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Acta Scientific Pharmaceutical Sciences (ISSN: 2581-5423)
Volume 6 Issue 6 June 2022
Immune System Response to COVID-19. An Endless Story
Mohamed Raslan1, Eslam MS1, Sara AR1 and Nagwa A Sabri2*
1Drug Research Centre, Cairo, Egypt
2Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University,
Cairo, Egypt
*Corresponding Author: Nagwa A Sabri, Department of Clinical Pharmacy, Faculty
of Pharmacy, Ain Shams University, Cairo, Egypt.
Research Article
Received: April 20, 2022
Published: May 16, 2022
© All rights are reserved by Nagwa A Sabri.,
et al.
Abstract
Background: Nowadays COVID-19 is the most widely spread viral infections all over the world. The relation between immune
system response, coordination, existing comorbid conditions, viral proofreading, and severity of corona virus infection and increased
mortalities requires some attention to be investigated and correlated.
Aim: Reviewing the immune system, types of immunity and investigating the effect of comorbidity and poly pharmacy on patients’
Discussion: Severity of COVID-19 infection can be attributed to immune dysregulation and loss of bridging between innate and
adaptive immunity. Several factors and comorbid conditions contribute in such dysregulation, like age, obesity, pre-existing diseases,
stress conditions. Besides, viral mutations that occurs as a result of proofreading mechanisms contributes in such diseases severity.
Clinical pictures showed high white blood cell count, lower lymphocyte count, and high levels of reactive protein (CRP) in those
patients died from COVID-19 compared to those recovered individuals. Several drug choices like hydroxychloroquine, Baricitinib,
Beta-glucans proved to be effective in management and regulation of disrupted immune responses and improving clinical pictures.
Conclusion: Immune dysregulation and other factors supporting such dysregulation showed to be the main leading cause for
exacerbation of COVID-19 symptoms and increased mortalities. Different therapeutic choices showed to be effective in restoring
immune coordination, and improving clinical signs and symptoms.
Keywords: COVID-19; Innate Immunity; Proofreading; Adaptive Immunity; Cytokines, Thymus-Derived Immunity
Introduction
Immune system
Immunity means a groups of cells, chemical substances, and
processes that is functioning to provide protection for the skin,
respiratory tract, intestinal tract and other body areas from foreign
invading pathogens such as microbes, viruses, cancer cells, and
are innate immunity and adaptive immunity [1,2].
against invading pathogens. It is characterized by being an antigen-
use immediately or within hours of facing an antigen. Also, it has
no immunologic memory and so, it can’t recognize or memorize the
same pathogen again when the body exposed to it another time [3].
antigen and so, it involves a lag time between antigen exposure
and maximal response. The key feature of adaptive immunity is its
Citation: Nagwa A Sabri., et al. “Immune System Response to COVID-19. An Endless Story". Acta Scientific Pharmaceutical Sciences 6.6 (2022).
memory capacity, which implies that when infection occurs again,
[4].
Innate immunity
This type of immune response to pathogens is dependent on
what is called “pattern recognition receptors” (PRRs). Innate
immune response allows a limited number of immune cells to
recognize and respond quickly to a large variety of pathogens with
similar structures, which is called “pathogen associated molecular
patterns” (PAMPs). Examples of PAMPs include lipopolysaccharides
(LPS) of bacterial cell wall components, and RNA produced during
viral infection [5,6].
Furthermore, innate immunity provides one of the important
immunological roles, including the rapid recruitment of immune
production of cytokines and chemokines [7].
Cytokines can activate many defensive systems. They also
stimulate local cellular responses to infection or damage. The key
an infection includes, tumor necrosis factor (TNF), interleukin 1
autoimmune disease. For that reason, cytokines are considered an
important therapeutic targets [7].
The biochemical sequence that is important in identifying and
opsonizing bacteria and other pathogens is called “complement
system”. It makes pathogens susceptible to phagocytosis that
encourage getting rid of dead cells or antibody complexes and
removes foreign substances present in tissues, blood, lymph, and
organs. Moreover, the complement system stimulates the adaptive
immune response by mobilizing and activating antigen-presenting
cells (APCs) [4].
Natural killer (NK) cells are principally involved in tumor
rejection and cell destruction infected by viruses. Perforins and
granzymes released by NK-cell granules stimulate the destruction
of infected cells, which also trigger apoptosis [8].
Furthermore, NK cells are a major producer of another cytokine,
development of antiviral immunity. One of the cell that contribute
17 is called innate lymphoid cells (ILCs). Examples of those cells
include ILC-1, ILC-2, ILC-3. Cytokines production help to direct the
to immune regulation [7].
Adaptive immune response begins after Innate immunity.
The two main divisions of adaptive immunity, are antibodies and
T-cell-mediated, which are mainly directed at different targets.
Antibodies bind to free viral particles that result in blocking of viral
infection to the host cell. T-cells act by identifying and destroying
infected cells. All viruses replicate within cells and spread directly
between cells without re-entering the extracellular environment
and so, resolution of infection is mainly relaying on T-cell function
than on antibody [9].
Antibodies is important as an immune-protective barrier against
reinfection. Antibodies are present at portals of entry, most often
mucosal surfaces. Thereby, investigators are designing vaccines
that optimally induce mucosal antibody. Innate mechanisms that
stimulate antigen-presenting cells are required for the onset of
adaptive immunity (APC) [10].
Chemokine and cytokine signals drive APC and lymphocytes
into lymphoid tissues and keep them there for a few days to
allow for successful interactions between these cells. Secondary
lymphoid tissues, through a supporting stromal cell network and
local chemokine gradients, aid in the coordinated interactions of
adaptive immune system cells [11].
If the virus reaches the circulation, the induction events occur
in the lymph nodes draining the infection site or in the spleen.
Virus antigens are often transported to lymph nodes by Dendritic
Cells (DCs). Some viruses are capable to compromise APC function,
such as herpes simplex virus and measles virus, which can inhibit
Dendritic cells maturation [9].
Discussion
Clinical picture of COVID-19 infected and recovered versus
deteriorated patients
A research study that included patients infected with
coronavirus from which 109 who died during hospitalization and
116 patients recovered reported that the median age of the death
Immune System Response to COVID-19. An Endless Story
Citation: Nagwa A Sabri., et al. “Immune System Response to COVID-19. An Endless Story". Acta Scientific Pharmaceutical Sciences 6.6 (2022).
subject group was older than the recovered ones (69 versus 40
years). The white blood cell (WBC) values in those patients who
versus 4.52 [3.62, 5.88]. ×10/L). Patients in the death group
versus 1.00 [0.72, 1.27]. ×10/L) and lymphocyte percentage (7.10
[4.45, 12.73]. % versus 23.50 [15.27, 31.25]. %) on admission, and
it continued to decrease during hospitalization (7.10 [4.45, 12.73].
% versus 2.91 [1.79, 6.13]. %) [12].
C-reactive protein (CRP) levels were also remarkably higher
in the death group on admission (109.25 versus 3.22 mg/L) and
showed no remarkable improvement after treatment (109.25
versus 81.60 mg/L). The death group patients experienced more
complications such as (59.6% vs. 0.9%) acute cardiac injury,
(89.9% versus 8.6%) ARDS, (18.3% versus 0%) acute kidney injury,
(11.9% versus 0%) shock, and (6.4% versus 0%) disseminated
intravascular coagulation [12].
Severity of COVID-19 in adult versus children and loss of
bridging between innate and adaptive immunity
COVID-19 infection showed to be less severe in children than
in adults in terms of symptoms, lung consolidation, and laboratory
abnormalities. The bases of such mechanism remains unknown.
It is postulated that this may be due to a fully functional thymus
in children, that plays a vital role in both lymphatic and endocrine
function and serves as a setting where T-cells develop which is
responsible for adaptive immunity. Thus we can postulate that
increased morbidity in COVID-19 infected older adults is mainly due
to compromisation of immune system secondary to dysregulated
adaptive immunity [13].
SARS coronavirus (SARS-CoV) is known to decrease the
system. When innate immune system fails to eliminate invading
4th to 7th day following the infection. This duration correlates
with the average time at which the patient symptoms exacerbate
in COVID-19 infection. Postulations explain why older adults are
more affected by SARS CoV-2 compared to children. The thymus-
derived immunity in children can bridge the gap between innate
and adaptive immune response. Innate immune responses in
elderly is delayed, that’s why they are more susceptible to develop
worsening symptoms, and vulnerable to COVID-19 complications.
Also, the decrease in plasmacytoid dendritic cells in the elderly
besides their comorbidities depletes the immune envelope [14].
Immune response dysregulation
Infection with SARS-CoV-2 showed to activates both innate and
adaptive immune response, that makes the resolution of COVID-19
sustained. On the other hand, fast and highly coordinated immune
response is considered the main defense mechanism against viral
adaptive immune defence may result in tissue damage at the site
of viral entry as well as systemic damage. Furthermore, excessive
injury (ALI) and ARDS [15-17].
The massive cytokine and chemokine release which is called
immune defense [18].
Studies showed relevant changes occurring to innate immunity
and adaptive immunity in COVID-19 infected patients. In particular,
lymphocytopenia and a modulation in total neutrophils are
common characteristic clinical pictures that seems to be directly
correlated with disease severity and death [17].
Investigations showed that, in patients suffering from severe
COVID-19, a remarkable decrease in circulating CD4+ cells, CD8+
cells, B cells, NK cells, monocytes, eosinophils, and basophils levels
injury, and severe pneumonia [19-21].
Elevated levels of serum cytokine and chemokine, besides
high neutrophil-lymphocyte-ratio (NLR) in SARS-CoV-2 patients
responses induction in COVID-19 and disease severity and adverse
outcomes. Moreover, a recent study showed that patients infected
with coronavirus had higher Hs-CRP and procalcitonin serum
risks of mortality [18].
Immune System Response to COVID-19. An Endless Story
Citation: Nagwa A Sabri., et al. “Immune System Response to COVID-19. An Endless Story". Acta Scientific Pharmaceutical Sciences 6.6 (2022).
Different immune cells like macrophages, THP-1 cells, and others
have been shown to be infected by MERS-CoV. Furthermore, SARS-
CoV has been shown to directly infect T-cells, and macrophages,
cytokines and chemokines levels [22,23].
Although ACE2 receptor is modestly expressed in the lung
monocytes, macrophages, and T cells, the mechanism of immune
cells infection by which SARS-CoV and SARS-CoV-2 is still unknown
[24].
A study in Wuhan that included 452 COVID-19 infected
patients showed that, patients infected with severe COVID-19
had a considerably decreased number of total T cells, helper and
suppressor T cells. In particular, among helper T cells, a decrease
in regulatory and memory T cells has been observed, on the other
hand, naïve T cells percentage was found increased [25].
Naïve T cells provide defenses against new and previously
unrecognized infection. This occurs by a coordinated cytokine
is mediated by memory T cells. The disruption of immunological
balance favoring naive T cell activity over regulatory T cell activity
Besides, the reduction in memory T cells could be involved in
COVID-19 relapse, that is why the number of recurrences has been
reported in recovered cases of COVID-19 [26].
Proofreading mechanism of coronavirus
Typically, a high error rate may exist in RNA virus replication.
This results in the existence of various groups of viral genome
mutation known as “quasispecies”. This low replicative viral
environments. Besides, it is also associated with an increased
chance of error catastrophe which may lead to viral vanishing,
[27,28].
antivirals against CoVs and other RNA viruses, because RNA
viruses can rapidly develop resistance to drugs while maintaining
proofreading function considered as an additional barrier in the
development of Nucleoside analogs as antivirals against CoVs [29].
Coronavirus genomes are among the biggest and most complex
RNA virus genomes, and nsp14 is highly conserved within the
Coronaviridae family. The nsp14 exonuclease proofreading function
have been a main contributor in the expansion and maintenance of
such large genomes to ensure replication competence [30].
Coronavirus in animals
Coronaviridae have a broad host range and cause a wide variety
of gastrointestinal, respiratory and systemic diseases in animals,
including infectious bronchitis in birds, a fatal disease with multi-
organ involvement in felines, and enteritis in pigs, cows, turkeys
and dogs. In humans, coronaviruses cause respiratory disease and,
to a lesser extent, gastroenteritis. SARS-CoV, which causes a severe
respiratory disease, seems to be an Enzootic Virus in Southeast
Asia. Several species that might be infected, such as masked palm
civets, are consumed as food in parts of China, and the ‘wet markets’,
at which live animals are bought and sold, are likely venues for the
initial crossover event to humans. The 2002–2003 outbreak of
of the virus by aerosols from live, exotic animals that were infected
with SARS-CoV to workers in these wet markets [31].
Serum from masked palm civets, raccoon dogs, and Chinese
ferret-badgers were shown to contain neutralizing antibodies that
the strains that were isolated from infected humans was detected
in masked palm civets [32].
Impact of pre-existing comorbidities
Evidence has demonstrated that individuals with pre-existing
comorbidities are susceptible to high mortality rates from
COVID-19.
Immune dysfunction
Immunity becomes activated during SARS-
CoV-2 infection, which result in a local
natural killer (NK) cells, T and B cells. The immune response
may result in a mild to moderate disease with fever, cough, and
tiredness, but this will be followed by resolution of the infection.
Immune System Response to COVID-19. An Endless Story
Citation: Nagwa A Sabri., et al. “Immune System Response to COVID-19. An Endless Story". Acta Scientific Pharmaceutical Sciences 6.6 (2022).
The occurrence of severe lymphopenia and the buildup of
fatigued T and NK cells in severe COVID-19 patients resulted in a
[33].
Besides, high levels of interleukin 6 (IL-6) remains elevated
over time, and associated with increased levels of IL-2, -7, -10,
critical and potentially life-threatening complications such as
severe pneumonia, ARDS, and multiple organ failure [34].
COVID-19 patients revealed that proportions of naïve CD4+ T
associated with mild cases. While in severe cases, it was observed
that a sharp decline in the percentage of CD8+ T and NK cells
occurred [35].
Moreover, results from investigations on hospitalized COVID-19
patients that had developed ARDS revealed a novel population
of developing neutrophils, which appeared to be closely related
to plasmablasts. However, investigation is required to determine
whether this novel subset of neutrophils contributes in
development of ARDS and other complications [36].
In COVID-19 patients who are severely infected, CD8+ T cells
and NK cells exhibited more signs of exhaustion than mild to
moderate patients. For example, elevated levels of programmed cell
death protein-1 (PD-1). Besides, increased cytotoxic T-lymphocyte-
on CD8+ [33].
Impact of age
Individuals over the age of 60 are more vulnerable to severe
COVID-19 symptoms and have a higher death risk [37]
patients have more noticeable immune compromisation compared
to younger patients, as lymphocyte counts are lower and pro-
aged, they become associated with immunosenescence and chronic
[38].
Much of the drop in protective viral immunity resulting from
defective T cell immunity. The decline of naïve T cell output due
to thymic involution and the accumulation of senescent T cells
leads to reduced viral host immunity. In mice studies, CD4+ T cells
were shown to be crucial against SARS due to their important role
in SARS-CoV clearance. This protection was lost in aged mice as
senescent CD4+ T cells responded poorly to antigen. Moreover,
the accumulation of senescent CD8+ T cells and B cells in older
storm upon SARS-CoV-2 infection [39].
Diabetes and obesity
Diabetes mellitus Type 2 is a disease characterized by chronic
increasing risk to human health. Diabetic individuals have
an increased susceptibility to COVID-19 infection. A study on
COVID-19 revealed that diabetic patients showed more likelihood
to develop pneumonia and were responsible for 11.7% of severe
cases [40].
cytokine storm. This has been already reported in COVID-19
patients, as C-reactive protein (CRP) and IL-6 levels were found to
can impair the immune response, increase oxidative stress and is
associated with the onset of premature senescence [39].
DPP4 inhibitors commonly used to treat diabetes have an anti-
which could impair the innate immune response during COVID-19.
Obesity has also been associated to a weakened immunological
response, with indications of weakened antibody and T cell
responses. Furthermore, ACE2 expression is increased in obese
people’s adipocytes and therefore may act as a potential target for
SARS-CoV-2 [39].
Effect of stress and depression
Chronic stress works as a trigger for anxiety and depressive
and glucocorticoids, which contribute to behavioral alterations. It
cytokine was elevated in the blood of individuals suffering from
depressive disorders. As per recent studies in major depression,
it was concluded that only the basal blood levels of IL-6 and TNF
were remarkably elevated [41].
Immune System Response to COVID-19. An Endless Story
Citation: Nagwa A Sabri., et al. “Immune System Response to COVID-19. An Endless Story". Acta Scientific Pharmaceutical Sciences 6.6 (2022).
Depression lead to immune system alteration leading to increase
and TNF which in turns induce cytokine storm in case of acute
respiratory distress syndrome causing failure in management of
critical cases with higher mortality rates in COVID-19 patients [42].
Drugs that affect immunity used in COVID-19 protocols:
Investigations showed that that immune-suppressive agents
like hydroxychloroquine, interleukin (IL)-6, and IL-1 antagonists,
are commonly used in rheumatology, and are also considered
as treatment in therapeutic protocols of COVID-19 especially in
severe cases [43].
Studies showed that patients treated with baricitinib had
treated with baricitinib (45%). Moreover, patients showed to
[44].
Beta-glucans are naturally occurring polysaccharides derived
from a variety of sources, including barley, yeast, algae, oats,
called Aureobasidium pullulans AFO-202 strain reported to have a
powerful immune stimulator action that can activate macrophages
and have positive immune actions on B-lymphocytes, natural
killer cells, and suppressor T cells [45]. AFO-202 beta glucan
supplementation showed to have immune-enhancing activity via
[46].
Furthermore, AFO-202 beta glucan stimulates neutrophil
activation, migration, and chemotaxis in order to destroy virus-
infected cells via IL8. Besides it causes a decrease of CCL2
(Monocyte chemotactic protein 1; MCP-1) and decrease of
for monocytes/macrophages, T-cells, NK cells, and dendritic cells
and so, suppressing immune response. This will lead to immune
regulation enhancement [47].
Conclusion
Immune dysregulation and other factors like immune
dysfunction, old age, obesity and diabetes, stress and depression
showed to be the main leading cause for exacerbation of COVID-19
symptoms and increased mortalities. Different therapeutic choices
like hydroxychloroquine, anti-interleukin (IL)-6, baricitinib, and
AFO-202 beta glucan showed to be effective in restoring immune
normal function, and improving immune response co-ordination,
besides they showed to improve clinical signs and symptoms and
alleviating disease severity and decrease mortalities.
Acknowledgments
The author would like to thank Drug Research Center for its
support in data collection and manuscript writing.
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