and neuronal

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migration disorders. There is a general consensus amongst the scientific community that Zika is
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responsible for these illnesses; but how? How does the virus that is practically harmless to
adults lead to dangerous deformities in foetuses?
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As the foetus is inside the mother's womb, it cannot be bitten by an infected mosquito and
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hence contracts the virus through transplacental infection: the virus is passed from the mother
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to the unborn child via the placenta. This organ plays a pivotal role in the healthy growth and
development of the foetus as it provides it with essential nutrients. Once it is infected, the virus
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replicates in its cells, disrupting the placental barrier meaning the pathogen can easily gain
access to the foetal brain. Breaching the barrier is the inceptive step to foetal demise; from here
the virus has been shown to efficiently target human cortical neural progenitor cells (NPCs);
these resemble stem cells as they have the ability to differentiate into other types of cells but
are already more specific. The death of these infected cells leads to the reduced thickness of
both NPC and neuronal layers and therefore an overall reduction in organoid size; the inevitable
increase in destroyed cells accelerates the flattening of neuronal layers, eventually causing
microcephaly. It is this ability to efficiently target and destroy neuronal cells that have inspired
scientists to consider the possible benefits that the virus’ pathological process could have
regarding brain cancer.

What is Brain Cancer and How is it Affected by the Zika Virus?

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Applying a singular, universal definition to brain cancer is difficult due to its varieties and
complexities, however, in short, cancer can be defined as ‘a class of diseases that are
characterised by out-of-control cell growth.’ As it is caused by rapid and unmanageable cell
division, cancer is essentially a disease of mitosis; but how does a process that is vital in the
growth and development of all multi-cellular organisms malfunction to become one of the
leading causes of fatality worldwide?

The lethal process of cancer development begins when a cell is transformed from normal to
cancerous; this occurs when the cell overrides or ignores the ‘checkpoints’ that control the rate
of mitosis. Often this is due to a DNA mutation that occurs in one of the genes that code for
control proteins that regulate growth, for example, the p53 gene. This gene is also referred to as
the ‘guardian of the genome’ and it usually functions to control the cell cycle. It is therefore not
particularly surprising that this gene was found to be mutated in over 50% of all human cancers.
Once crucial cell cycle genes begin to behave abnormally, cancer cells start to proliferate
fiercely via unchecked mitosis, eventually forming a mass of cancerous cells more commonly
known as a tumour.
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Not all tumours, however, are cancer; benign tumours remain at their original site and do not
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spread to infect other parts of the body. These are usually only fatal if they are pressing on vital
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organs; in regard to the brain, those located in critical areas can be life threatening. The more
concerning effects of tumours are from those that are malignant; these metastatic cells spread
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to and infect other areas of the body through angiogenesis. Development of new blood vessels
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is triggered by chemical signals from tumours, giving them access to their own oxygen and
‘food’ supply, as well as an avenue for escape to travel to various areas within the body.
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Metastasis is especially abundant throughout the brain; this is mainly due to the dense blood
supply that is required for the organ to function effectively which is especially attractive to
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cancerous cells. Consequently, studies have concluded that about a quarter of all malignant
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cancers will spread to the brain, and metastatic tumours are more commonly present in the
brain than cancers that originated there, therefore, most cases of brain cancer are a result of
this spread.

‘Brain cancer’ is a blanket term used to cover four main types of the disease: neuroblastoma,
medulloblastoma, pineoblastoma and glioblastoma. All brain cancers and tumours are relatively
dangerous and life-threatening, specifically when left untreated, however, the most common
form and also the one that is particularly dire and aggressive is glioblastoma (GBM). Less than
10% of patients affected with GBM survive beyond five years of diagnosis, even with continuous
and regular treatment. These tumours arise from astrocytes, the most numerous cell type within
the central nervous system. Their function ‘varies from axon guidance and synaptic support, to
the control of the blood brain barrier and blood flow.’ Origins of glioblastomas are usually in the
cerebral cortex, although it is possible to find them located in any region within the brain or

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spinal cord.

GBM tumours are highly heterogeneous; their cells vary in structure and behaviour. A unique
attribute that they possess is the way in which they can imitate stem cells: they are able to
regenerate tumours as well as develop copies of themselves. This quality does not exist in all
cancerous cells, making glioblastoma’s especially difficult to treat. The most effective way to
remove all glioblastomas from the brain, rather than constantly reducing the amount of GBM
tumours, would be by targeting and destroying these cancer-causing glioma stem cells (GSCs);
this is where the Zika virus’ harmful effects could potentially be utilised. Recent animal and
laboratory research has suggested that there is a possibility that a modified version of the virus
could be used to target and destroy glioma cells; Zika could also potentially be used in
combination with conventional treatment to maximise effectiveness and efficiency.

This breakthrough originates from the work carried out by researchers from the University of
California, Cleveland clinic, Washington University school of Medicine and the University of
Texas Medical Branch. The report titled ‘Zika virus has oncolytic activity against glioblastoma
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stem cells’ was published in the peer-reviewed Journal of Experimental Medicine.
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ZIKV Strains Dakar (1984) and Brazil (2015) Effect on Glioblastomas

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To properly investigate the effects of the Zika virus (ZIKV) on glioblastomas, four patient-derived
GSC models, representing the main transcriptional glioblastoma subtypes, were infected with an
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African strain (Dakar 1984) and an American strain (Brazil 2015) of the virus. This shows that
ZIKV was effective in destroying GSCs that are responsible for the regeneration of glioma cells
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that lead to tumours.

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Furthermore, preferential targeting of GSC cells by both ZIKV strains can be analysed by
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immunofluorescence microscopy; this is a method used to assess both the localisation and
expression levels of proteins of interest. This technique demonstrated that more than 60% of
GSCs were infected by one of the ZIKV strains 48 hours after initial infection. The amount of
GSCs infected by the ZIKV strains was measured by analysing those which expressed the
‘Sox2’ GSC marker; greater than 90% of cells infected by the ZIKV strains were positive for
this. This therefore shows that ZIKV potently infects GSCs, replicating within their cells at a
much higher and faster rate than in any of the other cells, for example differentiated glioma cells
(DGCs). ZIKV could infect these cells but it was not anywhere near as effective at reducing
proliferation rates as viewed with GSCs.

In addition to patient-derived GSC models, mice were also studied by recapitulating the relevant
conditions for human brain tumour therapy to further explore the relationship between the virus
and cancer.

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 In summary, the results of this study suggest that ZIKV preferentially targets GSCs; thus, it
could be hypothesised that genetically modified strains of ZIKV that optimise levels of safety
could have therapeutic efficacy for adults that are infected with glioblastomas. Despite the
theoretical effectiveness of the pathogen against these cells, would using ZIKV as a therapy for
cancer actually be any more successful in reducing mortality in comparison to the conventional
treatment available to patients now?

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