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1.1 Introduction
On December 31st, 2019, the World Health Organization WHO, China
Country Office received notification of instances of pneumonia with an
uncertain Etiology (unknown cause) in China (Bogoch et al., 2020). As of
3 January 2020, China's national authorities had reported a total of 44 people
with pneumonia of an undetermined cause to WHO; the cause of the outbreak
has yet to be determined or confirmed. WHO sought additional information
from national authorities in January 2020, to assess the risk (WHO, 2020).
The new SARS 2 virus appeared for the first time in Wuhan, China, in late
2019 in December and spread quickly, which prompted the World Health
Organization to declare a state of maximum health emergency in January 2020
and that the disease has become a global pandemic on 11 March 2020
(Pellegrino et al., 2020). Before 2019, six types of coronaviruses cause human
infection (NL63, OC43, E229, HKU1 SARS-CoV1 and MERS) (Liu et al.,
2021), which infect the upper respiratory tracts as well as the lower respiratory
tracts and cause severe symptoms for patients. SARS-CoV-2 is a virus that
affects the upper and lower respiratory tracts, resulting in severe acute
respiratory syndrome mainly due to the inflamma some activation and pyro-
ptosis (Yap et al., 2020).
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
pandemic was declared by the World Health Organization (WHO) on 11March
2020, after SARS-CoV-2 spread dramatically all around the world. The ongoing
epidemic is due to its unexpected beginning, persistent humanto-human
transmission, and rapid spread. There were (70, 39918) confirmed cases and
404,396 fatalities worldwide as of 9 June 2020. The percentage of those infected
with COVID-19 Respiratory droplets is high, most typically due to coughing or
talking. The virus is spread through respiratory secretions, which infect people
when they come into contact with mucosal membranes, either directly or
indirectly (Sanyaolu et al., 2021).
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Fig. (1): A graph retrieved from the World Health Organization website showing the first and
second waves in Iraq, according to the link https://g.co/kgs/Hbt9Gs.
According to the Dimensions website (2021), from the beginning of the
SARS-CoV2 pandemic until (23 September 2021), more than 621,576 total
research publications have been published on the topic of SARS-CoV2 by
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28,939 total organizations from 198 countries around the world participated in it
(Dimensions, 2021).
On its official website, the World Health Organization confirmed that most
people infected with the SARS-CoV-2 virus, and those who suffer from mild or
moderate symptoms, often recover without the need for special treatment. Only
the elderly and those who suffer from other diseases such as chronic respiratory
diseases, vascular diseases, diabetes, or heart disease are the ones who need a
treatment protocol (WHO, 2021).
There are also domestic Iraqi researches that had an important role in the
field of SARS-CoV2. A master's thesis (Raja 2021) was discussed at the
University of Kufa, Iraq, which was investigating the gene expression of the
angiotensin-converting enzyme 2, PARF, and the cytokine storm factors such as
IL6, TNF alpha, and CXCL10 factors (Raja, 2021).
A study by Habib et al (2020) showed that the SARS-CoV2 infection rate
had a positive correlation with regions regarding air travel facilities that
appeared to be more susceptible to COVID-19 due to people moving and the
entry of strangers from infected countries (Habib AlKanan, et al., 2020).
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2.1 Severe acute respiratory syndrome Coronavirus SARS COV-2:
Severe acute respiratory syndrome 2 Coronavirus (SARS COV-2) is
considered the virus that causes COVID-19 disease (Gorbalenya et al., 2020).
COVID-19 launch in Wuhan, Hubei Province, China, from time to time,
members of the Coronavirus family appear to cause infections in humans, but
not of the same importance as Covid 19, such as HCoVs, SARS –CoV, MERS-
CoV (Elrashdy et al., 2020). Reported symptoms include fever, cough, fatigue,
pneumonia, headache, diarrhea, hemoptysis, and dyspnea (Adhikari et al.,
2020).
2.2 Classification:
The virus is a Zoonotic source, as is for the infection to occur, it must be
passed from animal to human (Ronco et al., 2020). Until this moment, all
research and studies indicate that the SARS CoV-2 is of animal origin (Zoonotic
disease). SARS COV-2 has the same clinical features and genetic information as
SARS and MERS, as they both belong to the same family of beta-coronavirus
(Pellegrino et al., 2020). All seven HCOV (OC43-NL63, E229, HKU1, MERS,
SARS COV, and SARS-COV2) have a Zoonotic origin such as mice, pangolin,
bats, and other pets, as shown with figure (2). They have been classified into
four different genera according to their genomic and protein sequences Alpha,
Beta, Gamma, and Delta. The two genera (E229-NL63) are alpha, while the
other five are beta (Ye et al., 2020). The family Coronaviridae is organized into
2 subfamilies, 5 genera, 26 subgenera, and 46 species (Gorbalenya et al., 2020).
Category: Coronaviruses; Realm: Riboviria; Order: Nidovirales Suborder:
Cornidovirineae; Family: Coronaviridae, Subfamily: Orthocoronavirinae;
Genus: Betacoronavirus; Subgenus: Sarbecovirus; Species: Severe acute
respiratory syndrome-related coronavirus; Individuum: Severe acute respiratory
syndrome-related coronavirus-2 (SARSCoV-2).
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Fig. (2): SARS-CoV, MERS-CoV, and SARS-CoV- 2 full genome sequences and phylogenetic
tree of SARS-like coronaviruses (A) This tree depicts the evolution of SARS-like b-coronaviruses
in human (n 14 20), bat (n 14 22), civet (n 14 3), and pangolin (n 14 6)samples. Next strain
(https://github.com/blab/sars-like-cov) was used to create a phylogenetic tree comprising full
genome sequences of coronaviruses. Coronaviruses are enclosed spherical particles with a
diameter of 100e160 nm. A 26e32 kb positive-sense single-stranded RNA (ssRNA) genome is
found in them. The 50-terminal two thirds of the genome ORF1a/b encode polyproteins that
make up the viral replicas transcriptase complex in SARS-CoV, MERS-CoV, and SARS-CoV-2.
The remaining ORFs on the third of the genome code for four major structural proteins: spike
(S), envelope (E), nucleocapsid (N), and membrane (M), as well as some accessory proteins (Li
et al., 2020).
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the basic components of the virus, which are the spike, envelope, membrane,
and nucleocapsid protein. Among the main combinations, there are a series of
accessory genes (ORFs 3a, 3b, 6, 7a, 7b, 8b, 9b, and 16) which encode the
accessory proteins that regulate infection and evade immunity but which do not
incorporate with SARS COV-2 genome (Wang et al., 2020).
Fig. (3): The SARS-CoV-2 genomic structure is depicted schematically. The structure of SARS-
CoV-2 is spherical. A lipid envelope surrounds the virus, which is covered in spike glycoprotein.
The genomic arrangement of SARS-CoV-2 is typical of Betacoronavirus. The full-length RNA
genome is roughly 29,903 nucleotides long, and the 5′UTR contains a replicase complex (ORF1a
and ORF1b). The nsp1–nsp10 is encoded by ORF1a, while nsp1–nsp16 is encoded by ORF1b.
The structural proteins are encoded by four genes: the spike gene, the envelope gene, the
membrane gene, the nucleocapsid gene, and a poly (A) tail at the 3′UTR. The auxiliary genes are
strewn among the structural genes (Rastogi et al., 2020).
2.4 Pathogenicity
In general, viruses depend on the cell to produce many new virus copies of
the same type, since the virus is obligated to parasitize. Once infecting a
sensitive cell. Cell resources are harnessed for virus reproduction. A cell is
considered infected if the virus attaches itself to the special receptor on the cell
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membrane and enters the cell. And this process is carried out by proteins
specific to the virus (Krupovic et al., 2019).
For SARS COV-2, its life cycle begins when (S) protein is activated by two
proteins, by the cellular serine protease (TMPRSS2) and trypsin-like protease
from airways (TMPRSS11D). Protein S binds itself to the angiotensin-
converting enzyme 2 (ACE2) receptor (Bosch et al., 2003). The ACE2 enzyme
that is targeted by SARS CoV-2 is a homeostatic enzyme, which is responsible
and controlling for the isometric pressure balance of extracellular fluids as well
as arterial pressure in humans. It is found mainly on the ciliated cells of the
upper airway epithelium, tubular cells near the kidneys, the duodenum, small
intestine, liver, Sertoli cells, Leydig cells of the testis, and glandular cells of the
gallbladder. It is also present in the epididymis and cardiomyocytes, in the
tissues of the heart, pancreas, seminal vesicles, and placenta (The Human
Protein Atlas, 2021).
The fusion between a host cell and SARS COV-2 occurs in an endosome
fashion when a conformational change occurs between the virus's S protein and
angiotensin-converting enzyme 2 (ACE2). Then SARS COV-2 RNA is injected
into the cytoplasm of the host cell to be translated by the ribosomes into multiple
viral repeat proteins pp1a-pp1b, which are then processed by 3CLpro and PLpro
proteases is an essential coronavirus enzyme that is required for processing viral
polyproteins. This enzyme generates a functional replicase complex and enables
viral spread, from this fission, 16 NSPs are produced, which are accused of
producing the transcription and replication genes of the virus (Shereen et al.,
2020).
Whereas, structural proteins and accessory proteins are synthesized by
translating the positive RNA template into the negative RNA strand to produce
the mRNA. Finally, the RNA genomic and viral proteins are surrounded by the
structural proteins of SARS-CoV-2, this role is played by the Golgi apparatus
and the rough endoplasmic reticulum (Shereen et al., 2020).The stages of the
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disease can be divided according to severity into three stages: The initial stage is
characterized by mild or non-specific symptoms such as fever and dry cough. It
occurs at the beginning of infection or when taking some types of vaccines, and
it can be detected by RT -PCR swab, serological tests, and complete blood
count. At this stage, the recovery rate is high from the disease.
The second stage is describing by a reduction in the anti-viral response and a
raise in the proinflammatory response with viral multiplication and
inflammation located in the lungs as a norm; and the third stage, i.e., severe-
systemic hyperinflammation, by a severe inflammatory response. Taking the
clinical experience accumulated to date into account (Sarmiento-Monroy et al.,
2021).
Siddiqi K., et al (2020) state that it is also possible to add a fourth stage that
includes patients recovering after infection, but showing late complications such
as fibrosis of the pulmonary alveoli .
The pathogenesis of COVID-19 can be summarized as follows:
Acute respiratory distress syndrome ARDS is a common consequence of
severe viral pneumonia, particularly pneumonia produced by highly deadly
coronaviruses such as SARS-CoV-2 (Colafrancesco et al., 2020).
In a study by Mason et al., (2016) it was found that there is a relationship
between the genetic makeup of the patient and the development of HCOV
disease. Over 40 potential genes have been linked to the development or
outcome of ARDS, including interleukin 10 (IL-10), ACE2, tumor necrosis
factor (TNF), and vascular endothelial growth factor VEGF (Meyer & Christie,
2013). Increased levels of IL-6 and IL-8 in the blood have also been linked to
ARDS complications (Mason et al., 2016).
Cytokine storm: Once the fusion is complete, the virus replicates within the
host cells. This invasion of lung surface cells results in lung inflammation
and a negative cycle of oxidative stress-related processes, such as increased
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PARP and PARG activity, ADP ribose, and TRPM2 activity (Kouhpayeh
et al., 2020).
Gang Li et al., (2020) pointed that the Antigen-presenting cells
(APCs), such as macrophages, present SARS CoV-2 antigens to T cells
after viral cell contact. This mechanism results in T cell activation and
cytokine synthesis in diverse T cell subsets, such as Th17. This is followed
by a huge cytokine release due to a positive response loop between
cytokines and immune cells. During SARS-CoV-2 replication, however,
the viral genomic dsRNA activates interferon regulatory factors (IRFs) and
the TLR-3-induced NF-κB pathway, resulting in the generation of high
amounts of type I IFNs and proinflammatory cytokines (Gang Li et al.,
2020).
Hyper coagulation: Tissue factor (TF) is often involved in inflammation
induced coagulation, which results in an enhanced coagulation state (Iba et al.,
2019). TF is expressed on vascular endothelial cells and both mononuclear cells
in response to pro-inflammatory cytokines (mostnotably IL-6). It helps to speed
up the conversion of prothrombin to thrombin, which then converts circulating
fibrinogen to fibrin, resulting in fibrin-based blood clots (Van Der Poll et al.,
2017).
2.5 Immune response of Covid-19:
Types of immune response occur inside the body: a weak primary response
to Interferons, which allows the virus to multiply, and a severe secondary or late
immune response characterized by a massive of proinflammatory cytokines,
including interleukins IL6, IL1, TNF, MCP-1, and IP-10 proteins (Huang et al.,
2020). Further, neutrophils and macrophages, that generate an immune response
and a strong reaction in some Cases are destructive and harmful to the patient's
body (Prompetchara et al., 2020).
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receptors ACE2 and TMPRSS2 (Hoffmann, M., et al., 2020). The active
replication of the virus may result in the pyroptosis of infected cells leading to
the release of inflammatory signals (Yap, T., et al., 2020). The recognition of
these signals by adjacent cells (epithelial cells or alveolar macrophages) triggers
the secretion of inflammatory cytokines and chemokines in the micro-
environment resulting in the recruitment of antiviral innate and adaptive immune
cells (Tay, M., et al., 2020). Several studies have indicated that the impaired
innate antiviral defenses against SARS-CoV-2 coupled with the hyper-
inflammatory immune response to the virus is a major driver of disease severity
and mortality (Mehta, et al., 2020); (Blanco-Melo, et al., 2020). Indeed, patients
with severe SARS-CoV-2 infections exhibit high levels of circulating
inflammatory cytokines and increased T cell and monocyte recruitment into the
lungs (Xu, et al., 2020), which may cause lung damage and the cytokine release
syndrome. For this reason, immunosuppressive therapeutic agents such as
corticosteroids and IL-6 antagonists are being clinically tested to eventually
reduce the hyper-inflammation-mediated organ damage (Tay, M., et al., 2020).
Interleukin-3, a hematopoietic growth factor produced by T-cells (Niemeyer,
et al., 1989) and in a lesser extent by mast cells (Loentz, et al., 2000),
eosinophils (Kita, H., et al., 1991), and innate response activator B cells(Webar,
G., et al., 2015), was described to play a key role during inflammatory diseases.
For instance, we recently identified that IL-3 amplified acute inflammation in
sepsis by fuelling the cytokine storm, with high levels of IL-3 predicting death.
IL-3 has also been shown to induce experimental autoimmune encephalitis
(EAE) by promoting leukocyte migration into the brain (Renner, K., et al.,
2016). In contrast, IL-3 reduces the severity of collagen induced arthritis by
modulating the development of Foxp3 regulatory T-cells (Srivastava, R., et al.,
2011). The function of IL-3 during viral immunity, however, remains
rudimentary.
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recombinant IL-3, or CD123 receptor agonists, may therefore have the potential
as novel therapeutic agents in SARS-CoV-2 infected patients.
2.7 Epidemiology:
The new SARS 2 virus appeared for the first time in Wuhan, China, in late
2019 in December and spread quickly, which prompted the World Health
Organization to declare a state of maximum health emergency in March 2020
and that the disease has become a global pandemic (Pellegrino et al., 2020),
Figure (4).
Fig. (4): COVID-19 cases mentioned weekly by WHO area, and global deaths, as of 24
January 2021 (WHO, 2021).
Patients have reported a high fever (above 38°C), a dry cough, lethargy, and
breathing problems. The disease has been termed COVID-19 and has been
connected to a seafood market in Wuhan, China (C. et al., 2020;). It rapidly
spread to neighboring Far Eastern countries, followed by the Middle East and
Europe. Pneumonia, septic shock, metabolic acidosis, and bleeding are all
symptoms of the condition in severe situations (Helmy et al., 2020). The
incubation time is anticipated to be between 5 to 14 days and varies
from one patient to another depending on age and infected date (Xiao et al.,
2020). The virus has infected more than 150 countries and areas around the
world as of March 16, 2020.
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Materials and Methods
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References
« References »
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References
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Chapter One
Three Introduction
References
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Chapter One
Three Introduction
References
29
Chapter One
Three Introduction
References
30
Chapter One
Three Introduction
References
31
Chapter One
Three Introduction
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