Chapter 2

2.1 The viruses

A virus is an infectious agent that can only replicate within a host organism.

Viruses can infect a variety of living organisms, including bacteria, plants, and

animals. Viruses are so small that a microscope is necessary to visualize them, and

they have a simple structure. Viruses are found in almost every ecosystem on Earth

and are the most numerous type of biological entities. The study of viruses is known

as virology, a sub-speciality of microbiology. Since Dmitri Ivanovsky's, Russian

microbiologist, 1892 article describing a non-bacterial pathogen infecting tobacco

plants and the discovery of the tobacco mosaic virus by Martinis Beijerinck in 1898,

more than 9,000 virus species have existed described in detail of the millions of types

of viruses in the environment.

When a host cell is infected, it is compelled to create thousands of copies of the

original virus quickly. Viruses exist in the form of independent particles, or virions

when they are not inside an infected cell or in the process of infecting a cell. Virion

components include I genetic material, which is long molecules of DNA or RNA that

encode the structure of the proteins by which the virus acts; (ii) a protein coat, the

capsid, which surrounds and protects the genetic material; and (iii) an outside

envelope of lipids in some cases.

These viral particles come in a variety of shapes, from simple helical and icosahedral

to more complicated architectures. Most virus species have virions that are one-

hundredth the size of human hair and are too tiny to be seen using an optical

microscope.
 …………………………………… Figure 2.1

The origins of viruses are unknown in the evolutionary history of life: some may

have originated from plasmids, which are DNA fragments that can migrate between

cells, while others may have arisen from bacteria. Viruses play a crucial role in

evolution as a mechanism of horizontal gene transfer, which similarly increases

genetic variety as sexual reproduction. Some biologists believe viruses to be living

forms because they contain genetic material, reproduce, and evolve through natural

selection, even though they lack important traits such as cell structure, which are

generally thought to be required requirements for defining life. Viruses have been

dubbed "organisms at the brink of life" and "self-replicators" because they possess

some but not all of these characteristics.

Viruses spread in many ways. One transmission pathway is through disease-

bearing organisms known as vectors: for example, blood-sucking insects can carry

insects that feed on plant sap, such as aphids; often transmit viruses from plant to

plant and viruses in animals. Influenza viruses spread in the air by coughing and

sneezing. The faucal-oral route, passed by hand-to-mouth contact or in food or water,

transmits Norovirus and rotavirus, common causes of viral gastroenteritis. The

infectious dose of norovirus required to produce infection in humans is less than 100

particles. HIV is one of several viruses transmitted through sexual contact and by

exposure to infected blood. The variety of host cells that a virus can infect is called its

"host range". This can be narrow, meaning a virus is capable of infecting a few

species, or broad, meaning it is capable of infecting many.

Viruses were classified by their infectivity, filter-passing capabilities, and demand

for living hosts by the end of the nineteenth century. Only plants and animals had

been used to create viruses. In 1913, E. Steinhardt, C. Israeli, and R.A. Lambert used

this method to develop the vaccinia virus in fragments of guinea pig ocular tissue. H.

B. Maitland and M. C. Maitland isolated the vaccinia virus from minced hen kidney

suspensions in 1928. Their technology was not widely utilized until the 1950s when

poliovirus was mass-produced for vaccine manufacture on a vast scale.

In 1931, American pathologists Ernest William Good pasture and Alice Miles

Woodruff cultured influenza and numerous other viruses in fertilised chicken eggs,

paving the way for further research. Enders, Weller, and Robbins grew poliovirus in

cultured cells from aborted human embryonic tissue in 1949, making it the first virus

to be grown without solid animal tissue or eggs. Hilary Koprowski and later Jonas

Salk were able to develop an effective polio vaccine because of their work.

The German engineers Ernst Ruska and Max Knoll invented electron microscopy

in 1931, and the first photographs of viruses were obtained. Wendell Meredith

Stanley, an American biochemist and virologist, discovered that the tobacco mosaic

virus was mostly made of protein in 1935. This virus was split into protein and RNA

portions a short time later. Because the tobacco mosaic virus was the first to be
crystallized, its structure could be studied in detail. Bernal and Fankuchen obtained

the first X-ray diffraction images of the crystallised virus in 1941. Rosalind Franklin

found the entire structure of the virus in 1955 using her X-ray crystallographic

images. Heinz Fraenkel-Conrat and Roble Williams demonstrated the purification of

tobacco in the same year.

The second half of the twentieth century was the golden age of virus discovery,

with the discovery of the majority of known animal, plant, and bacterial virus species.

Equine arterivirus was found in 1957, as was the cause of Bovine virus diarrhoea (a

pestivirus). Baruch Blumberg identified the hepatitis B virus in 1963, and Howard

Temin described the first retrovirus in 1965. Temin and David Baltimore separately

described reverse transcriptase, the enzyme that retroviruses employ to create DNA

copies of their RNA, in 1970. The retrovirus now known as HIV was initially isolated

in 1983 by Luc Montagnier's team at the Pasteur Institute in France. Hepatitis C was

identified in 1989 by Michael Houghton's team at Chiron Corporation.

2.1.2 Classification of viruses

The goal of classification is to describe the diversity of viruses by naming and

categorising them according to their commonalities. André Lwoff, Robert Horne, and

Paul Tournier were the first to design a virus categorization system based on the

Linnaean hierarchical system, which was published in 1962. This system used

phylum, class, order, family, genus, and species to classify organisms. Viruses were

classified based on shared qualities (not those of their hosts) and the type of nucleic

acid that makes up their genomes.

The goal of classification is to describe the diversity of viruses by naming and

classifying them according to their commonalities. André Lwoff, Robert Horne, and
Paul Tournier were the first to use the Linnaean hierarchical approach to classify

viruses in 1962. Phylum, class, order, family, genus, and species were used to classify

organisms in this system. Viruses were classified based on their shared qualities

(rather than those of their hosts) and the type of nucleic acid used to construct their

genomes.

To ensure family homogeneity, the ICTV created the present classification system and

published criteria that put a stronger emphasis on specific virus features. A unified

taxonomy (a standardized classification scheme for viruses) has been established.

Only a small portion of the entire viral variety has been researched. The ICTV has

recognized six realms, ten kingdoms, seventeen phyla, two subphyla, 39 classes, 59

orders, eight suborders, 189 families, 136 subfamilies, 2,224 genera, 70 subgenera,

and 9,110 species of viruses as of 2020.

2.1.2.1 Baltimore classification system

The Baltimore classification system was created by Nobel Laureate and scientist

David Baltimore. In current virus categorization, the ICTV classification method is

used in conjunction with the Baltimore classification system. The process of mRNA

synthesis is used to classify viruses according to the Baltimore classification system.

Viruses must synthesise mRNAs from their genomes in order to build proteins and

replicate themselves, but each virus family employs various ways to do so. Single-

stranded (ss) or double-stranded (ds) viral genomes, RNA or DNA, may or may not

require reverse transcriptase (RT). Furthermore, ssRNA viruses can be sense (+) or

antisense. Viruses are divided into seven groups according to this classification:

 I: dsDNA viruses (e.g. Adenoviruses, Herpesviruses, Poxviruses)

 II: ssDNA viruses (+ strand or "sense") DNA (e.g. Parvoviruses)

 III: dsRNA viruses (e.g. Reoviruses)

 IV: (+)ssRNA viruses (+ strand or sense) RNA (e.g. Coronaviruses,

Picornaviruses, Togaviruses)

 V: (−)ssRNA viruses (− strand or antisense) RNA (e.g. Orthomyxoviruses,

Rhabdoviruses)

 VI: ssRNA-RT viruses (+ strand or sense) RNA with DNA intermediate in life-

cycle (e.g. Retroviruses)

 VII: dsDNA-RT viruses DNA with RNA intermediate in life-cycle (e.g.

Hepadnaviruses)

…………………………………… Figure 2.2

2.1.3 The role of virus in human disease

When a virus infects a cell, it can cause a variety of outcomes. Many viruses do

not cause any harm or sickness. Some viruses, on the other hand, assault and replicate

within certain cells. Once fully developed, the daughter viruses burst through the cell

membrane and travel throughout the body. A lytic infection is a term for this type of

infection. If host immunity is strong enough, the host, interrupting the virus cycle and

curing the infection, may eventually kill the virus-infected cell. This is not true for all

viral infections, though. The viruses may be able to stay in the cell without harming it,

making it a carrier. Although the patient appears to be recovered, the infection is still

present and can transmit to others. Furthermore, the illness may recur after some time

has passed.

…………………………………… Figure 2.3

Viruses must also be able to tolerate the immune system in order to spread. Viruses

that cause disease only when the immune system is compromised in some ways are

known as opportunists, and opportunistic infection is one of the most common issues

in people with diseases like AIDS. Several viruses have a reservoir in animals or

plants from which they infect humans. The following are some of the most common

viral reservoirs.

The innate immune system is the body's first line of defiance against infections. This

consists of cells and other defiance mechanisms that protect the host against infection.

This provides some protection from the viral onslaught for the time being. Once

within, adaptive immunity encounters and remembers the pathogen. This is a more

long-lasting form of immunity that can last a lifetime against a specific viral strain.

Antibodies specific to the virus are created. Humoral immunity is the term for this.

Several viruses have an animal or plant reservoir from where they affect humans.

Some of the common reservoirs of viruses include;

…………………………………… Table 2.1

Antibodies come in two varieties. The first, known as IgM, is extremely powerful in

neutralizing viruses but is only produced for a few weeks by immune system cells.

IgG antibodies are the ones that last a lifetime. Cell-mediated immunity is the second

line of defiance, and it involves immune cells known as T cells.

2.1.4 Coronaviruses 

Coronaviruses are a family of viruses that cause diseases in mammals and birds.

In humans, the virus causes respiratory infections that include the common cold,

which is usually mild, and rarely fatal, such as severe acute respiratory syndrome,

Middle East respiratory syndrome, and the novel coronavirus that caused the 2019-20

outbreak. It may cause diarrhoea in cows and pigs, and in chickens, it may cause

diseases of the upper respiratory tract. There are no approved vaccines or antivirals to

prevent or treat these viruses.

Coronaviruses belong to the family Orthocoronaviruses (scientific name:

Orthocoronavirinae) in the family Coronaviridae in the order Nightingale viruses.

Coronaviruses are covered viruses with a positive-sense single-stranded RNA genome

and possess a homologous helical nucleocapsid. The genome of coronaviruses is

about 26 to 32 kilobase in size and is the largest among RNA viruses.

The name "coronavirus" derives from the Latin word 'corona', which is meaning

crown or corona. The name refers to the characteristic appearance of virus particles

(freons) that appear through an electron microscope, where they have indentations of

surface protrusions, giving them the appearance of a king's crown or solar corona.

Coronaviruses were discovered in the 1960s, the first viruses were the infectious

bronchitis virus in chickens and two viruses from the nasal cavity of human patients
with colds named human coronavirus 229E and human coronavirus OC43. Since then

other members of this family have been identified including 2003 SARS coronavirus,

2004 NL63 human coronavirus, 2005 HKU1 human coronavirus, 2012 MERS

coronavirus, and 2019-nCoV novel coronavirus. It is believed that human-to-human

transmission of coronaviruses occurs mainly between close people during direct

contact through respiratory droplets from sneezing and coughing. Most of these

viruses have a role in causing serious respiratory infections and may even lead to

death.

2.1.4.1 Classification of Coronaviruses

Coronaviruses form the subfamily Orthocoronavirinae, which is one of two sub-

families in the family Coronaviridae, order Nidovirales, and realm Riboviria.They are

divided into the four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus

and Deltacoronavirus. Alphacoronaviruses and betacoronaviruses infect mammals,

while gamma coronaviruses and delta coronaviruses primarily infect birds.

 Genus: Alphacoronavirus;[66]

o Species: Alphacoronavirus 1 (TGEV, Feline coronavirus, Canine

coronavirus), Human coronavirus 229E, Human coronavirus

NL63, Miniopterus bat coronavirus 1, Miniopterus bat coronavirus

HKU8, Porcine epidemic diarrhea virus, Rhinolophus bat coronavirus

HKU2, Scotophilus bat coronavirus 512

 Genus Betacoronavirus;[67]

o Species: Betacoronavirus 1 (Bovine Coronavirus, Human coronavirus

OC43), Hedgehog coronavirus 1, Human coronavirus HKU1, Middle

East respiratory syndrome-related coronavirus, Murine

 coronavirus, Pipistrellus bat coronavirus HKU5, Rousettus bat

coronavirus HKU9, Severe acute respiratory syndrome–related

coronavirus (SARS-CoV, SARS-CoV-2), Tylonycteris bat coronavirus

HKU4

 Genus Gammacoronavirus;[18]

o Species: Avian coronavirus, Beluga whale coronavirus SW1

 Genus Deltacoronavirus

o Species: Bulbul coronavirus HKU11, Porcine coronavirus HKU15

…………………………………… Figure 2.3

2.1.4.2 Human coronavirus

Coronaviruses are believed to cause a large proportion of colds in adults and

children. Coronaviruses cause colds with main symptoms, such as fever and swollen

appendages, especially in humans in the winter and early spring. Pneumonia

coronaviruses may cause either viral pneumonia directly or secondary to bacterial

pneumonia. They may also cause bronchitis, directly from either viral bronchitis or

secondary to bacterial bronchitis. The common human coronavirus discovered in

2003 is severe acute respiratory syndrome coronavirus (SARS-related coronavirus),

which causes severe acute respiratory syndrome (SARS), and has a unique pathogenic

potential. This is because it causes the upper and lowers together.

There are seven types of human coronaviruses:

 Human Coronavirus 229E (HCoV-229E)

 Human Coronavirus OC43 (HCoV-OC43)

 Associated Corona Virus

 Human Coronavirus NL63 (HCoV-NL63)

 HKU1 human coronavirus

 Novel Coronavirus/Novel Coronavirus 2012 (HCoV-EMC).

 Novel coronavirus (2019-nCoV), commonly referred to as Wuhan pneumonia or

Wuhan coronavirus.
2.1.4.3 Coronavirus disease 2019 (COVID-19) 

(COVID-19), also known as severe acute respiratory syndrome coronavirus 2019, is a

zoonotic septic respiratory disease caused by the severe acute respiratory syndrome

coronavirus (SARS-CoV-2). This virus is very close to the SARS virus. It was first

detected in the Chinese city of Wuhan in 2019 and has since spread around the world,

causing the global coronavirus pandemic. From the beginning of the pandemic until

today, more than 328,649,355 million cases of coronavirus have been reported in all

countries of the world, resulting in more than 5,541,890 million deaths. The ratio of

the number of deaths to the number of diagnosed injuries is estimated at 3.4%, but it

varies according to age and the presence of other diseases.

Common symptoms of (COVID-19) are fever, cough, and shortness of breath, while

muscle aches, sputum production, and sore throat are not common. While most

infections follow a benign, asymptomatic course, number progress to more serious

forms such as severe pneumonia and multiple organ dysfunction.

While the majority of cases have mild symptoms, people with acute respiratory

distress syndrome (ARDS) may experience organ failure, septic shock, and blood

clots. The time between exposure to the virus and the onset of symptoms ranges from

two to 14 days, with an average of five days. Long-term damage to organs

(particularly the lungs and heart) has been observed, and there is concern about a

large number of patients who have recovered from the acute phase of the disease but

still have a range of symptoms - including extreme fatigue, memory loss and other

cognitive problems, mild fever and weakness Muscles, shortness of breath, and other

symptoms - for several months after recovery

The virus spreads between people during close contact, often through small droplets

of droplets produced by coughing, sneezing, and speaking. These droplets usually fall

to the ground or to surfaces rather than travel through the air over long distances.

Some people may become ill by touching contaminated surfaces and then touching

their faces. The virus is most contagious during the first three days after symptoms

appear, although infection can occur before these symptoms appear and from people

who do not show symptoms of the disease.

Moreover, the use of a face covering is recommended for those who suspect they have

the virus and those who care for them. The recommendations for covering the face

that people use are in conflict with some authorities recommending them, some

against them, and others advising them to use it. There is limited evidence for or

against the use of masks (medical or other) by healthy individuals in our community.

The infection is usually transmitted from one person to another by respiratory droplets

resulting from coughing or sneezing. The time between exposure to the virus and the

onset of symptoms ranges from two to 14 days, with an average of five days. The

standard diagnostic method is to perform a smear (PCR) taken from the nasopharynx

or from the throat. The infection can also be diagnosed by combining symptoms and

risk factors with a CT scan of the chest that shows signs of pneumonia.

2.2 The Vaccine

 A vaccine is a biological preparation that gives active resistance to a selected disease.

Vaccines generally contain a pathogen-like organism medium and are usually made

up of weakened or killed varieties of the bacterium, its toxins, or one among its

surface proteins. This intercessor stimulates the body' system to acknowledge this

germ as a threat to that and destroy it, and keeps a replica of it in order that the
immune system will establish it and destroy it simply if any of those organisms

attacked it again. the method of administering the vaccine is named the vaccination

process.

Vaccination effectivity has been well studied and verified, for instance respiratory

illness vaccine, human papillomavirus vaccine, variola vaccine. Vaccination is that

the initial effective thanks to prevent infectious diseases. Widespread immunity from

vaccines is basically chargeable for the world obliteration of smallpox and also the

reduction of different diseases comparable to polio, measles, and tetanus in most

regions of the world. the globe Health Organization has indicated that presently

accredited vaccines are out there to forestall or contribute to the interference and

management of twenty five infectious diseases. Vaccines may be preventive (eg:

prevent or improve the results of a future disease through a natural or wild pathogen),

or curative (eg, there are prescribed vaccines against cancers, see Vaccines against

cancer).

The time period pollen and inoculation is derived from Variolaevaccinae (cowpox),

Edward Jenner coined the call to indicate cowpox. He used it in 1798 below his

extensive title "Inquiry into the Smallpox Vaccine Known as Cowpox Vaccine",

wherein he defined the protecting impact of this vaccine in opposition to smallpox. In

1881, to honor Jenner, scientist Louis Pasteur advised that the time period have to be

improved to cowl each new vaccine later discovered.

Vaccines usually comprise attenuated, inactivated or useless organisms or purified

merchandise derived from them. There are numerous kinds of vaccines in use.[38]

These constitute one-of-a-kind techniques used to attempt to lessen the hazard of

contamination even as maintaining the cap potential to result in a useful immune

response.

2.2.1 Types of Vaccines

 Attenuated vaccine

 Inactivated vaccine

 Toxoid

 Subunit vaccine

 Conjugate vaccine

 Outer membrane vesicles

 Heterologous vaccine

 Genetic vaccine

 Viral vector vaccine

 DNA vaccine

 RNA vaccine

An mRNA vaccine (or RNA vaccine) is a novel type of vaccine which is composed of

nucleic acid RNA, packaged within a vector such as lipid nanoparticles. Among the

COVID-19 vaccines are a number of RNA vaccines under development to combat the

COVID-19 pandemic and some have been approved or have received emergency use

authorization in some countries. For example, the Pfizer-BioNTech vaccine and

Moderna mRNA vaccine are approved for use in adults (with the Pfizer vaccine also

fully approved for teens aged 16 to 17) in the US.

There are eight licensed vaccines for COVID-19, and they include Pfizer-Biotech,

Moderna, AstraZeneca, Sputnik, Sinovac, Sinopharm, and Johnson & Johnson,

among others. Studies and previous work related to the severe acute respiratory

syndrome coronavirus (SARS-CoV) vaccine is useful because it is similar to the

emerging virus (SARS-Cove 2) in many of its properties, as both types use ACE2 as a

route to invade human cells.

2.3 The Cytokines

A cytokine is a protein, polypeptide, or glycoprotein utilized in sign transduction

and intercellular verbal exchange. B cells make cytokines that prompt T cells, and T

cells produce kinds of cytokines that still boom and prompt the wide variety of T

cells. Cytokines have a key position in immune approaches and embryonic

improvement.

The phrase cytokine includes parts, the primary is cytokine, because of this that

mobileular, and the second, kina, because of this that movement, that means that it

movements cells. Cytokines are chemical signals, just like hormones and

neurotransmitters, which can be used to permit a mobileular to talk with different

cells. The own circle of relatives of cytokines includes a collection of water-soluble

proteins and glycoproteins with hundreds of 5,000 to 20,000 Daltons.

Compared to hormones, hormones are secreted from specialized organs with inside

the frame and transported to the blood, at the same time as neurotransmitters are

launched through nerves, and cytokines are produced through one-of-a-kind kinds of

cells. Its significance sticks out with inside the kinds of herbal and purchased

immunity, because it intervenes in lots of infectious and inflammatory diseases,

injury, infections and sepsis (blood poisoning). But its venture isn't always restrained

to the immune device only, its position in verbal exchange among cells throughout

embryonic improvement is likewise great.

2.3.1 Type of Cytokines

There are five types of cytokines: interleukin, interferon, colony-stimulating

factor, tumor necrosis factor and chemokine.

2.3.1.1 Interleukins

Interleukins are a subset of a larger group of cellular messenger molecules called

cytokines, which are modulators of cellular behavior. The first interleukins were

identified in the 1970s. The name "interleukin" was chosen in 1979, to replace the

various different names used by different research groups to designate interleukin-1

(lymphocyte activating factor, mitogenic protein, T-cell replacement factor III, B-cell

activating factor, B-cell differentiation factor, and hedecin). (Heidikine)) and

interleukin-2 (TSF, etc.). This decision was made during the Second International

Lymphokine Workshop in Switzerland (27-31 May 1979 in Ermatingen). Initially

investigators believed that interleukins were made chiefly by leukocytes (white blood

cells) to act primarily on other leukocytes, and for this reason they named them

interleukins, meaning “between leukocytes.” Because leukocytes are involved in

mounting immune responses, interleukins were thought to function only as

modulators of immune functions.

Although this is an important function of interleukins, it is now known that

interleukins also are produced by and interact with a host of cells not involved in

immunity and are involved in many other physiological functions. Thus the role that

interleukins play in the body is much greater than was initially understood.

Interleukins are formed in a wide range of cells in the body, including white blood

cells, also called leukocytes. These cells expel or destroy bacteria and other harmful

substances that enter the body.

Different types of interleukins are found in different types of white blood cells. Three

types of interleukins have been studied: interleukin-1, interleukin-2, and interleukin-3.

These interleukins work together and trigger a chain reaction that will arm the body's

white blood cells against disease. For example, if you have a wound, and bacteria

enter the wound, white blood cells detect the presence of bacteria at the site of the

wound. These cells then release interleukin-1, which in turn signals other white blood

cells called T cells to help destroy the bacteria. In turn, the T cells release interleukin-

2 and similar chemicals, which stimulate various cells in the immune system to attack.

See: Immunology. There is promising evidence that interleukins can treat cancer and

many other diseases. Both IL-1 and 2 can be produced in the laboratory.

Interleukins are classified into several types from IL-6 to IL-37.

 interleukin 6

Interleukin 6 is defined as the cytokine responsible for controlling the immune

response and cell proliferation and differentiation. Human interleukin-6 is a specific

gene on chromosome 7p21 and consists of 212 amino acids, including a 28-amino

acid signal peptide. This type of cytokine has many pro-and anti-inflammatory

properties. IL-6 secretion has also been observed in atherosclerosis, Alzheimer's

disease, systemic lupus erythematosus, multiple myeloma, rheumatoid arthritis (RA),

autoimmune disease, chronic inflammatory diseases and various types of cancer etc.

Therefore, the control of IL-6 secretion is particularly important during disease,

particularly its activation after the activation of the immune response. T cells,

macrophages, endothelial cells, fibroblasts, and monocytes are the cells responsible

for secreting interleukin 6. IL-6 targets are B cells, T cells, basophils, eosinophils, and

neutrophils. The functions of IL-6 on B cells are B-cell differentiation as well as IgM,
IgE and IgA production. Moreover, IL-6 also controls T-cell activation,

differentiation and survival. IL leads to leukocyte activation. As a result, after injury,

a cytokine storm causes T and B cell activation and differentiation. Increased levels of

IL-6 are seen in low diagnoses or metastatic cancers. IL-6 secretion causes antibody

production by B cells and promotes autoantibody hypergammaglobulinemia. In

addition, IL-6 causes autoimmunity, chronic inflammation, positive activation of CD4

cells, which leads to Th17 differentiation, or positive inhibition of CD4 T cells, which

suppresses Treg differentiation.

2.3 The relationship between Covid-19 disease and IL-6

Interleukin 6 is an important cytokine whose production is related to various

inflammatory diseases. Subjects with SARS-CoV-2 had high levels of IL-6 that were

correlated with patient symptomatology including pulmonary inflammation and

extensive lung damage. Additionally, patients with SARS-CoV-2 infection had low

levels of suppressor of cytokine signalling-3, which regulates and stimulates the

negative feedback mechanism of IL-6. On the same line, another study reported that

IL-6 levels were higher in severe COVID-19 patients and this may be used as one of

the bases for predicting the transition from mild to severe infection.

Interleukin 6 is a major factor in inflammation and a viral cytokine storm in COVID-

19 patients. Some studies have reported that a humanized monoclonal antibody

against the Interleukin 6 receptor, tocilizumab, can be used in the treatment of

COVID-19 based on its cytokine storm blocking property. A recent Chinese

retrospective study showed that tocilizumab improved fever, C-reactive protein levels,

and hypoxemia without leading to any significant adverse reactions in 21 severe

COVID-19 patients. Tocilizumab can only be used in patients with COVID-19 who
have reached the end of a high viral load, have interstitial pneumonia, severe

respiratory failure, and high levels of LL-6 and/or D-dimer/CRP/ferritin/fibrinogen.

TNF-α is an important mediator of cytokine and chemokine production and has a role

in acute and chronic systemic inflammatory responses. The level of TNF-α was found

to be elevated in COVID-19 patients and was correlated with disease severity. In

COVID-19 patients, anti-TNF-α therapy may be a potential option, and a randomized,

controlled trial of adalimumab was conducted. In addition, corticosteroids and

immunosuppressants can be used to suppress the cytokine storm and are systemically

modified in patients with COVID-19. However, recent studies have shown that

hydrocortisone use was associated with higher plasma SARS-CoV-2 viral load and

delayed viral clearance in COVID-19 patients.

2.4 TP53 gene

The TP53 gene is known as the gene responsible for generatıng protein 53, which

contributes greatly to the inhibition of the growth process of tumours. If this gene is

mutated - that is, changed in some way, environment or inheritance, it allows

damaged cells to survive, eventually developing into cancerous cells. The TP53 gene

is located on chromosome 17 in any cell. Loss of this gene leads to the occurrence of

cancer in a large year. As we mentioned earlier, this gene works for itself by

expressing and secreting p53 protein, and this type of protein works on binding to

DNA. The p53 gene is a tumor suppressor gene, that is, its activity stops tumor

formation. If a person inherits only one functional copy of the p53 gene from their

parents, they are at risk of developing cancer and usually develop many independent

tumors in a variety of tissues by early adulthood. This condition is rare, and is known

as Li-Fraumeni syndrome. However, mutations in p53 are found in most types of

tumors and thus contribute to the complex network of molecular events that lead to

tumor formation.

2.4.1 Protein 53 (P53)

Protein 53 (also defined as a tumours suppressor protein 53) is a human tumours

suppressor gene that is encoded by the TP53 gene on chromosome 17 in humans. P53

has a significant role in multicellular organisms as it is involved in regulating the cell

cycle and thus plays a key role in tumours suppression and cancer prevention. Thus,

p53 was described as the "protector of the genome", and the "guardian", referring to

its role in maintaining the stability of genetic information by preventing genetic

mutations. The name p53 indicates the protein's molecular mass as 53 kids (kids) as

calculated by SDS Page. However, the actual mass of the protein is 43.7 kids by

calculating the amino acid residues.

2.4.2 Structure of P53

Human p53 consists of 393 amino acids, and is divided into seven axes:

1. N-terminal: transcription-activation domain (TAD) also known as activation

domain 1 (AD1) that activates transcription factors: residues 1-42.

2. Activation domain 2 (AD2) is important for apoptotic activity: residues 43-63.

3. A proline-rich region important for the apoptotic activity of p53: residue 64-92.

4. Principal DNA-binding domain (DBD). Contains one atom of zinc and several

amino acids arginine: residues 100-300.

5. Signal field to identify the nucleus, residues 316-325.

6. homo-oligomerisation domain (OD): residues 307–355.

7. C-terminal: Responsible for reducing the activity of the main DNA binding

domain: residues 356-393.

2.4.3 The effect of coronavirus on P53

The tumours suppressor protein p53 is widely known as “the guardian of the

genome” because of its ability to prevent the emergence of transformed cells by

inducing cell cycle arrest and apoptosis. Modern studies refer that P53 is considered

as a direct target gene of the type I interferon (IFNα/β) pathway. Therefore, it is

activated by specific cytokines upon viral infection.

This provides new insight into the function of p53 in antiviral innate immunity. This

tumours suppressor has been recently introduced because virus infection activates

p53. According to several scientific studies, p53 is the main factor in antiviral innate

immunity by both inducing apoptoses in infected cells and enforcing type I IFN

production. Both actions coordinated by this tumours suppressor help thwart the

replication of a wide variety of viruses. In addition, P53 helps explain why this

protein is conserved in invertebrate organisms, which do not suffer from cancer-

related diseases.

Previous studies have proved that type I interferons can inhibit the growth of the

replication of coronaviruses and that IFNβ is more effective than IFNα. Anyhow,

clinical studies have revealed that coronavirus infections induce very low levels of

type I IFNs, which contributes to rampant viral replication and a weakened immune

response. The low-level IFN refers to the vigorously replicating RNA virus suggests

that coronaviruses might either evade or inactivate the innate immune response.

However, the molecular mechanism of the low dosage IFN production remains
unclear. That shows that PLP2 decreases the stability and transcriptional activity of

p53 by increasing the MDM2-mediated ubiquitination and nuclear export of p53.

PLP2 inhibits antiviral responses by attenuating the p53-mediated production of type I

IFN and apoptosis and, as a result, enhances viral replication. Intriguingly, we found

that p53 directly transactivates IRF7 to regulate the transcription of type I IFN genes,

which provides strong evidence for the role of p53 in the innate immune system.