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Received: 29 October 2020
-
Revised: 21 December 2020
-
Accepted: 23 December 2020
DOI: 10.1002/rmv.2217
REVIEW
Role of p38 mitogen‐activated protein kinase signalling in
virus replication and potential for developing broad
spectrum antiviral drugs
Yogesh Chander
1,2
|Ram Kumar
1,3
|Nitin Khandelwal
1,4
|Namita Singh
2
|
Brij Nandan Shringi
3
|Sanjay Barua
1
|Naveen Kumar
1
1
National Centre for Veterinary Type Cultures,
ICAR‐National Research Centre on Equines,
Hisar, Haryana, India
2
Department of Bio and Nano Technology,
Guru Jambeshwar University of Science and
Technology, Hisar, Haryana, India
3
Department of Veterinary Microbiology and
Biotechnology, Rajasthan University of
Veterinary and Animal Sciences, Bikaner, India
4
Department of Biotechnology, GLA
University, Mathura, India
Correspondence
Naveen Kumar, National Centre for
Veterinary Type Cultures, ICAR‐National
Research Centre on Equines, Hisar, Haryana
125001, India.
Email: naveenkumar.icar@gmail.com
Funding information
Science and Engineering Research Board,
Grant/Award Numbers: CRG/2018/004747,
CRG/2019/000829, CVD/2020/000103
Summary
Mitogen‐activated protein kinases (MAPKs) play a key role in complex cellular
processes such as proliferation, development, differentiation, transformation and
apoptosis. Mammals express at least four distinctly regulated groups of MAPKs
which include extracellular signal‐related kinases (ERK)‐1/2, p38 proteins, Jun
amino‐terminal kinases (JNK1/2/3) and ERK5. p38 MAPK is activated by a wide
range of cellular stresses and modulates activity of several downstream kinases and
transcription factors which are involved in regulating cytoskeleton remodeling, cell
cycle modulation, inflammation, antiviral response and apoptosis. In viral infections,
activation of cell signalling pathways is part of the cellular defense mechanism with
the basic aim of inducing an antiviral state. However, viruses can exploit enhanced
cell signalling activities to support various stages of their replication cycles. Kinase
activity can be inhibited by small molecule chemical inhibitors, so one strategy to
develop antiviral drugs is to target these cellular signalling pathways. In this review,
we provide an overview on the current understanding of various cellular and viral
events regulated by the p38 signalling pathway, with a special emphasis on targeting
these events for antiviral drug development which might identify candidates with
broad spectrum activity.
KEYWORDS
MAPK, p38, signalling pathway, virus infection
1
|
INTRODUCTION
As per the report of the International Committee on Taxonomy of
Viruses (ICTV, 2019), 4958 viral species are listed across 14 orders,
143 families and 846 genera.
1
Some emerging viruses are
problematic adding to the list of the major disease outbreaks
that have occurred throughout history. Viral epidemics still
occur and the world is currently facing an outbreak of a new
coronavirus disease (COVID‐19). Whereas the most successful
approach to control virus infections is to use vaccines, this
strategy is not an option for many infections. A potentially more
effective general approach to control virus infections is to develop
effective antivirals.
2
The majority of antiviral drugs approved
by Food and Drug Administration (FDA), act by directly targeting
viral encoded factors.
3
However, successful directly‐acting drugs
may eventually fail due to the emergence of drug‐resistant
Yogesh Chander and Ram Kumar contributed equally to this study.
Rev Med Virol. 2021;1–16. wileyonlinelibrary.com/journal/rmv © 2021 John Wiley & Sons Ltd.
-
1
mutants.
3
Therefore, alternative antiviral approach needs to be
explored.
Mammalian cells respond to various biotic and abiotic stresses
through signal transduction pathways. Kinases and phosphatases
play a key role in activation/deactivation of various molecules
involved in the signal transduction pathways.
4
Completion of the
human genome project in the beginning of 21st century identified
518 kinases (the so called kinome).
5
Kinases are implicated in various
physiological processes to maintain homeostasis and, their dysregu-
lation could result in pathology. Infections by pathogens, including
viral infections, are also associated with perturbation of the kinome.
Each step of the virus replication cycle is believed to be regulated by
multiple kinases.
6,7
The family members of mitogen‐activated protein kinase (MAPK)
are the key kinases involved in most signal transduction pathways.
8
Mammalian cells express at least four distinctly regulated groups
of MAPKs, p38 proteins, extracellular signal‐related kinases‐1/2
(ERK‐1/2), Jun amino‐terminal kinases (JNK1/2/3) and ERK5. These
MAPKs are activated by specific MAPKKs (MAPK kinase): MKK3/6
for p38, MEK1/2 for ERK1/2, MEK5 for ERK5 and MKK4/7 (JNKK1/
2) for the JNKs (Figure 1). Each MAPKK can be activated by multiple
MAPKKK (MAPK kinase), thereby increasing the complexity and di-
versity of MAPK signalling. Each MAPKKK is believed to confer
responsiveness to distinct stimuli. The activation of classical MAPK
signalling pathway begins at the host cell plasma membrane where
various cell surface receptors phosphorylate MAPKKKs. The
MAPKKKs then phosphorylate MAPKKs which subsequently activate
MAPKs. The activated MAPKs eventually modulate the transcription
factors that drive context‐specific gene expression. Although, in
Figure 1,the MAPK signalling pathway is depicted as simple linear,
unidirectional groups of protein kinases, in the real sense it is quite
complex wherein a high degree of cross‐talk exists between
the MAPK cascade and the other signalling pathways such as nuclear
factor‐kappa B (NF‐κB), phosphatidylinositol‐3‐kinase (PI3‐K)/pro-
tein kinase B (Akt), and janus kinase/signal transducer and activator
of transcription (JAK–STAT) pathways.
The host cell activates the signalling pathway with the basic aim
of inducing an antiviral state, including production of antiviral cyto-
kines. However, viruses can misuse the activated pathways for
completion of various stages of their replication cycle. Depending on
the nature of interacting proteins, the net outcome of the activation
of p38 signalling pathway may be in favor (proviral) or detrimental to
virus replication. Cellular factors and signalling pathways, which are
critical for completion of various steps in the virus life cycle but
are dispensable for the host, could serve as potential drug targets.
9
Since the genetic variability of the host is quite low as compared to
the viruses, host‐targeting antiviral agents are considered to mini-
mize drug resistance.
10
Certain acute viral infections such as severe
acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2),
11
Ebolavi-
rus (EBOV),
12
dengue virus (DENV)
13
H5N1 influenza virus
14
lead to
hyperactivation of the immune response (cytokine storm), mediated
via intracellular cell signalling pathways and eventually resulting in
immunopathology.
15
Therefore, besides restricting virus replication,
inhibiting the activity of cell signalling pathways may also minimize
immunopathology.
15
Additionally, virus replication can be controlled
by potentiating innate immune response which includes administra-
tion of ligand that triggers innate immune receptors and blocking
immunoinhibitory interactions and cytokine therapy.
15
This review
discusses the various upstream regulators of p38, its downstream
substrates and their role in virus replication and pathogenesis,
with the basic aim of targeting these virus–host interaction events
for antiviral drug development.
2
|
p38 SIGNALLING PATHWAY
p38 is usually activated in response to stress therefore, it is also
considered as a stress‐activated MAPK.
8
p38 has four splice vari-
ants (isoforms) which include p38α(MAPK14), p38β(MAPK11),
p38γ(MAPK12) and p38δ(MAPK13).
16
All p38 isoforms are known
to share approximately 60% sequence similarity within the p38‐
MAPK group and 40%–45% with the other MAPK family mem-
bers.
17
p38 signalling can be activated by abiotic and biotic stress
including viral infections (Figure 1). The activation of p38 signalling
is mediated via a variety of cell surface
18,19
as well as intracellular
receptors
20
(Figure 1). In most instances, the activated receptor/
adaptor proteins recruit membrane proximal upstream regulator
MAPKKK which activates p38‐MAPK, mediated via intermediate
kinases MAPKK. MAPKKs such as MKK3 and MKK6 catalyzes
the phosphorylation of a conserved Thr–Gly–Tyr motif of p38.
21
Additionally, MKK4, an upstream kinase of JNK, can also activate
p38.
22
MAPKK‐independent activation of p38 has also been
described in T cells.
21
Likewise, in endothelial cells, G‐protein‐
coupled receptors (GPCRs) directly recruit transforming growth
factor‐β‐activated protein kinase 1‐binding protein 1 (TAB1) to
induce p38 activation.
23
However, the eventual biological response
of p38 pathway is based on the substrate selectivity of upstream
kinases. Activated p38 further induces activation of several tran-
scription factors/effector proteins (Figure 1) which eventually reg-
ulates DNA replication and repair (mediated via growth arrest and
DNA damage‐inducible protein GADD45 alpha [GAdd45‐α], heat
shock protein 90 [Hsp90] and casein kinase 2 [CK2]), transcription
(mediated via NF‐κB, interferon regulatory factor 3 [IRF3], IRF7,
activating transcription factor [ATF], cAMP‐response element
binding protein [CREB], cMyc, activator protein 1 [AP‐1], STAT
and nuclear factor of activated T‐cells [NF‐AT]), and translation
(mediated via MAPK interacting kinase 1 [MNK1]/eukaryotic
translation initiation factor‐4E [eIF4E], T‐cell intracellular antigen
[TIA‐1], TIA‐1‐related protein [TIAR], IRES‐specific cellular trans-
acting factors [ITAF], polypyrimidine tract‐binding protein [PTB],
eukaryotic initiation factors [eIFs] and far upstream element‐binding
protein 1 [FUBP‐1]) of more than 100 cytoplasmic and nuclear
substrates. Activated p38 also regulates several other cellular pro-
cesses such as apoptosis (mediated via p53, caspases and CCAAT‐
enhancer‐binding protein homologous protein [CHOP]), cellular
trafficking and cytoskeleton remodelling (mediated via Rabenosyn‐5
2
-
CHANDER
ET AL.
A[Rab‐5A] and early endosome antigen 1 [EEA1]; Figure 1). In
addition, p38‐mediated activation of transcription factors such as
NF‐κB, IRF3, IRF7, ATF, CREB, cMyc, AP‐1, STAT and NF‐AT results
in activation of several proinflamamtory cytokine genes (Figure 1).
However, hyperactivation of the signalling pathway(s) may lead to
cytokine storm
15
which has been observed in some acute viral
infections such as SARS‐CoV‐2,
11
EBOV,
12
DENV
13,14
and H5N1
14
and leads to tissue damaging immunopathology.
Like other kinases, p38 activity is regulated by phosphorylation
and de‐phosphorylation.
24
A number of phosphatases are involved in
termination of p38 kinase catalytic activity. The major group includes
the family members of dual‐specificity phosphatases.
25
Besides,
FIGURE 1 p38 Signalling pathway: p38 is activated by a wide range of cellular stresses as well as in response to inflammatory cytokines.
Upon activation, these receptors transduce signals to downstream kinases by utilizing number of adaptor and accessory proteins such as
cAMP, DAG, GRB2, SOS, Rac1, Cdc42, FADD, TRADD, RIP, TRAF, MyD88, TIRAP, TRIF, TRAM, IRAK, TRAF6, 1RAcP, MyD88, IRAK, TAB1,
TRAF6, TRAF6. Both cell surface (such as GPCRs, RTKs, TNFRs, TLRs, IL‐1R and TGFβR) and intracellular (such as RIG‐I, MDA‐5) receptors
can activate phosphorylation (activation) of p38, which is mediated via MAPKKKs (TAK1, ASK1/2, DLK 1, TPL2, MEKK 1‐4, MLK2/3, and
TAO1/2) and MAPKKs (MKK3/4/6). In addition, physiological stress can directly activate Rac1 and Cdc42 (receptor‐independent)‐mediated
induction of p38 signalling cascade. Besides, ZAP70 can also activate p38 in MAPKK/MAPKKK‐independent manner. The activation of p38
can be inhibited by phosphatases, scaffold proteins and miRNAs. Activated p38 further stimulate several transcription factors/effector
proteins which eventually regulates DNA replication and repair (mediated via GAdd45‐α, Hsp90 and Ck2), transcription (mediated via NF‐κB,
IRF3, IRF7, ATF, CREB, cMyc, AP‐1, STAT, NF‐AT) and translation (mediated via MNK1/eIF4E, TIA‐1, ITAF, PTB, eIFs, FUGP‐1) of more than
100 cytoplasmic and nuclear substrates. p38 activation also involves regulation of several other cellular processes such as apoptosis (mediated
via p53, caspases, CHOP), cellular trafficking and cytoskeleton remodeling (mediated via Rab‐5A and EEA1). In addition, p38‐mediated
activation of transcription factors such as NF‐κB, IRF3, IRF7, ATF, CREB, cMyc, AP‐1, STAT and NF‐AT results in activation of several
proinflammatory cytokine genes. Like cellular processes, p38‐mediated regulation of transcription factors and effector proteins also modulate
several viral processes such as replication, transcription and translation of viral genome, virus induced apoptosis, trafficking of viral proteins
and assembly of viral replication complexes. Although p38 activation leads to induction of proinflammatory cytokines genes which limit the
virus replication but its hyperactivation may lead to cytokine storm (immunopathology). Since p38 supports several steps of virus replication
cycle and may involve in inducing cytokine storm, inhibitors targeting p38 signalling pathways may restrict virus replication, besides
controlling cytokine storm and hence these may serve as novel therapeutic agents
CHANDER ET AL.
-
3
scaffolding proteins which simultaneously interact with multi‐
components
26
as well as microRNAs (miRNAs),
27,28
may also regulate
p38 activity.
3
|
ROLE OF p38 IN VIRUS REPLICATION
A wide variety of viruses are known to directly interact with p38 or
its substrates. While some of the interactions are proviral others are
inhibitory to virus replication. On the contrary, some viruses may
subvert p38 functions to effectively replicate inside cells. The cellular
events that involve virus‐p38 interactions are discussed.
3.1
|
p38‐Dependent regulation of inflammatory
response during viral infections
The major outcome of the activation of MAPK pathway is the pro-
duction of proinflammatory cytokines which eventually produce an
antiviral state. The p38 regulates virus‐induced inflammatory re-
sponses by regulating expression of proinflammatory cytokines,
arachidonic acid metabolite, chemokines and cell adhesion molecules.
Suboptimal production of these mediators leads to immune defi-
ciency whereas aberrant expression may result in cytokine storm
(immunopathology). p38 regulates the production of these inflam-
matory mediators (cytokines) at the level of messenger RNA (mRNA)
transcription, translation and processing (splicing, stability, decay and
translocation).
3.1.1
|
Modulation of transcription factors
p38‐mediated regulation of cytokine gene expression involves mod-
ulation of both transcriptional and epigenetic factors.
29
Out of the
several upstream regulators, predominantly TAK (transforming
growth factor‐β‐activated protein‐1)‐mediated p38 activation results
in inflammatory response. It involves activation of a number of
transcriptional factors such as NF‐κB, ATF, CREB, c‐Myc, AP‐1, NFAT
and IRFs.
30
Furthermore, p38 may also directly modulate the func-
tions of transcription factors or it may be mediated via its substrates
such as MAPK‐activated protein kinase 2/3 (MK2/3), mitogen‐and
stress‐activated kinase 1 (MSK1/2) and MK5 (also known as p38‐
regulated/activated protein kinase, PRAK).
31
p38‐mediated MK2
activation results in an inflammatory response (involving transcrip-
tion factors such as NFAT, AP‐1 and Myc) whereas p38‐mediated
MSK1 activation results in the suppression of inflammatory response
which is mediated via CREB and ATF1.
32‐35
p38 upstream regulator TAK1 may also directly activate certain
transcription factors which predominantly involve NF‐κB and IRFs.
30
In resting (inactive) stage, NF‐κB resides in the cytoplasm where
inhibitory‐κB (IκB ) prevents its localization into the nucleus by
binding with it. TAK1‐mediated degradation of IκB, which is mediated
via inhibitory‐κB kinase‐α (IKKα) and IKKβ, allows the release of
NF‐κB (called NF‐κB activation). The activated NF‐κB then enters
into the nucleus to activate the transcription of several proin-
flammatory cytokine genes. Like TAK1, some viruses such as Sendai
virus (SeV) and Rous sarcoma virus (RSV) may also induce the
activation of NF‐κB by directly phosphorylating IKKs.
36,37
In the
nucleus, p38 induces acetylation of NF‐κB by recruiting p300 and
CREB‐binding protein (CBP), which eventually triggers cytokine in-
duction.
38
Additionally, TAK1 also leads to IRF3/IRF7 phosphoryla-
tion, mediated via TBK1 and kinase I kappa B kinase i (IKKi).
39
Upon
activation, IRF3 and IRF7 induce transcriptional activation of in-
terferons (IFN‐α, IFN‐β and IFN‐γ). The activation of IRF3 leads to
type I IFN induction (INF‐α, INF‐β) as is observed in influenza A vi-
ruses (IAV) infection.
40
Similarly, chikungunya virus leads to IRF7
phosphorylation which upregulates the IFN‐γ and TNF‐α production.
Like several other kinases, TAK1 also plays a dual role in the
viral life cycle. On the one hand, it facilitates virus replication
whereas on the other hand it participates in the induction of
antiviral immune response. For example, human immunodeficiency
virus 1 (HIV‐1) Vpr protein activates NF‐κB and AP‐1, mediated via
TAK1. By interacting with the viral promoters, NF‐κB and AP‐1
eventually facilitate viral genome synthesis.
41
On the other hand,
TAK1‐p38 signalling activates NF‐κB to induce antiviral innate
immune response.
42
In contrast, for effective propagation, several
viruses are known to downregulate TAK1‐mediated antiviral innate
immune responses. For instance, transporter associated with anti-
gen processing; a virus‐inducible endoplasmic reticulum (ER)‐asso-
ciated protein inhibits TAK1 to suppress antiviral immune
response.
42
Similarly, during coxsackie virus A 16 infection, phos-
pholipase β2; GPCR‐associated protein inhibits virus‐induced TAK1
phosphorylation which eventually suppresses the activation of
antiviral responses.
43
However, the over activation of antiviral re-
sponses (cytokine storm) may lead to host damage (immunopa-
thology) as commonly seen in H5N1 influenza virus, SARS‐CoV‐2,
EBOV, DENV and feline infectious peritonitis virus infection.
15
In
such instances, cytokine storm may be therapeutically managed by
administration of small molecule chemical inhibitors that suppress
activation of p38 and/or other related signal transduction pathways
(Table 1).
In addition to NF‐κB, viruses may also induce an inflammatory
response by activating another transcription factor such as AP1
(a p38 substrate). Virus‐induced AP1 activation results in the pro-
duction of antiviral cytokines, besides inducing apoptosis. These
cellular events are detrimental to the virus replication.
81
Pharma-
cological inhibition of p38 activation during SeV and RSV infection
suppresses AP1 that results in decreased cytokine production (IFN‐β,
C–C motif chemokine ligand 2, chemokine ligand‐8 and interleukin‐6
[IL‐6])
81
thereby facilitating virus replication.
The ATF/CREB family is another group of transcription factors
which regulate cell proliferation and apoptosis by regulating the
production of IL‐32, an antiviral cytokine.
82
For example, CREB‐
induced IL‐32 induction inhibits IAV replication.
83
Likewise, p38‐
mediated phosphorylation of STAT‐1 antagonizes virus infection via
activation of IFN pathway.
84
For example, STAT1 serves as a natural
4
-
CHANDER
ET AL.
host restriction factor against hepatitis C virus (HCV),
85
herpes
simplex virus‐1 (HSV‐1),
86
hepatitis E virus (HEV)
87
and IAV.
88
p38 also regulates cyclooxygenase‐2 (COX‐2)/prostaglandin E‐2
signalling pathway to produce several inflammatory mediators. COX‐
2 potentiates the host immune response against IAV by upregulating
IL3‐mediated STAT1/2/3 phosphorylation and protein kinase R (PKR)
activation.
89
In contrast, COX‐2 also facilitates transcription and
translation of viral genes, for example, in cytomegalovirus (CMV),
70
HCV, DENV,
90
mouse hepatitis coronavirus (MHV),
91
feline
calicivirus (FCV), murine norovirus
92
and sapovirus.
93
3.1.2
|
Modulation of RNA‐binding proteins
p38 recruits RNA‐binding proteins (RBPs) at AU‐rich elements
(AREs) of viral/cellular mRNA at its 30‐untranslated region (30‐UTR).
For example, p38‐mediated recruitment of human antigen R and
KH‐type splicing regulatory protein at cytokine mRNA prevents its
degradation.
94,95
p38 itself can bind with AREs of several cytokines
(IL‐8, IL‐6, IL‐3, IL‐2 and IL‐1) and cellular enzymes (COX2) to
determine the stability of their mRNA.
96
3.1.3
|
Modulation of translation
p38 participates both in cap‐dependent and internal ribosomal entry
sites (IRES)‐mediated translation of cellular/viral mRNA. p38 directly
phosphorylates MAP kinase‐interacting kinases 1 (MNK1), which
supports the initiation of mRNA translation via phosphorylation of
eIF4E and recruiting eIF4G at translation initiation complex.
97
The
eIF4E recognizes and binds with 7‐methylguanosine‐containing 50
cap of mRNA during translation initiation. By facilitating translation
of cytokines and other inflammatory mediators, p38/MNK1 pathway
plays a key role in inducing inflammatory response following viral
infections.
97,98
Alternatively, p38‐dependent but MNK1‐indepen-
dent, induction of type I IFNs and IL‐12 mRNA translation has also
been implicated in SeV infection.
99
3.2
|
p38‐Dependent regulation of immune
response in viral infections
p38 is known to modulate both innate and acquired antiviral immune
responses. This involves regulation of immune cell proliferation, cell
TABLE 1p38 signalling as target for antiviral drug development
Association with p38 Cellular target Target virus Inhibitors References
Upstream p38
regulators
ASK1 PCV2 Thioredoxin
44
MKK3/6 ARV Dorsomorphin
45
p38 p38 EMCV, HP‐AIV, HBV, HSV,
CVB3, NDV, RV,
EBV, MHV, PyV and EV71
SB203580, SB202190, NJK14047,
BCT197, BX‐795,
SB239063, p38kinhIII, wogonin,
oxymatrine, vemurafenib
46‐56
p38‐regulated kinases MSK1/2 RSV, EBOV, HIV‐1 and KSHV H89, SB747651A
57,58
Casein kinase II HCV, HIV, HDV, HSV,
BTV and HPV
DRB (5,6‐dichloro‐1‐β‐ d‐
ribofuranosylbenzimidazole),
chrysin, benzothiophenes, hypericin,
DMAT (MBS384443), TBCA
(tetrabromocinnamic acid), TBB
(4,5,6,7‐tetrabromobenzotriazole)
and CX4945
59‐65
p38‐dependent cell
cycle regulator
CDC25B AIV NSC95397
66
eEF2K/eEF2 CVB3 Emodin
67
p38‐associated enzyme COX‐1/2 DENV‐2, PSaV, HCMV,
MHV and FCV
NS398, indomethacin celecoxib, tolfenamic
acid, curcumin and SC‐560
68‐72
HDAC HIV‐1 Valproic acid (VPA)
73
ADAM17 HIV‐1 TAPI‐2
74
p38‐associated
translational
factors
MNK1/eIF4E BPXV CGP57380
75
eIF4E/eIF4 G CoV and BPXV 4E2RCat, 4EGI‐1, apigenin
76
p38‐dependent
transcriptional
factors
c‐Myc Adenovirus, HSV‐1 and AIV CB‐839
77
CREB VZV XX‐650‐23
78
c‐FOS KSHV Cycloheximide (CHX)
79
p53 PRV PFT‐α
80
CHANDER ET AL.
-
5
differentiation, antigen presentation and cell migration.
100
p38 pro-
motes proliferation and differentiation of immune cells by triggering
the production of chemokines/cytokines such as granulocyte–
macrophage colony‐stimulating factor, erythropoietin and cluster of
differentiation 40.
101‐104
p38 Substrate myocyte enhancer factor‐2
(MEF2) regulates myocyte differentiation which plays essential roles
in T‐cell proliferation and transformation during human T‐lympho-
tropic virus 1 (HTLV‐1) infection.
105
p38‐Dependent expression of
cluster of differentiation 1day (CD1d) molecules (structurally similar
to major histocompatibility complex [MHC] class I) also promotes
vaccinia virus, vesicular stomatitis virus and lymphocytic choriome-
ningitis virus antigen presentation to natural killer T (NKT)
cells.
106,107
Once recognizing viral antigen in the context of CD1d
molecules, the NKT cells rapidly produce cytokines and activate cells,
regulating both innate and adaptive immune responses. Similarly,
chemokine ligand 14 suppresses human papillomavirus‐associated
head and neck cancer through antigen‐specific CD8+T‐cell re-
sponses by upregulating MHC‐I expression.
108
In addition, MK2/3
activates lymphocyte‐specific protein 1 (LSP1) which acts as an
intracellular F‐actin binding protein on immune cells and regulates
neutrophil motility, adhesion to matrix protein and trans‐endothelial
migration. LSP1 facilitates HIV‐1 transport into the proteasome.
109
3.3
|
p38‐Dependent transcription and translation
of viral genome
Viruses are heavily dependent on the host machinery for transcrip-
tion and translation of their genome. Efficient replication of viruses
involves supportive functions of over a thousand different cellular
proteins. p38 has also been extensively studied for its role in tran-
scription and translation of cellular as well as viral genome.
3.3.1
|
Regulation of replication and transcription of
viral genome
p38 modulates over 30 different transcription factors which regulate
the expression of several cellular and viral genes. Some of the tran-
scriptional factors directly bind with the viral promoters and facili-
tate expression of the viral genes. For example, by binding with
the long terminal repeats (LTRs) of HIV‐1, NFAT and NF‐κB facilitate
the expression of viral genes.
110‐112
p38‐mediated regulation of virus replication also involves
epigenetic modulation of host/viral genome. For example, HTLV‐1
Tax protein triggers p38/MEF2/CREB signalling axis which results in
recruitment of histone acetyl transferases (HATs) such as p300, CBP,
and PCAF (p300/CBP‐associated factor) at viral LTRs. This facilitates
the disassembly of nucleosome (opening double helix of DNA) and
hence the expression of viral genes).
113
Similarly, MEF2‐mediated
acetylation of Epstein–Barr virus (EBV) protein BamHI Z fragment
leftward open reading frame 1 (BZLF1) results in its activation which
eventually initiates lytic viral replication.
114
Likewise, activation of
p38/MSK1/CREB1 axis facilitates Kaposi's sarcoma‐associated
herpesvirus,
115
Varicella‐Zoster virus (VZV) and HBV
116
replication
via recruitment of HATs. Besides regulation of the expression of early
genes, p38‐MEF2 may also trigger p38‐MAPK dependent phos-
phorylation of ATF‐2/c‐jun which ensures gene expression in late
(lytic) phase of virus replication.
117
In contrast, p38‐dependent transcriptional repression of viral
genes may aid in the maintenance of viral latency. For example, p38
downstream substrates c‐Myc and Sp1 (specificity protein 1) recruits
histone deacetylase‐1 (HDAC1) which leads to the repression of HIV‐
1 gene expression and hence maintenance of latency.
73
Likewise,
during EBV latency, p38‐regulated class II HDAC binds with MEF2
and induces its proteosomal degradation. This leads to inhibition of
the nuclear translocation of MEF2, which is required for acetylation
of BZLF1 promoter and hence its expression, eventually resulting in
maintenance of viral latency.
114,118
3.3.2
|
p38‐Dependent translation of viral proteins
p38 regulates both cap‐dependent and IRES‐mediated translation of
viral mRNA. A large number of viruses exploit the cap‐dependent
mechanism of mRNA translation which is mediated via activation of
p38/MNK1/eIF4E2 axis.
10
For example, buffalopox virus exploits the
cellular machinery of translation by recruiting MNK1/eIF4E.
119
p38
also recruits several RBPs in order to initiate IRES‐mediated trans-
lation initiation of cellular/viral genome. For example, in picornavirus
infection, p38 facilitates recruitment/activation of several RBPs such
as PTB, eIFs, and ITAFs for efficient translation of viral mRNA.
120,121
Similarly, p38‐regulated TIA‐1 and TIAR interact with 50‐UTR of
enterovirus‐71 (EV71) genome and 30stem‐loop of flaviviruses (West
Nile virus [WNV] and DENV) to support translation initiation of viral
proteins.
122‐124
Likewise, the depletion of TIA‐1 or TIAR results in
reduced viral mRNA and protein synthesis along with reduced virus
yields during Newcastle disease virus (NDV) infection.
125
FUBP‐1,
another p38 downstream protein, binds with IRES of EV71 mRNA
and supports its translation.
126
In contrast, FUBP1 inhibits replica-
tion of Japanese encephalitis virus (JEV) via interacting with
viral UTRs.
127
Some p38 downstream substrates such as MK2/3 and MK5 also
regulate viral mRNA translation by either phosphorylating HSP27 or
via inhibiting PKR. The activated HSP27 is known to facilitate IRES‐
mediated EV71 replication.
128
In contrast, HSP27 also negatively
regulates several RNA virus replications which is mediated via
potentiating antiviral immunity. For example, HIV‐1,
129
classical
swine fever virus (CSFV)
130
and Zika virus infections.
131
PKR is
activated via double stranded RNA, an intermediate in the synthesis
of several RNA viruses. Activated PKR phosphorylates eIF2αwhich
inhibits global protein translation. This may also limit viral replication.
Therefore, in order to efficiently replicate, viruses such as IAV an-
tagonizes the function of activated PKR by phosphorylating MK2/3, a
p38 substrate. The activated MK2/3 interacts with p88 to inhibit
PKR thereby selectively restoring the viral mRNA translation.
132
6
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ET AL.
3.4
|
Modulation of apoptosis during viral infections
3.4.1
|
Role of p38 in virus‐induced apoptosis
Induction of apoptosis includes both extrinsic and intrinsic signals
(Figure 2). Four overlapping mechanisms are employed by the viruses
to induce p38‐mediated induction of apoptosis. The first one involves
transcriptional regulation of apoptotic proteins. For example, SARS‐
CoV 3a protein induces p38‐dependent upregulation of p53 which
triggers the release of cytochrome‐c and activates caspase‐9 to
induce apoptosis. Similarly, HIV‐1 glycoprotein 120 (gp120) induces
p38 which results in NF‐κB and p53‐mediated apoptosis.
133
The
second mechanism involves p38‐dependent enhanced expression of
TNF‐α and Fas ligand. For example, DENV induces apoptosis by
upregulating p38‐dependent TNF‐α expression in mice. Third
mechanism involves p38‐dependent induction of cysteine proteases
(caspases 3/8/9). For example, p38‐mediated caspases 3 activation
during coxsackievirus B3 (CVB3) infection leads to death of car-
diomyocytes. Similarly, caspase 3/8/9 activation is also associated
with DENV and IAV‐induced apoptosis. Fourth, accumulation of
unfolded/misfolded proteins or overloading of viral proteins in ER
eventually leads to ER stress which may also induce apoptosis. For
example, IAV recruits inositol requiring enzyme 1 in ER which in-
teracts with TNF receptor‐associated factor 2 and apoptosis signal‐
regulating kinase 1 (ASK1) to induce p38‐mediated apoptosis. Like-
wise, some RNA viruses activate PERK (RNA‐dependent protein ki-
nase [PKR]‐like ER kinase) which induces eIF2α/ATF4‐mediated
activation of CHOP, a substrate of p38 (Figure 2).
134
The activated
CHOP induces apoptosis via caspase cascades (caspase 11).
3.4.2
|
Regulation of p38‐induced apoptosis by
viruses
The early induction of apoptosis may result in nonproductive virus
replication. Therefore, in order to effectively replicate inside the host,
a virus must subvert the cellular apoptotic machinery to inhibit
apoptosis. HIV‐1 Nef protein inhibits ASK1‐dependent p38 activa-
tion that enhances cell survivability and hence increases virus
yield.
135
In addition, HIV‐1 Nef protein also interacts and competi-
tively inhibits p53 functions to inhibit apoptosis.
135
Likewise, IAV
NS1 protein downregulates AP‐1 to inhibit apoptosis.
136
Several vi-
ruses inhibit p38‐mediated apoptosis by activating PI3K/Akt signal-
ling pathways.
137
In addition, some viruses are known to exploit
STAT3 for inhibiting p38‐dependent apoptosis.
138,139
This is medi-
ated via suppression of p53 activity or induction of anti‐apoptotic
proteins such as Bcl‐2 and Bcl‐xL. Some viruses encode viral FADD‐
like interleukin 1 beta converting enzyme inhibitory proteins (vFLIP)
that have cellular death‐effector domain (DED), like those present in
caspases‐8 and Fas‐associated protein with death domain (FADD),
the extrinsic apoptotic receptor. The vFLIPs encoded by molluscum
contagiousum virus (MC159L) and equine herpesvirus 2 (EHV2)
(MC159L and E8) bind with the DED(s) of caspase 8 or FADD to
inhibit apoptosis and cell death.
140
The vFLIP, encoded by human
herpesvirus 8 (EHV2; ORF K13) inhibits NF‐κB‐induced apoptosis.
141
FUBP1 (p38 substrate) also antagonizes apoptosis by suppressing
transcriptional activity of p53. For example, the E1A protein of
adenovirus 5 stabilizes the p53‐FUBP1 interaction and antagonizes
p53‐dependent apoptotic mechanism.
142
However, induction of apoptosis during late phase of viral life
cycle may be beneficial for dissemination of the infection to the
adjacent cells. p38 has two major downstream substrates‐p53 and
STAT3. p53 induces apoptosis whereas STAT3 antagonizes p53
function. During the resting stage, STAT3 is located in the cytoplasm.
Upon p38‐mediated phosphorylation, it translocates into the nucleus
where it inhibits p53 phosphorylation thereby leading to inhibition of
apoptosis (cell survival). To ensure effective apoptosis, SARS‐CoV
protein 3a not only induces p38‐mediated activation of p53 but it
also interacts with and inhibits nuclear translocation of STAT3.
143
3.5
|
Modulation of cell cycle and virus growth
p38 modulates activity of several transcription factors and other
kinases/metabolic enzymes which eventually regulates cell cycle
progression as well as apoptosis. However, whether the end effect
would result in cell survival or apoptosis is determined by the nature
of downstream kinase/transcription factors involved. p38‐mediated
cell survival involves modulating the activity of cyclins and cyclin‐
dependent kinase (CDK) inhibitors which eventually regulate cell
cycle arrest at G1/S and G2/M to facilitate cell repair/differentiation.
The p38 performs cell survival function by either inducing cell
cycle arrest (allows sufficient time for DNA repair) by activating
Gadd45‐α (growth arrest and DNA damage‐inducible protein
GADD45 alpha) and inhibiting cell cycle control protein 2 (CDC2).
Gadd45‐α is known to induce G2/M arrest which facilitates the
repair of cellular DNA and cell survival.
144
In HIV‐1 infected cells,
GADD45‐α represses the transcription of HIV‐1 genes
145
thereby
facilitating the induction of latent viral infection which is a major
barrier to HIV‐1 eradication.
145
p38 also inhibits CDC2 activity,
mediated via inhibiting CDC25B/C (also known as M‐phase inducer
phosphatase 2/3) that eventually results in the delay of G2 phase.
Some viruses can replicate only in dividing cells and therefore they
are known to activate CDC2. For example, VZV glycoprotein gI,
146
EBV protein EBNA‐LP,
147
HEV ORF3
148
and HSV‐1 ICP0
149
activate
CDC2. The activated CDC2 facilitates cellular and viral mRNA
translation, mediated via recruitment of eukaryotic elongation factor
2 (eEF2).
150
However, viruses such as CVB3
67
and HIV‐1
151
exploits
eEF2 for translating their protein, besides inducing CDC2‐dependent
cell progression which is essential for their replication. In contrast,
some viruses require nondividing cells for their replication and
have the capacity to inactivate CDC2. For instance, reoviral S1
gene‐encoded ς1s nonstructural protein,
152
papilloma virus E2
153
and HIV‐1 Vpr protein.
154
Besides inducing cell cycle arrest, virus‐p38 interaction is also
shown to reprogram cellular apoptosis so as to keep the cells in
CHANDER ET AL.
-
7
dividing phase for their optimal replication. The reprogramming of
apoptosis by p38 is mediated via phosphorylation of CK2 and Hsp90/
cell division cycle 37 (Hsp90/Cdc37). CK2 inhibits caspase‐mediated
apoptosis and triggers DNA damage response which eventually fa-
cilitates cell cycle progression from G1 to S phase and G2 to M phase.
Hsp90‐Cdc37 is a co‐chaperone that binds and stabilizes several
kinases (CDK4, CDK6 and eIF‐2α) required for cell cycle progression.
Viruses are known to exploit both of these p38 substrates (CK2 and
Hsp90‐Cdc37) to ensure their efficient replication. For example, CK2
phosphorylates HCV (NS5A) and bluetongue virus (NS2) pro-
teins
59,155
which are required for viral RNA synthesis and assembly.
Similarly, HSP90‐Cdc37 supports viral assembly and genome
synthesis of duck hepatitis B virus (hepadnavirus).
156
3.6
|
Modulation of cell cytoskeleton and virus
growth
Besides regulating several intracellular cell signalling cascades, p38
also regulates remodeling of cell cytoskeleton. Viruses employ
several distinct mechanisms to exploit p38‐dependent endocytic
remodeling (vesicular transport) to facilitate intracellular transport of
virus/viral proteins
157
and cell‐to‐cell transmission (viral synapses).
p38‐mediated activation of EEA1 and Rab5A
158
are required for
early endosomal fusion and endosomal trafficking
159
which assist in
endocytosis of RSV and IAV.
160
Similarly, Rab5A facilitates endocy-
tosis (entry) of DENV and WNV.
161,162
Besides endocytosis, Rab5A
and EEA1 also modulate virus replication complexes (assem-
bly).
163,164
For instance, CSFV NS4B is known to interact with
Rab5
163
whereas HCV NS4B interacts with EEA1 and Rab5A for the
optimal assembly of the virion components.
164
Zeta‐chain‐associated protein kinase 70 (ZAP‐70; an upstream
regulator of p38) modulates actin cytoskeleton and polarization of
microtubule‐organizing center.
165
HIV‐1 exploits this remodelled
cytoskeleton activity for efficient cell‐to‐cell transmission by forming
virological synapses.
166
This is due to the fact that ZAP70 defective
lymphoid cells exhibit restricted cell‐to‐cell HIV‐1 transmission
capability.
166
Type‐I transmembrane protease ADAM17 (disinterring and
metalloproteinase domain‐containing protein 17) is required for
cleavage and release of a soluble ectodomain (exosomes) from
membrane‐bound proproteins. This is required for the release of
FIGURE 2 Role of p38 signalling in virus‐induced apoptosis: p38 participates in regulating both intrinsic and extrinsic pathways of
apoptosis. Endoplasmic stress response which is activated upon accumulation of viral proteins in the endoplasmic reticulum recruits IRE1
which activates p38‐dependent apoptosis. p38 can also be induced by activation of PRRs such as RIG‐1, MDM5 and TLRs. Activated p38
regulates apoptosis at various levels which includes (i) stabilization of p53 that induce cytochrome‐c release form mitochondrial wall by up‐
regulating apoptotic protein (BaX) that eventually activates caspases 3/9. (ii) Direct activation of caspases cascade. (iii) modulating CHOP
activity, which is mediated via PERK/eIF2α/ATF4 signalling cascade. (iv) inducing cytokine stress (upregulate expression of TNFα) and
(v) upregulating expression of FasL
8
-
CHANDER
ET AL.
diverse groups of membrane‐anchored cytokines, cell adhesion
molecules, receptors, ligands, and enzymes. The p38‐mediated acti-
vation of ADAM17 leads to epidermal growth factor receptor‐
dependent cell proliferation. Several viral families are known to
exploit these transmembrane proteases for optimum infectivity. For
example, HIV‐1 Nef protein facilitates the release of ADAM17‐con-
taining exosomes. It activates virus supportive intracellular signalling
via cleavage of pro‐TNF‐α into mature form. This supports the
infectivity of incoming HIV‐1 in quiescent CD4
+
T lymphocytes.
167
Likewise, ADAM17 also facilitates the entry of papillomavirus by
induction of growth factors which triggers the formation of an
endocytic entry platform.
168
By regulating expression of the cytoskeleton proteins such as
Rho family GTPases‐RhoA, (Ras homology family member A), Racl
(Ras‐related C3 botulinum toxin substrate 1), and CDC4, p38‐asso-
ciated transcriptional factor serum response factor (SRF) maintains
the cytoskeleton integrity of cardiac cells.
169
The CVB3‐encoded 2A
protease cleaves SRF to dissociate its transactivation domain
from the DNA‐binding domain. This leads to downregulation of SRF‐
mediated gene expression which ultimately results in the disruption
of cytoskeleton integrity, hence resulting in cardiac pathology.
170
4
|
TARGETING p38 SIGNALLING FOR ANTIVIRAL
DRUG DEVELOPMENT
Over 250 antiviral drugs have been approved by the FDA
3
but the
majority of these act by directly targeting viral encoded factors.
3
In
fact, successful drugs (directly acting) may eventually fail because of
the emergence of drug‐resistant mutants.
171,172
Indeed, drug resis-
tance has been observed against most of the virus‐directed antiviral
drugs approved so far. Therefore, alternative approaches towards
antiviral drug development need to be explored.
More than 80 kinase inhibitors have been evaluated which are
in some stage of clinical trial and over 35 distinct kinases have been
developed to the level of phase I clinical trial.
173
Most of the
currently known kinase inhibitors target at the kinase activation
loop in the ATP binding site
173
and have been initially investigated
for the treatment of cancer.
174
Increasing evidence also suggests
kinases as potential drug targets against viral infections.
175
In
viral infections, p38 signalling pathway may be targeted to fight at
least at two fronts, restricting virus replication and minimizing
immunopathology induced due to the over activation of immune
response.
4.1
|
Inhibiting virus production
As indicated above, viruses may exploit enhanced cell signalling ac-
tivity for completion of its replication cycle. The viral replication cycle
is a multistep process that includes attachment, entry, genome syn-
thesis, assembly of newly synthesized virion particles and budding.
Each step of the viral life cycle involves host cell kinases with a single
kinase regulating single or multiple steps of the viral life
cycle.
79,136,176,177
p38‐mediated regulation of transcription factors
and effector proteins support several viral processes such as repli-
cation, transcription, translation, virus‐induced apoptosis, trafficking
of viral proteins and assembly of viral replication complexes
(Figure 1). Therefore, targeting these host‐dependency factors may
also serve as a novel strategy for antiviral drug development
(Figure 1). For instance, p38 signalling pathway is needed for efficient
synthesis of SARS‐CoV‐2 subgenomic mRNA.
1
Likewise, NJK14047
(p 38 inhibitor) inhibitor blocks synthesis of HBV pregenomic RNA
and covalently closed circular DNA
6
and BX‐795 inhibits p38‐medi-
ated expression of HSV‐1 genes.49
9
In consequence, it is likely that
targeting the signalling pathway(s) which regulate multiple steps of
viral replication cycle could be a most effective strategy to develop
antiviral drugs.
175
Kinase requirement is usually common among the members of a
particular virus family.
75
Nevertheless, p38 is also known to support
replication of multiple viral families which includes IAV, RSV, HBV,
HSV‐1, coxsackievirus, NDV, rotavirus, encephalomyocarditis, coro-
navirus and enterovirus).
46‐56
In this context, p38 inhibitor
SB203580 which is known to block SARS‐CoV‐2, human coronavirus
229E and DENV
178‐181
replication, may serve as a broad‐spectrum
antiviral agent.
4.2
|
Blocking cytokine storm
Cell signalling pathways are activated with the basic aim of inducing
an antiviral state. p38‐mediated activation of transcription factors
such as NF‐κB, IRF3, IRF7, ATF, CREB, cMyc, AP‐1, STAT and NF‐AT
activate several proinflamamtory cytokine genes, which usually limit
virus replication (Figure 1). However, certain acute viral infections
such as SARS‐CoV‐2,
11
EBOV,
12
DENV
13,14
and H5N1
14
lead to the
hyperactivation of signalling pathways, producing a cytokine storm
(Figure 1). More than 150 cytokines are induced during cytokine
storms but those primarily involved include TNF‐α, IL‐6 and IFNs.
15
The cytokine storm leads to tissue damaging immunopathology.
Under such instances, p38 signalling pathway may be therapeutically
managed in minimizing the immunopathology induced by the cyto-
kine storms (Table 1). For instance, p38‐specific inhibitor SB203580
inhibits cytokine storm induced in response to SARS‐CoV‐2, EBOV
and DENV infection.
178‐181
Likewise, PD169316
182
and SB 239063
52
which also target p38 signalling pathway restrict EV71‐and rhino-
virus‐induced cytokine storms.
Considering the p38 requirement for optimal virus replication
and its role in inducing cytokine storm, it is tempting to speculate
that p38 suppression may have dual effects, first restricting viral
production in the target cells and secondly, blocking the cytokine
storm. For example, p38 inhibitor SB203580 restricts SARS‐CoV‐2
replication by targeting the viral genome synthesis, besides sup-
pressing p38‐mediated cytokine storm.
178
Similarly, SB203580 and
SB202190 were also shown to suppress EBOV replication (at entry
level) and the associated cytokine storm.
183
Likewise, oxymatrine
CHANDER ET AL.
-
9
was shown to restrict IAV replication and virus‐induced
immunopathology.
184
Besides directly inhibiting p38 phosphorylation (activation),
regulating p38 upstream (such as ASK1, MKK3/6) or downstream
(such asMSK1/2, casein kinase II, CDC25B, COX1/2, HDAC,
ADAM17, MNK1/eIF4E) kinases also serve as targets for antiviral
drug development (Table 1). However, most of these studies have
been conducted on a laboratory scale while only few of them have
entered clinical trials.
5
|
CHALLENGES OF p38‐DIRECTED ANTIVIRAL
THERAPY
A major criticism of the host‐directed antiviral therapy is the side
effects which may emerge due to suppression of certain cellular
functions. Some kinase inhibitors have been shown to induce toxicity
and off‐target effects which could result in hypertension, hypothy-
roidism, skin reactions, cardiotoxicity and proteinuria.
185,186
How-
ever, host‐directed therapeutic agents which are in clinical use
against cardiovascular and inflammatory diseases or cancers have
minimal or no adverse side effects.
187
Nevertheless, p38 inhibitor SB‐
681323 has also been shown to be well tolerated in treating
neuropathic pain.
188
The major advantage of host‐directed antiviral therapy is
considered to be due its potential in minimizing the drug resistance,
as compared to the directly‐acting antiviral agents. However, drug
resistance against some host‐directed agents can, in fact, occur under
certain circumstances. For instance, long‐term selection pressure of a
host‐directed antiviral agent allows the virus the opportunity to
adapt to use an alternate host factor.
189
Likewise, under long‐term
selection pressure, virus can alter its affinity towards the target that
confers resistance.
190
In addition, long‐term kinase inhibition may
induce pressure on the host cells to acquire resistance against the
targeted agent through kinase mutations.
191‐194
6
|
CONCLUSIONS
Classically, antiviral drugs are developed by targeting certain viral
proteins but, under selective pressure, viruses quickly acquire drug
resistance. The human genome encodes 518 kinases that have been
implicated in the regulation of various physiological processes to
maintain homeostasis. Like several other biotic and abiotic stresses,
viral infections are also associated with perturbation of the “kinome.”
Some of the cellular kinases are dispensable for host cell viability
but might be needed during virus infection and thus serve as novel
targets for antiviral drug development. Some kinases are required for
multiple viral family members and therefore may be targeted for the
development of broad‐spectrum antiviral drugs. Since the virus
cannot easily regain the missing cellular events by mutations, host‐
directed antiviral therapies should have a reduced risk of generating
drug‐resistant viruses. We have provided insights into how viruses
interact with p38 signalling pathway (p38/associated MAPKS/sub-
strates) and how these virus‐host interaction events can be thera-
peutically managed in restricting virus replication and minimizing
immunopathology (cytokine storm). Most of these p38 inhibitors are
under preclinical development. Further studies on cytotoxicity and
antiviral efficacy of these inhibitors in clinical trials are essential.
ACKNOWLEDGEMENTS
This work was supported by the Science and Engineering Research
Board (Grant number CRG/2018/004747, CRG/2019/000829
and CVD/2020/000103), Department of Science and Technology,
Government of India.
AUTHORS CONTRIBUTIONS
Naveen Kumar, Yogesh Chander and Ram Kumar wrote the original
draft. Naveen Kumar, Ram Kumar, Nitin Khandelwal, Namita Singh,
Sanjay Barua, and Brij Nandan Shringi edited the manuscript. Naveen
Kumar and Sanjay Barua received the funding.
ORCID
Naveen Kumar
https://orcid.org/0000-0003-3974-9409
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How to cite this article: Chander Y, Kumar R, Khandelwal N,
et al. Role of p38 mitogen‐activated protein kinase signalling
in virus replication and potential for developing broad
spectrum antiviral drugs. Rev Med Virol. 2021;1–16. https://
doi.org/10.1002/rmv.2217
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