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Molecular mechanisms and signaling pathways in-
volved in immunopathological events of COVID-19
1. Hearing Disorders Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2. Neurobiomedical Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
3. Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
4. Department of Anatomical Sciences and Biology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
* Corresponding author: Somayeh Niknazar, E-mail: niknazar@sbmu.ac.ir
Received 13 April 2021; Revised from 29 June 2021; Accepted 26 July 2021
Citation: Peyvandi AA, Niknazar S, Zare Mehrjardi F, Abbaszadeh H, Khoshsirat S, Peyvandi M. Molecular mechanisms and signaling pathways involved in
immunopathological events of COVID-19. Physiology and Pharmacology 2021; 25: 193-205. http://dx.doi.org/10.52547/phypha.25.3.11
ABSTRACTABSTRACT
Keywords:
SARS-CoV-2 Infection
Signal transduction pathways
Cytokine storm
Ali Asghar Peyvandi1, Somayeh Niknazar1* , Fatemeh Zare Mehrjardi2, Hojjat-Allah Abbaszadeh3,1,4, Shahrokh
Khoshsirat1, Maryam Peyvandi1
iD
Introduction: COVID-19, a novel coronavirus that causes severe acute respiratory
syndrome (SARS-CoV-2), is currently regarded as the most serious viral disease. During
corona infection, viruses bind to host proteins and employ a variety of cellular pathways
for their own purposes. Cell signaling is important for the regulation of cellular function.
SARS-CoV-2 infection alters multiple signal transduction pathways that are critical for cell
survival. The virus causes a severe and prolonged period of hypercytokinemia with misusing
of these signaling cascades. Hyperactivation of the host immune system after infection with
SARS-CoV-2 is the main cause of death in COVID-19 patients. Thus, to develop effective
therapeutic approaches, it is necessary to rst understand the problem and the underlying
molecular pathways implicated in host immunological function/dysfunction. A number of
intracellular signaling cascades have been implicated in infected cell pathways, including
MAPK pathway, NF-κB pathway, JAK–STAT signaling pathway, PI3K/AKT/mTOR
pathway and TLRI signaling cascades. Here, we have presented the molecular insights on
the potential mechanisms involved in immunopathological events of COVID-19.
www.phypha.ir/ppj
Review Article
Physiology and Pharmacology 25 (2021) 193-205
Introduction
Infectious diseases such as inuenza, acquired immu-
nodeciency syndrome (AIDS), malaria and meningitis
remain the leading causes of death in human populations
worldwide (Morens et al., 2004). Humans are infected
with a new coronavirus that causes serious pneumonia,
which was recognized on 11 2020 by the WHO as coro-
navirus disease 2019 (COVID-19) (Lai et al., 2020).
COVID-19 cause epidemic in all countries and rapidly
increasing pandemics move (Gössling et al., 2020). It is
not the rst outbreak of severe respiratory disease from
coronavirus. Coronaviruses have caused three infectious
diseases in only the past two decades, namely Middle
East respiratory syndrome (MERS), severe acute respi-
ratory syndrome (SARS) and COVID-19 (Rockx et al.,
2020; Mahase, 2020).
Severe acute respiratory coronavirus syndrome 2
(SARS-CoV-2) is genetically related to SARS-CoV,
the rst pandemic threat of a new and fatal coronavi-
rus that appeared at the end of 2002 and triggered an
epidemic of SARS. SARS-CoV was extremely lethal
but disappeared due to strong public health control
(Petersen et al., 2020). According to a recent report,
SARS-CoV-2 and SARS-CoV overlap about 80% of
their genes (Gralinski and Menachery, 2020; Xu et al.,
2020). Another analysis found a 96% similar sequence
between SARS-CoV2 and the isolated CoV from Rhi-
nolophus afnis, suggesting bats as a virus source (Xu et
al., 2020). COVID-19 symptoms involve cough, fever,
headache and experiencing shortness of breath. Further-
more, most COVID19 patients developed lymphope-
nia, with markedly elevated concentration of cytokines
such as interleukin (IL)-1b and IL-6 (Prompetchara et
al., 2020). COVID-19 uses the angiotensin-converting
enzyme II (ACE2) as an entry receptor to infect lung
alveolar epithelial cells (Velavan and Meyer, 2020).
COVID-19 has the capacity to induce symptoms that
range from common cold to acute respiratory distress
syndrome (ARDS) (Liu et al., 2020b; Zimmermann
and Curtis, 2020). In older COVID19 patients with one
or more co-morbidities such as hypertension, diabetes
mellitus, cerebrovascular disease and chronic obstruc-
tive pulmonary disease, serious disabilities occur (Barr
et al., 2009; Chen et al., 2015). Despite the increasing
rate of SARS-CoV-2 transmission and death, no treat-
ment has yet been developed. Studies have shown that
viruses have developed a variety of highly sophisticated
strategies that affect host cell transcription in purpose
to replicate or to survive (Watanabe et al., 2010; Zuniga
et al., 2008; Fernandez-Garcia et al., 2009). Extracellu-
lar signals regulate cellular homeostasis in multicellular
organisms (Krajcsi and Wold, 1998). Several pathways
are associated with the COVID-19 pathogenesis and a
signicant number of proteins are targeted by SARS-
CoV-2 (Figure 1). Here, we focus on signaling path-
ways and molecular mechanisms that are involved in
COVID-19 pathogenesis and manipulate host innate
immune defenses such as cytokine response pathways.
In addition, the study of the mechanisms involved in the
pathogenesis of COVID-19 can aid scientists in devel-
oping treatments and vaccines that are effective in re-
moving the morbidity and mortality in patients (Table 1).
Molecular Biology of COVID-19 Physiology and Pharmacology 25 (2021) 193-205 | 194
FIGURE 1.FIGURE 1. Signaling pathways involved in COVID-19
pathophysiology. SARS-CoV-2 down-regulates ACE2
expression and result in production of proinammato-
ry cytokines and inammatory mediators. Angioten-
sin-I is transformed into angiotensin-II by the action of
ACE. ACE2 catalyzes Ang-II conversion to Ang (1-7),
which promotes anti-inammatory effects (Gheblawi
et al., 2020). Since action of ACE2 is impaired during
viral infection, Ang II cause chronic stimulation of
AT1R. AT1R signaling induces p38 MAPK activation
and inammatory mediator’s production such as TNF
and IL-6. The cytokines IL-6 and TNF bind to specic
receptors and promote further NF-κB nuclear translo-
cation and phosphorylation of p38 MAPK, which will
result in cytokines storm (Feng et al., 2019; Grimes and
Grimes, 2020). IL-6 activates JAK/STAT-3 pathway.
Toll-like receptors identify SARS-CoV-2 RNA and
trigger the inammatory response through expression
of interferon gene and NF-κB pathway (Battagello et
al., 2020). PI3K activation lead to Akt phosphorylation
and subsequent activation of mTOR. PI3K-Akt-mTOR
pathway was also found to regulate cytokine production
in COVID-19 (Ramaiah, 2020).
ACE2, Angiotensin-converting enzyme II; Ang, Angio-
tensin; AT1R, Angiotensin II type 1 receptor; MAPK,
Mitogen activated protein kinase; TNF, Tumor necrosis
factor; IL, Interleukin; NF-κB, Nuclear factor kappa-B;
JAK, Janus kinase; STAT, Signal transducer and activa-
tor of transcription; SARS, Severe acute respiratory syn-
drome; COVID-19, Coronavirus disease 2019; PI3K,
Phosphatidylinositol-3-kinase; mTOR, Mammalian tar-
get of rapamycin.
Research strategy
The search for scientic papers was performed by re-
searchers in the electronic databases, including Web
of Science, Medline (PubMed) and Scopus. The initial
search was carried out in the PubMed database based on
the combinations of the following words: SARS-CoV-2,
MAPK pathway, NF-κB pathway, JAK–STAT signal-
ing, PI3K/AKT/mTOR pathway and TLRI signaling
cascades, cytokine storm and immune defenses.
Mitogen activated protein kinase (MAPK) pathway
In response to certain environmental stimuli, MAPK
signaling pathways are responsible for controlling sev-
eral cell functions such as proliferation, differentiation
and apoptosis (Cowan and Storey, 2003). The three
main MAPK pathways in mammals are MAPK/extra-
cellular signal-regulated kinase (ERK), Jun amino-ter-
minal kinases/stress-activated protein kinases (JNK/
SAPK) and p38 MAPK. Pro-inammatory substances
and environmental stimuli primarily activate the p38
MAPK pathway, which has a signicant effect on a sub-
set of physiological events such as immune response
and inammatory processes (Deak et al., 1998). Activa-
tion of the p38 pathway is required to increase the lev-
els of pro-inammatory cytokines such as IL-6, tumor
necrosis factor (TNF) and IL-1, which appear to play
critical roles in the cytokine storm induced by SARS-
CoV-2 infection (Catanzaro et al., 2020). Indeed, the
excessive immune reaction to COVID-19 infection may
be triggered by overly up-regulated p38 activity, as two
mechanisms have claried. Activation of p38 MAPK
has been involved in the ACE2 endocytosis (Xiao et al.,
2013; Koka et al., 2008; Deshotels et al., 2014). First,
the ACE2 activity is lost during SARS-CoV-2 viral en-
try. ACE2 inhibits related ACE activity by decreasing
angiotensin-II and increasing angiotensin 1-7. The stim-
ulation of angiotensin II type 1 receptor (AT1R) by an-
giotensin II leads to the activation of p38 MAPK and
phosphorylation of A disintegrin and metalloprotease
17 (ADAM-17) (Xu and Derynck, 2010; Scott et al.,
2011). Phosphorylation increases ADAM17’s catalytic
Physiology and Pharmacology 25 (2021) 193-205 | 195 Peyvandi et al.
TABLE 1:TABLE 1: Potential treatment against COVID-19 disease.
Virus Mechanism of modulation Implications for therapy Ref
SARS-
CoV-2
MAPK Pathway
Silmitasertib (CK2 inhibitor)
Ralimetinib (p38 inhibitor)
ARRY-797 (p38 inhibitor)
Losmapimod (p38 inhibitor)
Dilmapimod (p38 inhibitor)
(Bouhaddou et al., 2020)
(Grimes and Grimes, 2020a)
NF-kB pathway
Artesunate (Inhibitor of
NF-kB downregulation)
Aspirin (Inhibition of ATP-binding
to IKKβ)
Sulfasalazine (Inhibitor of the NF-kB
activation)
(Uzun and Toptas, 2020)
(Elkhodary, 2020)
JAK–STAT signaling
Ruxolitinib (JAK/STAT pathway
inhibitor)
Baricitinib (a selective JAK1 and
JAK2 inhibitor)
(Bagca and Avci, 2020)
(Cingolani et al., 2020b)
Toll-like Receptor Signaling
Pathway
Tocilizumab (IL6 inhibitor)
Anakinra (IL1 inhibitor) (Birra et al., 2020)
PI3K/AKT/mTOR pathway Inhalation of buformin or phenformin (Lehrer, 2020)
activity, resulting in increased ACE2 shedding and re-
duced conversion of angiotensin II into angiotensin 1–7,
culminating in renin-angiotensin system (RAS)-mediat-
ed adverse consequences in a positive feedback cycle
(Patel et al., 2014; Xu et al., 2017). Angiotensin 1-7 is
critical for suppressing MAPK cascades and reducing
inammation (Zhang et al., 2014).
Angiotensin II promotes proinammatory, pro-vaso-
constrictive and pro-thrombotic activity through p38
MAPK activation, which is reversed by angiotensin 1-7
down-regulation of p38 activity. When ACE2 is lost
during viral infection, it may shift the balance towards
harmful p38 signaling via angiotensin II (Grimes and
Grimes, 2020). ACE2 activity was found in both the
lung and the heart. SARS-CoV-2 binds in the respira-
tory epithelium and lung alveoli to the same ACE2 re-
ceptor (Chen et al., 2020; Li et al., 2020). When a virus
gets inside a cell, induce ACE2 shedding. Deciency of
ACE2 is associated with alveoli damage and increases
permeability of the pulmonary vascular by angiotensin
II (Li and De Clercq, 2020). Angiotensin II levels were
directly linked with degree of lung injury and viral load
in a study of COVID-19 patients, indicating RAS imbal-
ance in COVID-19 etiology (Liu et al., 2020c).
Second, it has been previously shown that SARS-CoV
directly up-regulates p38 activity through a viral pro-
tein, identical to several other RNA respiratory viruses
that can hijack p38 activation to facilitate reproduction.
Because SARS-CoV and SARS-CoV-2 are so similar,
the latter may use a similar mechanism. As a result,
SARS-CoV-2 might cause widespread inammation by
directly activating p38 and down-regulating a crucial
inhibitory pathway, all while exploiting p38 activity to
reproduce (Grimes and Grimes, 2020).
According to a report, permissive cell SARS- CoV-in-
fection triggered the p38 MAPK signaling pathway.
Up-regulation of the p38 MAPK pathway triggers the
activation of IL-6, TNF-α and IL-1 pro-inammatory
cytokines (Zarubin and Jiahuai, 2005). MAPK-activat-
ed protein kinase-2 (one of the downstream effectors of
p38 MAPK) is triggered in response to SARS-CoV-in-
fection in Vero E6 cells (Foltz et al., 1997; Mizutani
et al., 2004). Diffuse alveolar damage, which includes
signicant infection and viral load in type II pneumo-
cytes, and also pulmonary edema, is the most common
nding in COVID-19 postmortem tissue from all vital
organs (Bradley et al., 2020; Carsana et al., 2020). CT-
scans with several ground glass opacities are common
and have diagnostic value (Parekh et al., 2020). Angio-
tensin II levels are particularly high in ACE/angiotensin
II receptor blocker naive COVID-19 cases and elevated
concentrations are related to greater intensity (Liu et al.,
2020a). Immune effector cells release massive amounts
of pro-inammatory cytokines and chemokines, lead to
lethal uncontrolled systemic inammation (Cameron et
al., 2008; Channappanavar and Perlman, 2017; Huang
et al., 2020a). Furthermore, because some COVID-19
patients have endothelial cell apoptosis, these biologi-
cal effects could be linked to increased MAPK signaling
activity (Grimes and Grimes, 2020; Zhou et al., 2020).
The over-activation of p38 MAPK in infected cardio-
myocytes, which has been demonstrated to cause apop-
tosis, impair contractility and promote brosis, could be
part of the reason for cardiac dysfunction in COVID-19
patients (Grimes and Grimes, 2020). Another pathway
involved in SARS-CoV infection is the c-jun NH2-ter-
minal kinase (JNK) pathway, which may result in a
rise in proinammatory factors, as well as increased
lung harm (Mizutani, 2010; Liu et al., 2014). JNK sig-
naling pathway could be a target for SARS-CoV-2 as
it includes proteins which are similar in both viruses.
This mechanism induces ACE2 receptor binding and
opened the way for COVID-19 virus internalization into
the respiratory tract’s alveolar epithelial cells. JNK sig-
naling is implicated in the extrinsic and intrinsic apop-
totic pathway, tissue cytokine production, inammation
and metabolism (Vellingiri et al., 2020).
Although the role of RAS in the pathophysiology of
SARS-CoV-2 is still being explored, a recent study indi-
cated that blocking RAS with ACE inhibitors or angio-
tensin receptor blockers may reduce overall mortality in
COVID-19 patients (de Abajo et al., 2021). The special-
ized viral entrance mechanism of SARS-CoV-2 deacti-
vates a key counterbalancing mechanism that the cell
employs to reduce p38 signaling through ACE2 activa-
tion, which causes inammation while also extending
the viral lifespan. As a result, SARS-CoV-2 may cause
excessive inammation by directly activating p38 and
downregulating a key inhibitory pathway, while also
exploiting p38 activity to proliferate. COVID-19 infec-
tion could be reduced if p38 is suppressed medically.
Losmapimod is the most researched p38 inhibitor in
clinical trials and it has a good efcacy. Therefore, p38
MAPK inhibitor could be benecial in patients with se-
Molecular Biology of COVID-19 Physiology and Pharmacology 25 (2021) 193-205 | 196
rious COVID-19 health problems (Grimes and Grimes,
2020).
Nuclear factor kappa-B (NF-κB) signaling pathway
The NF-κB signaling pathway regulates a variety of es-
sential genes in the innate and adaptive immune systems
(Hoesel and Schmid, 2013; Liu et al., 2017). NF-κB sig-
naling pathway plays a key role in gene expression in-
volving cytokine/chemokine encoding and anti-apoptot-
ic genes (Tak and Firestein, 2001; Gupta, 2003). NF-κB
and its inhibitor (the inhibitory kappa B kinases, IkB)
are present as a complex. Release from this complex
requires IkB kinase (IKK) activation. The kinase com-
plex of the IKK is the central element of the cascade of
the NF-κB. Essentially, it consists of two kinases (IKKα
and IKKβ) and a regulatory sub-unit, NEMO (NF-kB
essential modulator) /IKKγ (Bonizzi and Karin, 2004).
In most unstimulated cells, NF-κB dimers are kept in-
actively in the cytosol by interacting with IkB proteins
(Oeckinghaus and Ghosh, 2009). After activation, the
IKK complex will induce the phosphorylation of the
IkB proteins leading to their degradation (Viatour et al.,
2005). The degradation of these inhibitors by the IKK
complex upon their phosphorylation resulting in the nu-
clear translocation of NF-κB and the induction of target
gene transcription (Magnani et al., 2000). In other types
of cell, including mature B cells, macrophages as well as
a signicant number of tumor cells, NF-κB may also be
recognized as a nuclear protein which is constitutively
active (Oeckinghaus and Ghosh, 2009).
During a virus infection, the NF-κB signaling path-
way is activated and the gene expression of interferon
beta (IFN-β)/ TNFα/ IL8 are increased (Pfeffer, 2011;
Liu et al., 2017), suggesting that IKK-mediated NF-κB
signaling is necessary for the host’s innate immune re-
sponse (Banoth et al., 2015). In the Vero E6 cells, full-
length N protein considerably enhances NF-κB activity.
In addition, T helper cells develop proinammatory cy-
tokines by NF-κB signaling (Liao et al., 2005). NF-κB
activation is a characteristic of most infections, includ-
ing those caused by viruses, which lead to defensive
and pathological reactions. Following mice infection
with rSARS-CoV-MA15, increased expression of in-
ammatory cytokine TNF, C-C motif (CC) chemokines
[CC chemokine ligand (CCL) 2, CCL5], C-X-C motif
(CXC) chemokines [CXC chemokine ligand CXCL1,
CXCL2, and CXCL10], and IL-6 were found in neu-
trophils and infected lungs. Elevated levels of IL-6
and chemokines such CCL2 and CXCL10 have also
been found in human lungs with fatal SARS (Jiang et
al., 2005; Tang et al., 2005; Cameron et al., 2007). Re-
searchers recently investigated the regulatory relation
between the protein SARS-CoV-2 mediated pro-in-
ammatory cytokine/chemokine response and the NF-
κB signaling pathway (Huang et al., 2020b; Ingraham
et al., 2020; Islam and Fischer, 2020; Neufeldt et al.,
2020; Rian et al., 2021). Huang et al. (2020b) showed
that a signicant transcriptomic transition in infected
cells, characterized by a change to an inammatory phe-
notype with activation of NF-κB signaling and NF-κB
target genes by day 1 post-infection, leads to the loss of
the mature alveolar program in a human in vitro model
that simulates the initial apical infection of alveolar epi-
thelium with SARS-CoV-2, leads to a loss of the mature
alveolar program. Differentially expressed genes are
enriched for components of pathways related to NF-
κB, TNF-α and IL-17 signaling in bronchial epithelial
cells infected with SARS-CoV-2 (Enes and Pir, 2020).
Elements in the ACE2 gene regulate pirin, a negative
regulator of the NF-κB subunit RELA (p65). Pirin ex-
pression is thought to be reduced when SARS-CoV-2
disrupts ACE2 (Fadason et al., 2020). Furthermore, in
human bronchial epithelial cells, SARS-CoV-2 spike
protein subunit 1 (CoV2-S1) caused high rates of NF-
κB activation, the development of pro-inammatory cy-
tokines and chemokines including IL-1, TNF, IL-6 and
CCL2, as well as mild epithelial damage. S1 interaction
with the human ACE2 receptor, as well as early acti-
vation of the endoplasmic reticulum stress, subsequent
unfolded protein response and MAP kinase signaling
pathways, were all necessary for CoV2-S1-induced NF-
κB activation. CoV-2-S1 had a higher NF-κB activation
than CoV-S1, which may be attributed to CoV-2-S1’s
higher afnity for the ACE2 receptor (Hsu et al., 2020).
Previous research has shown that an elevated cytokine/
chemokine response during extreme SARS infection in-
dicates a dysregulated immune response. In vivo, IL-6 is
the primary stimulator of signal transducers and activa-
tors of transcription (STAT-3), and STAT3 is needed for
complete NF-κB pathway activation, particularly during
inammation (Hirano and Murakami, 2020; Murakami
et al., 2019). Both NF-κB and STAT-3 are triggered as a
result of SARS-CoV-2 infection in the respiratory sys-
tem, resulting in activation of the IL-6 amplier, a mech-
Physiology and Pharmacology 25 (2021) 193-205 | 197 Peyvandi et al.
Molecular Biology of COVID-19 Physiology and Pharmacology 25 (2021) 193-205 | 198
anism for STAT-3 hyperactivation of NF-κB, leading
to a variety of inammatory and autoimmune diseases
(Murakami et al., 2019). Moreover, previous study re-
ported that thalidomide as an immunomodulatory agent
modulates the NF-κB activities in combination with
celecoxib (the cyclooxygenase-2 inhibitor) which can
restrict the symptoms of inammation if used to treat
severe pneumonia (Hada, 2020). Since immunomodu-
latory drugs can affect the cytokine storm, these drugs
may be effective in treating COVID-19. Immunomod-
ulation of NF-κB activity and inhibitors of NF-κB (IκB)
degradation, in combination with TNF-α inhibition may
reduce the cytokine storm and lessen the severity of
COVID-19. Inhibition of NF-κB pathway may be useful
in treating COVID-19 in its most severe form.
Many of the drugs appear to have binds to the NF-
κB cascade of immune regulation in COVID-19. Dexa-
methasone is one of two glucocorticoids (the other being
prednisolone) that has an inhibitory effect on the NF-
κB pathway (Ye et al., 2020; D’Acquisto et al., 2002).
Remdesivir (GS-5734) is a nucleotide analogue that in-
hibits the RNA dependent RNA polymerase, causing vi-
ral replication to be disrupted. It decreases the cytokine
storm and severe illness by lowering dsRNA-related
activation of the NF-κB pathway. Remdesivir patients
had a faster time to recover in the Adaptive COVID-19
Treatment Trial, which compared to a placebo (Beigel
et al., 2020). TNF-α, TNF-1β, IgG and IFN-γ are all
reduced by hydroxychloroquine, which suppresses the
NF-κB pathway (Liang et al., 2018).
Janus kinase (JAK)–STAT pathway
The JAK-STAT pathway signaling mechanism, may
be a valuable marker of a strong immune response to
COVID-19 infections (Bouwman et al., 2020). Accord-
ing to one study, SARS-CoV-2 triggers the biochemical
mechanisms mediated by JAK–STAT in the lungs, lead-
ing in viral cell proliferation and transmitting (Singh et
al., 2020). In another study, inhibiting the JAK-STAT
pathway reduced hyperinammatory conditions while
having no effect on viral clearance (Rojas and Sarmien-
to, 2021). The JAK-STAT pathway is also activated by
IL-6 (Billing et al., 2019). The nding demonstrates
that induction of the JAK-STAT pathway, particularly
through cytokines such IL-6, is associated with the in-
ammatory response to COVID-19 (Luo et al., 2020b).
Angiotensin II binds to the AT1R and activates the JAK-
STAT pathway, leading to the production of IL-6 (Ni et
al., 2020). The SARS-CoV-2 S protein inhibits ACE2,
causing an increase in angiotensin II expression and,
as a result, enhanced IL-6 production. Anti-inamma-
tory drugs, in particular JAK-STAT inhibitors may be
useful against increased cytokine levels and may be ef-
fective to prevent viral infection. Ruxolitinib is a JAK1
and JAK2 inhibitor that suppresses STAT activation and
nuclear translocation by blocking JAK kinase activity.
Ruxolitinib also suppresses the IL6/JAK-STAT3 path-
way, decreasing IL-6 levels in the blood (Caocci and La
Nasa, 2020; Kusoglu et al., 2020). The role of baricitinib
(a specic JAK1 and JAK2 inhibitor) in the treatment
of COVID-19 has been proposed, despite its true safety
prole has yet to be determined (Cingolani et al., 2020a).
Toll-like receptor (TLR) signaling pathway
The TLRs are important in the innate immunity by
detecting microbes to invade pathogens. TLR signaling
pathways are the recruitment of different adaptor mole-
cules resulting in the activation of NF-κB and the IFN
regulatory factor transcription factors dictating the out-
come of TLR’s innate immune responses (Barton and
Medzhitov, 2003). While the immune system’s effec-
tive functioning protects the body from infections, the
cytokine storm associated with extreme COVID-19
manifestations is mainly caused by the adaptive immune
system’s over-expression and exhaustion, rather than an
innate immune response (Coperchini et al., 2020). The
virus’s spread is limited by the host immune response
during infection or mild COVID-19 disease, but the
innate immune response may also trigger immune-re-
lated dysfunction, resulting in extreme pneumonia in
cases of high viral load (Soraya and Urmia, 2020). In
viral diseases, TLR activators have both defensive and
therapeutic effects. The study also discovered that the
SARS-CoV-2 spike protein binds to TLR1, 4 and 6 with
a higher afnity for TLR4 than the others (Khadke et al.,
2020). A recent study offers that TLRs may be involved
in both the initial viral clearance failure and the subse-
quent production of the deadly clinical manifestations
of severe COVID-19 primarily ARDS. Lung macro-
phages can play a critical role in massive release of IL-6
and other cytokines such as IL-1β, IL-10, IL-12 and
TNF-α via activation of TLRs in patients with severe
COVID-19 (Onofrio et al., 2020).
In addition to the development of proinammato-
ry cytokines, TLRs’ interaction with virus particles
has immunopathological effects that lead to death in
COVID19 patients (Patra et al., 2020). TLR4’s patho-
logic role in patients with an excessive inammatory
response has been documented in other SARS-CoV-2
studies. COVID-19 patients had substantially high-
er levels of CCL 2, CCL7, CCL8, CCL24, CCL20,
CCL13, CCL3, CXCL 2, CXCL10 and IL-1b, and its
down-stream inammatory signaling molecules (IL1R1,
Myeloid differentiation primary response [MYD88], in-
terleukin 1 receptor associated kinase 1 [1IRAK1], TNF
receptor associated factor [TRAF6], NF-KBIA, NF-
KB1, RELA). TLR4 and related/down-stream signaling
molecules (CD14, MYD88, IRAK1, TRAF6, TIRAP,
TICAM) as well as most NF-κB signaling pathway
genes (NF-KBIA, NF-KB1, RELA, NF-KB2) were also
highly up-regulated, implying that activation of the NF-
κB signaling pathway by TLR4 is thought to be respon-
sible for the up-regulation of inammatory responses
in COVID-19 infection patients (Sohn et al., 2020).
Furthermore, COVID19 patients have a higher level of
neutrophil myeloperoxidase, which triggers oxidized
phospholipids and TLR4 pathway activation causes ox-
idative injury during the pulmonary process of infection
(Khadke et al., 2020; Onofrio et al., 2020). Tocilizum-
ab, an anti-IL-6 monoclonal antibody is used to treat
rheumatoid arthritis, may be useful in the treatment of
critically ill patients with COVID-19 (Kaly and Rosner,
2012). Findings support the use of therapeutic approach-
es such as dexamethasone that inhibits TLR4-mediated
inammatory signaling through molecular checkpoints
(Sohn et al., 2020).
Phosphatidylinositol-3-kinase (PI3K)/ AKT/ mamma-
lian target of rapamycin (mTOR) pathway
The PI3K/AKT/ mTOR signaling pathways is an im-
portant intracellular signaling pathway in the regulation
of the cell cycle and cell growth. Therefore, it is specif-
ically associated with cellular proliferation, quiescence
and survival. The plasma membrane protein AKT is
phosphorylated and activated when PI3K is activated
(King et al., 2015). Insulin-like growth factor, epidermal
growth factor, sonic hedgehog signaling molecule insu-
lin and CaM can enhance the PI3K / AKT pathway (Man
et al., 2003; Peltier et al., 2007; Ojeda et al., 2011; Ra-
falski and Brunet, 2011). The mTOR signaling pathway
modulates protein synthesis in response to stress, hor-
mones and genetic factors. Rapamycin inhibits mTOR
by interfering with the PI3K/AKT/mTOR pathway and
activating AMP-activated protein kinase (Huang, 2013).
MTOR signaling is required for inuenza develop-
ment and regulates the antibody response, resulting in
cross-protective immunity against lethal inuenza virus
infections. Treatment of serious pneumonia caused by
H1N1 inuenza with rapamycin and steroids has been
shown to enhance reporting outcomes in human studies
(Chuang et al., 2014; Wang et al., 2014; Lehrer, 2020).
The PI3K/AKT/mTOR signaling responses have a key
role in MERS-CoV infection which making it a target
for therapeutic intervention. Buformin or phenformin
(mTOR inhibitor ) inhalation may be an effective nov-
el treatment for coronavirus (Lehrer, 2020). Cytokine
storms are the main reason of COVID-19-related serious
illness and death. The most signicant cause of cytokine
storms can be the antibody-dependent enhancement.
mTOR inhibitors may suppress antibody-dependent en-
hancement and decrease the severity of COVID19 by
selectively inhibiting memory-B cell activation (Zheng
et al., 2020).
The mTOR–PI3K–AKT pathway was identied as
a key signaling pathway in SARSCoV2 infection in a
recent report. The in vitro testing of three mTOR inhibi-
tors showed that they signicantly inhibited SARSCoV2
(Garcia Jr et al., 2020). Regarding to recent reports, acti-
vation of the PI3K/ AKT/ mTOR pathway appears to be
important to promote replication of different viruses and
drugs that inhibit PI3K/ AKT/ mTOR signaling path-
ways may be recommended for SARS-CoV-2 infec-
tion. In order to identify potential drug targets, a human
protein–protein interaction map for SARSCoV2 was
recently developed. The proposed drugs included the
mTOR inhibitors rapamycin and sapanisertib, as well
as the mTORC1 protein complex modulator metformin.
Metformin-treated COVID19 patients have been shown
to have a lower mortality rate (Bramante et al., 2020;
Cariou et al., 2020; Luo et al., 2020a).
Inammatory cytokines can be a double-edged sword
when it comes to viral infection and disease pathogene-
sis. To battle viral infection and avoid a cytokine storm,
the innate immune system must be ne-tuned (Säemann
et al., 2009). As a result, clinical trials should include
early and short-term intervention with mTOR inhibitors
to reduce the undesirable immunosuppressive effect.
Furthermore, IL-6 may play a crucial role in the cyto-
Physiology and Pharmacology 25 (2021) 193-205 | 199 Peyvandi et al.
kine storm’s substantial negative consequences and IL-6
inhibition has been used to treat severe COVID19 dis-
ease with respiratory distress (Zheng et al., 2020). In ad-
dition to mTOR inhibitors, combination therapy with an
anti-IL6 antibody could be included in the clinical trial
for patients suffering SARS-CoV2 pneumonia (Zheng
et al., 2020).
Conclusion
Infection with SARS-CoV-2 changes multiple signal
transduction pathways, which contribute to important
physiological functions of the cell. The balance of sig-
naling pathway activities is important for cell death, or
cell survival determination. The virus takes over mech-
anisms from the host cell to utilize it for its own ben-
et. SARS-CoV-2 involved MAPK signaling pathway,
NF-kB pathway, PI3K/ AKT/ mTOR pathway, JAK–
STAT pathway and toll-like receptors cascades through
different mechanisms. In certain infected individuals,
SARS-CoV-2 induces excessive and prolonged cyto-
kine/chemokine responses. ARDS, or multi-organ dys-
function, is caused by the cytokine storm and it leads to
physiological deterioration and death. The virus manip-
ulates these signaling pathways for inhibiting cytokine
antiviral effects.
Acknowledgment
This work was supported by the Hearing Disorder Re-
search Center of Shahid Beheshti University of Medical
Sciences.
Conict of interest
The authors declare no conict of interest.
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