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Open Access Journal [doi: 10.46683/jmvi.2021.34] Review Article
Journal of Molecular Virology and Immunology
An Overview of Innate Immune Response to Human Rhinovirus Infection
Human Rhinovirus Enfeksiyonuna Doğuştan Gelen Bağışıklık Tepkisine Genel Bakış
Shuaibu Abdullahi HUDU1 [ID]
1Department of Medical Microbiology and Parasitology, Faculty of Basic Clinical Sciences, College of Health Sciences, Usmanu
Danfodiyo University, Sokoto, Nigeria.
Article Info: Received: 25.05.2021. Accepted: 11.06.2021.
Correspondence: Shuaibu Abdullahi Hudu; PhD, Department of Medical Microbiology and Parasitology, Faculty of Basic
Clinical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto, 840232 Sokoto State, Nigeria. E-mail:
hudu.shuaibu@udusok.edu.ng
Abstract
Human rhinoviruses (HRV) are mainly associated with catarrh or the common cold and quite possibly
cause one of the most unavoidable diseases in human beings. Although the HRV infections of the upper
respiratory tract are generally somewhat harmless, there is increasing proof that HRV pave the way for more
hazardous infections, promote asthmatic intensifications, and lead to severe diseases in the lower respiratory
tract. Respiratory tract epithelial cells are the essential targets for rhinovirus and other respiratory pathogens.
In the presence of rhinovirus, respiratory tract epithelial cells mount both supportive of provocative reactions
and antiviral natural invulnerable reactions to clear the infection effectively. A portion of antiviral reactions
include the expression of interferons (IFNs) and endoplasmic reticulum stress-actuated unfolded protein
reaction and autophagy. In patients with chronic (persistent) lung diseases, these reactions may be either
imperfect or incited in overabundance prompting insufficient getting free from infection and supported
aggravation. In this review, components hidden behind innate antiviral invulnerability and the dysregulation
of a portion of these instruments will be examined in patients with chronic lung diseases.
Keywords: Human rhinovirus, Catarrh, Common cold, Immunology.
Özet
İnsan rinovirusları (HRV) esas olarak nezle veya soğuk algınlığı ile ilişkilidir ve büyük olasılıkla
insanlarda en kaçınılmaz hastalıklardan birine neden olurlar. Üst solunum yollarının HRV enfeksiyonları
genellikle bir şekilde zararsız olsa da HRV'nin daha tehlikeli enfeksiyonların önünü açtığına, astım şiddetini
artırdığına ve alt solunum yollarında ciddi hastalıklara yol açtığına dair artan kanıtlar vardır. Solunum yolu
epitel hücreleri, rinovirus ve diğer solunum yolu patojenleri için temel hedeflerdir. Rinovirus varlığında,
solunum yolu epitel hücreleri, enfeksiyonu etkili bir şekilde temizlemek için hem provokatif reaksiyonları hem
de antiviral doğal bağışıklığın koruyucu reaksiyonlarını destekler. Antiviral reaksiyonların bir kısmı,
interferonların (IFN) ekspresyonunu ve endoplazmik retikulum stresle harekete geçen katlanmamış (unfolded)
protein reaksiyonunu ve otofajiyi içerir. Kronik (persistan) akciğer hastalığı olan hastalarda, bu reaksiyonlar
yetersiz olabileceği gibi aşırı reaksiyonlara da neden olabilir, bu durum enfeksiyonun temizlenmesini
güçleştirirken ve alevlenmesini destekler. Bu derlemede, kronik akciğer hastalığı olan hastalarda doğuştan
gelen antiviral yanıttaki savunma açıklarının arkasına gizlenmiş bileşenler ve bu araçların bir kısmının
düzensizliği (disregülasyonu) incelenecektir.
Anahtar Kelimeler: İnsan rinovirusu, Nezle, Soğuk algınlığı, İmmünoloji.
©Copyright JMVI. Licenced by Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0).
Hudu SA. J Mol Virol Immunol 2021; 2(3): 75-85.
76
Introduction
Human rhinoviruses (HRV) are the most
widely recognized viral agents of infection in
people and constitute the major cause of the
common cold. A rhinovirus infection replicates
optimally at a temperatures between 33 and
35°C, which is found in the nose [1]. Rhinoviruses
belong to the genus of Enterovirus in the family
Picornaviridae [2]. The induction of
proinflammatory cytokines and subsequent
recruitment and activation of both innate and
adaptive immune cells following the infection of
respiratory epithelial cells by the virus are
important phases of host response against the
virus, which can also be involved in the
exacerbation of both chronic obstructive
pulmonary disease (COPD) and asthma. The
detection of pathogen-associated molecular
patterns (PAMPs) by specific host cell receptors
triggers pathogen-host interactions. Pattern
recognition receptors (PRRs), which are
expressed in innate immune cells, play a pivotal
role in the specific identification of microbial
pathogens and activation of intrinsic signaling
pathways. The subsequent production of various
cytokines and chemokines result in innate
immune responses, such as inflammatory
response constituting the foundation to eliminate
infective pathogens. The innate immune system
helps to direct adaptive immune responses to
fight against pathogens [3].
Figure 1. Pathways involved in type I interferon (IFN) production. Toll-like receptors (TLRs) recognize viruses
located in the endocytic compartment. ssRNA (single-stranded ribonucleic acid) viruses are recognized by
TLR7 and TLR8, and double-stranded ribonucleic acid (dsRNA) viruses are recognized by TLR3. RIG-1 and
dsRNA-dependent protein kinase R (PKR) recognize dsRNA produced by viruses in the cytoplasm compartment.
Adapted from reference [4]. Other abbreviations: MyD88 [Myeloid differentiation factor 88], TRIF [TIR
(Toll/interleukin-1 receptor)-domain-containing adapter-inducing interferon-β], TRAM [TRIF- related adaptor
molecule], TBK [TANK-binding kinase], IKK-I [inducible IκB kinase], IRF [interferon-regulatory-factor], RSV
[respiratory syncytial virus], HSV [herpes simplex virus], VSV [vesicular stomatitis virus], and MCMV [murine
cytomegalovirus]
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In addition to the activation of host immune
pathways, the excessive production of
inflammatory cytokines by activated PRRs can
pose extensive damage to the infected cell and
tissue. PPRs can identify pathogen specific
components, such as viral antigens,
lipopolysaccharides of bacteria, and genomes of
infectious agents. Toll-like receptors (TLRs),
retinoic acid-inducible gene (RIG)-I-like receptors
(RIG-1-like receptor - RLR family) and nucleotide-
binding oligomerization domain (NOD)-like
receptors (NOD-like receptor - NLR family) and
DNA (deoxyribonucleic acid) receptors (cytosolic
sensors for DNA) constitute common platforms of
PRR as shown in Figure 1 [5]. Signaling pathways
including type I interferon (IFN) response, natural
killer kappa B (NK-κB) and mitogen-activated
protein kinases (MAPKs) are activated following
endogenous stimuli or pathogen interactions with
PRR, leading to the induction of proinflammatory
and antiviral responses [6]. Novel therapeutics for
the treatment of diseases associated with
respiratory viruses can be achieved through the
complete understanding of virus recognition and
subsequent cell signaling mechanisms leading to
the production of pro-inflammatory cytokines and
IFNs [7]. New therapeutic agents can also be
developed with the deeper understanding of
persistent inflammation mechanisms.
Transmembrane sensors
TLRs are type I transmembrane proteins that
are associated with either cell membrane or
intracellular vesicles. The secretion of type I IFNs
(α and β), as well as proinflammatory cytokines
and chemokines [tumor necrosis factor-α,
interleukin (IL)-1, IL-6, and IL-8] is initiated upon
the detection of PAMPs including various viral
components by TLRs leading to the direct
elimination of pathogens through the recruitment
of immune cells, such as neutrophils and
macrophages and the stimulation of IFN-related
genes or induction of the adaptive branch of the
immune system [6,8]. In addition, viral infections
are dominantly detected by the innate immune
system through nucleic acid identification, but
several studies have also demonstrated that the
recognition of certain viruses occurs in nucleic
acid in an independent manner [9-11]. TLRs 3, 7,
8 and 9 reside almost exclusively in intracellular
compartments, such as endosomes, which can
recognize nucleic acid of viral pathogens. The
TLR3 recognition of double-stranded ribonucleic
acid (dsRNA), an intermediate product produced
during the replication of most viruses in the cell,
induces the production of proinflammatory
cytokines and chemokines [12], as well as type I
IFN (IFN-β) antiviral response induced through
the activation of nuclease factor-κB (NF-κB)
[13,14]. Hewson et al. [15] showed that the HRV
infection of human bronchial epithelial cells
induced TLR3 expression using the BEAS-2B cell-
line. In that study, TLR3 was also found as a
potent inducer of antiviral response (IFN-β)
against rhinovirus by strengthening the innate
immune arm of host response. The deficient
expression of TLR3 could have a link to deficient
IFN-β responses and increased susceptibility to
HRV infections in asthmatics. On the other hand,
TLR7 and TLR8 are activated via interaction with
single-stranded RNA (ssRNA). This type of
activation may be an important mechanism for
enveloped viruses which access cytosol through
endosomes [6]. Kurt-Jones et al. [10]
demonstrated that the recognition of the fusion
protein of human respiratory syncytial virus (RSV)
through TLR4 mediated innate immune response
against the virus. RSV persisted longer in the
lungs of TLR4-deficient mice with higher viral
propagation compared with normal healthy
individuals, which also showed a lower level of
virus elimination due to reduced monocyte
infiltration and IL-12 production. The activation of
TLR2 through the sensing of the hemagglutinin
protein of measles virus (MV) not only induce
proinflammatory cytokines, such as IL-6 but also
upregulate the expression of the MV receptor
(CD150), which contributes to the spread and
pathogenicity of the virus [11]. The activation of
TLR2 following interaction with viral fusion protein
has also been reported for glycoprotein B of
human cytomegalovirus [9]. Studies have shown
that the interaction of HRV with intercellular
adhesion molecule 1 (ICAM-1) plays an important
role in cytokine production in addition to viral
entry and replication [16]. The p38 kinase, a
serine-threonine kinase, is a member of the MAPK
superfamily that is activated through
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78
phosphorylation by the direct interaction of virus
with the cell during an early HRV infection,
independent of virus replication and protein
production. This is reported to result in the
activation of the NF-κB transcription pathway and
peak cytokine expression during the early hours
of post-infection [17]. Wang et al. [18] showed
that immunoregulatory protein tyrosine kinase,
Syk, which is the downstream of the ICAM-1
signaling pathway, plays a crucial role in the
activation of p38 MAPK and inflammatory cytokine
production before virus replication [18].
Therefore, ICAM-1 signal transduction initiates
proinflammatory response upon HRV interaction.
Cytosolic receptors
RIG-1 and melanoma differentiation-
associated protein 5 (MDA5) are RNA helicases
located in cytosol and play critical antiviral roles
in the elimination of replicating the virus through
the identification of dsRNA in cell cytoplasm [4].
Yoneyama et al. [19] showed that the production
of IFNα/β was induced following the Newcastle
disease virus infection and dsRNA transfection.
The critical regulators of innate immune response
including transcription factors NF-κB and IRF-3
are activated in response to the interaction of the
RNA helicase domain with dsRNA through the
caspase recruitment domain. DsRNA is a main
virus genome produced in the cytosol of HRV-
infected cells upon receptor-mediated endocytosis
and subsequent virus conformational changes and
genome injection into the cytoplasm and acts as
an important mediator of innate response
stimulation [20]. However, the recognition of
dsRNA by these PRRs appears to be specific to cell
and virus types. For instance, Wang et al. [20]
demonstrated that the maximum sensing of
rhinovirus dsRNA and the subsequent IFN
response are achieved through MDA5 and TLR3
but not RIG-I using both the BEAS-2B human
bronchial epithelial cell line and primary tracheal
epithelial cells isolated from lung transplant
donors. Further experiments showed that IRF3
was used by both PRRs as a common downstream
intermediate to regulate the expression of IFN. In
that study, both major and minor serotype groups
showed similar immune responses, which is in
agreement with the gene expression patterns of
both minor and major HRV groups reported in a
study by Chen et al. [21]. In contrast, the
infection of the A549 cell line by RSV quickly
induced the expression of both RIG-I and TLR3,
further demonstrating virus-type specific
recognition by PRRs. The binding of the RSV
genome to RIG-I, as a primary sensor, induced
early antiviral response through the activation of
IRF3 and NF-κB. Here, TLR3 expression is
secondary to the RIG-I pathway, which only
affects late-phase gene expression [22]. Although
other studies have shown that rhinovirus group A
infections of primary bronchial epithelial cells
induce a high level of type I IFN and a variety of
IFN-stimulated genes (ISGs) [20,21], Kotla et al.
reported that the infection of the A549 cell line
with the HRV group B strain (HRV14) failed to
elevate type I IFN [23]. The low level of IFN-β
mRNA in that study can be explained by the
impaired activation of IRF3 in the presence of
activated NF-κB and ATF-2, which seems to
contradict intact innate immunity in virus group A.
MDA5 is degraded in poliovirus-infected cells, as
well as in rhinovirus type 1a, although it is stable
in rhinovirus type 16 and 14 [23,24]. A recent in-
depth study by Slater et al. [7] demonstrated the
role of RIG-1 in addition to TLR-3 and MDA5 in the
recognition of major and minor HRV groups and
innate response based on both in vitro and in vivo
models. The authors showed that the endosomal
sensing of HRV through TLR-3 subsequently
induced cytoplasmic RIG-I and MDA5 expressions
early in the infection to reach maximal IFN and
pro-inflammatory cytokine induction.
Inflammasome
Inflammasome is another type of cytoplasmic
PRRs, which regulates the activation of the
proinflammatory cytokines, including pro-IL-1β
and pro-IL-18 through the conversion of
procaspase-1 to caspase-1. They recognize
pathogen components and danger-associated
molecular patterns. They are multiplex molecules
consisting of the NLR family, apoptosis-associated
speck-like protein containing a CARD-caspase
recruitment domain, and apoptotic protease-
activating factor-1 (Apaf-1) [25]. Several studies
have demonstrated that inflammasome activation
is regulated by the concentration of intracellular
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ions. The perturbation of cell membrane and the
subsequent drop in cytosolic potassium levels by
some microbial toxins induce NLRP3
inflammasome activation [26]. The ion
homeostasis of cells can be modulated by
viroporins, a group of proteins commonly
produced by respiratory viruses. A wide range of
stimuli, such as ultraviolet irradiation and virus
infections activate NLRP3 through an increase in
the intracellular Ca2+ concentration. In 2013,
Triantafilou et al. [27] demonstrated that the
infection of primary bronchial cells by rhinovirus
activated NLRP3 and NLRC5 inflammasomes, and
caspase 1, and led to IL-1β secretion. Viroporin
2B disturbed the homeostasis of calcium by
targeting the Golgi complex and endoplasmic
reticulum and reduced Ca2+ in these organelles.
The detection of NLRP3 and NLRC5 inflammasome
activation may explain stronger inflammation and
exacerbations in the respiratory tract [27].
Viperin is the most induced protein in the
class of antivirals. The antiviral activity of viperin
has been reported against several viruses [28].
Viral proteins required for viral assembly and
maturation are inhibited by viperin, which is
highly elevated in HRV infections [21]. In a
previous study, there was a significant correlation
between the mRNA level of viperin and the
symptomatic period of the HRV infection [28].
Viperin induction was dependent on time and HRV
replication. Induction started at 12 hours after
infection and significantly increased at 48 hours
[28]. The role of viperin may be more prominent
in the late stage of the infection, and this protein
may act as a member of antiviral response to HRV
infections [28]. Human β-defensin 2 and inducible
nitric oxide synthase are antiviral proteins that
have been shown to be induced in HRV in both in
vitro and in vivo studies [29,30]. Phospholipid
scramblase 1, which plays an indirect role in
antiviral response, is also induced in HRV
infections [31].
Interferon response
IFN was first discovered more than half a
century ago as a factor released by the chick
chorioallantoic membrane challenged by influenza
virus [32]. There are three classes of IFNs
designated as type I (13 α subtypes, β, κ, ε, ο, τ
and δ), II (IFNγ), and III (IFNλ) [33]. NF-κB, IRF-
3, and ATF-2-c-Jun are important transcription
factors in the expression regulation of type I IFN
[19]. Type I IFNs are important components of
antiviral response with direct antiviral effects on
infected and adjacent cells. It has been shown
that more than 300 ISGs are activated following
the interaction of type I IFN with the
corresponding receptor. However, small numbers
of ISGs are directly involved in antiviral response
[34]. The attenuated induction of the IFN-induced
genes related to apoptosis, innate immunity, and
antigen processing, especially in the early stage
of viral infections may be a reason for failure in
virus elimination, resulting in severe cases of the
disease. On the other hand, the pathogenicity of
different virus strains can be determined by the
early induction of ISGs [35].
Type I IFNs (α/β) play an important role in
mounting a robust antiviral response of cells
through several ISG-mediated pathways,
including protein kinase R (PKR), Mx GTPase
pathway (myxovirus resistance 1), 2’,5’-
oligoadenylte-synthetase-directed ribonuclease L
(RNaseL) pathway and ISG15 ubiquitin-like
pathway as shown in Figure 2 and controlling virus
propagation in all steps including the inhibition of
virus transcription and translation [33]. An in vitro
study using primary respiratory tract epithelial
cells showed that IFN-α and IFN-γ were not
induced in HRV-infected cells, but IFN-β was
detected in HRV16-infected cells [21]. The
detection of phosphorylated signal transducer and
activator of transcription 1 demonstrated the role
of IFN in the induction of intracellular signaling,
but the IFN-β signaling pathway only had a partial
effect on the expression of genes in HRV-infected
cells [21]. In that study, the importance of IFN-β
in antiviral gene expression was consistent with
the increase of HRV production in asthmatic
patients with deficient cell antiviral response,
including impaired RV-induced IFN-β production
[21].
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Figure 2. Jak/STAT signaling cascade. This cascade is activated by INF-α/β binding to the type I IFN receptor.
This results in the production of antiviral proteins, such as 2ʹ-5ʹ-oligoadenylate synthase (OAS) and IFN-
induced GTP-binding protein Mx1. Adapted from references [33,36].
One of the critical stages of innate antiviral
responses in cells infected with a virus is the swift
elimination of infected cells by the induction of
apoptosis. Virus replication and establishment is
prevented by the early apoptosis and subsequent
phagocytosis of virus-infected cells before the
initiation of cellular lysis. In a study by Takaoka et
al. [37], it was shown that IFNs also played an
important role in antiviral responses through the
regulation of apoptosis in vesicular stomatitis
virus infections in mice. The production of IFN-α/β
by infected cells enhances apoptosis by inducing
tumor suppressor p53. Therefore, p53 is
considered as a critical element of host defense in
viral infection and early cell apoptosis in innate
antiviral response. A subsequent study showed
that increased HRV virus replication in cultured
primary bronchial epithelial cells obtained from
asthmatic subjects compared with normal healthy
individuals was related to deficient type I IFN
response and resistance to the early apoptosis of
virus-infected cells. This could explain the more
severe symptoms associated with the lower
respiratory tract among patients with asthma,
which may be due to decreased virus elimination
at the early stage of the infection, further
confirming the critical role of type I IFNs and
apoptosis related to HRV infections [38]. On the
other hand, Bochkov et al. [39], who compared
the genes involved in HRV-infected primary
bronchial epithelial cells from asthmatic donors
with HRV-infected cells from normal individuals
showed no significant differences in the
production of INFs type I and III between the two
groups. Type I IFN was reported to prime infected
and neighboring cells to an antiviral state and
early apoptosis with the subsequent phagocytic
removal of the replicating virus, which confined
the extent of inflammatory responses in the
respiratory tract upon infection [40]. Therefore,
type I IFN is a potential therapeutic for treating
the exacerbations of asthma of virus origin,
limiting virus replication by restoring cell
apoptosis response to the normal level [40].
PKR is a constitutively expressed
serin/threonine protein kinase and IFN-induced
protein, which regulates protein synthesis in
response to stress signal, mostly by viral
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infection. In addition to antiviral protection, PKR
plays an important role in cell growth regulation
and differentiation. PKR is a main regulator of the
antiviral response of the cell. It can inhibit virus
replication through the inhibition of protein
synthesis through eukaryotic translation initiation
factor 2A (EIF2A), induction of antiviral genes
through NF-κB, and triggering of apoptosis in
virus-infected cells [41]. Phosphorylated serine
residue 51 of EIF2A inhibits GDP recycling and
leads to impairment in protein synthesis.
Phosphorylation of EIF2Aα is associated with the
antiproliferative and antiviral activity of PKR [33].
DsRNA can activate or inhibit PKR following
binding and exerting conformational changes.
Viruses have developed mechanisms to escape
the immune system through the inhibition of PKR
at different levels [42]. The DsRNA-binding
domain of influenza virus nonstructural protein 1
inhibits the activation of PKR, as well as type I IFN
synthesis [43]. The E3L and K3L proteins of
Vaccinia virus inhibit the PKR pathway through the
sequestering of dsRNA molecules and inhibition of
PKR autophosphorylation, respectively [44]. Chen
et al. [21] showed that HRV infections significantly
induced the PKR system in addition to the Mx
pathway, viperin, and the coupled 2’-5’-
oligoadenylate synthetase (OAS)/RNase L
pathway. PKR plays an important role in HRV
antiviral response.
The replication of the virus is eliminated
through another innate pathway called the 2′,5′-
(OAS)/RNase L system. The OAS gene is induced
by IFN signaling through IFN-stimulated response
elements. In this system, cytoplasmic viral dsRNA
is recognized by OAS as PRRs, which is
constitutively expressed in the cell. Activated OAS
produces 2-5A from ATP. The binding of 2-5A to
RNase L monomers converts them into activated
dimers with RNase activity, degrading the single-
stranded RNAs of both viral and cellular origin
[45]. Some viruses develop a potent inhibitor for
RNase L, which may play a role in the in vivo
pathogenesis of the virus [46]. The antiviral role
of OAS has been investigated against
picornaviruses, including coxsackieviruses,
poliovirus, and encephalomyocarditis virus [45].
All four types of OAS (OAS1, 2, 3 and L) have been
shown to be significantly induced in human
tracheobronchial cells infected with both major
and minor HRV groups [21].
Mx proteins comprising Mx1 and Mx2 play an
antiviral role against a wide variety of viruses.
Type I IFN stimulates the expression of Mx
proteins through an IFN-stimulated response
element present in the gene promoter. MxA
proteins accumulate in intracellular membranes,
including the endoplasmic reticulum in cell
cytoplasm and target both cytoplasmic and
nuclear viruses. They inhibit viral replication at
early stages, which prevents the generation of
mechanisms by the virus to escape the Mx
antiviral. Mx proteins inhibit viral replication by
inhibiting virus RNA synthesis and nucleocapsid
transport. Viral components, mostly
nucleocapsids, are trapped and degraded by MxA
monomers [33]. Turan et al. [47] showed that the
transcription step of influenza virus was efficiently
interfered through the interaction of nuclear Mx
with PB2-NP proteins. Both subtypes of Mx
proteins, Mx1 and Mx2, are significantly induced
by HRV infections [21].
HRV-induced inflammatory response
In addition to molecules with direct anti-viral
effects, HRV infections induce pro-inflammatory
mediators that clear infections through immune
cells recruitment to the site of infection. The
production of cytokines contributes to the
eradication of pathogens in vivo, but the
insufficient induction of proinflammatory
cytokines can cause systemic inflammatory
response syndrome, and it is associated with the
pathophysiology of inflammation [3,48]. Three
types of inflammatory mediators are released in
response to HRV infections: those that recruit and
activate specific leukocytes, such as IL-8 and IL-
6, those involved in anti-viral defense, such as
IFNβ and IFNα, and those like IL-1 which amplify
local inflammation [49]. The induction of
respiratory tract inflammation and initiation of the
exacerbation of respiratory tract diseases have
been associated with the significant elevation of
inflammatory mediators, including IL-1, 6 and 8,
granulocyte-macrophage colony-stimulating
factor (GM-CSF), regulated on activation, normal
T cell expressed and secreted (RANTES), and
eotaxin [21].
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IL-1 family mediators are produced by
respiratory tract epithelial cells during the very
early stage of the HRV-induced inflammatory
cascade and play an important role in the
establishment of inflammation. Piper et al. [50]
showed that HRV infections induced the release of
IL-1α, IL-β and IL-18 by epithelial cells, and
autocrine IL-1 signaling had an undeniable role in
the production of pro-inflammatory cytokines in
HRV infections. The upregulation of pro-
inflammatory cytokines was reported to be
inhibited by IL-1 blockage without contributing to
IFN and INF-driven responses induced by HRV
infections. Therefore, the inhibition of the IL-1
pathway can be considered as an optimal
therapeutic strategy to moderate inflammatory
responses in acute exacerbations.
IL-8 has been shown to be involved in several
inflammatory disorders. Studies have reported an
increased level of IL-8 in nasal aspirates during
the virus-induced exacerbation of respiratory
tract diseases. IL-8 plays an important role in
neutrophil chemotactic activity and recruitment,
which may be involved in virus-induced
respiratory pathogenesis and clinical outcome.
Studies have also demonstrated a positive link
between the severity of respiratory tract
symptoms and an increase in the respiratory tract
hypersensitivity of asthmatic patients and the
level of neutrophil chemoattractants, such as IL-
8, as well as neutrophil counts in nasal secretions
[51,52]. Although studies indicate that individuals
with asthma have defective IFN-β production in
response to HRV infections, which results in a
subtle defect in immune response, the production
of IL-6, RANTES, IL-8 and GM-CSF in this group
was similar to healthy individuals, suggesting that
proinflammatory response to viral infections
remains intact and is necessary to eliminate
infections from the respiratory tract [40].
The rapid induction of granulocyte colony-
stimulating factor (G-CSF) followed by IL-8 in the
nose upon infection is associated with an increase
in neutrophils in blood and nasal fluid,
respectively. Sputum neutrophilia is followed by
upper respiratory neutrophilia and also correlated
with changes in G-CSF and IL-8, suggesting that
the HRV infection gradually moves to the lower
part of the respiratory tract [53]. Johnston et al.
[54] showed the induction of IL-8 in the low-grade
rhinovirus infection of the transformed lower
respiratory tract epithelial cell (A549). The
authors found that IL-8 release was time- and
dose-dependent and increased for up to five days
in the post-infection period depending on virus
receptor interaction and partially on viral
replication. Both in vitro and in vivo studies have
reported that CXCL10 is induced by HRV infections
[55]. Other respiratory viruses have been shown
to induce CCL2 and CXCL11. CXCL13, which is
traditionally limited to lymphoid organs, is
markedly elevated in respiratory tract epithelial
cells, although its role in the pathogenesis of the
virus requires further investigations [28].
Intranasal challenging of volunteers with HRV
showed a significant decrease in peripheral T
lymphocytes, which was associated with severe
cold symptoms and frequent virus shedding [56].
In a study by Gern et al. [53], the pattern of Th1-
and Th2-like cytokine responses (as indicated by
IFN-γ and IL-5 sputum mRNA, respectively) was
compared to the virological and clinical outcomes
of HRV infections in asthmatic individuals. Both
branches were observed to be activated during
the acute phase. Time required to eliminate the
virus from sputum and peak symptom scores
during the acute phase were inversely related to
the IFN-γ/IL-5 ratio. Therefore, profound Th1-like
cytokine response during the HRV-induced
common cold would play a critical role in
restricting virus propagation and respiratory
symptoms. However, impaired immune response
to this viral infection may occur as a result of Th2-
like responses in asthmatic patients. The
simultaneous elevation of IFN-γ and IL-5 may be
strong inflammatory stimuli [53]. Therefore,
exogenous IFN-γ may have a potential
therapeutic effect on reducing respiratory tract
dysfunctions.
Conclusion
Conductive respiratory tract epithelial cells
that function as both a barrier for and a trigger of
appropriate immune responses are the main
target of HRV. Respiratory tract epithelial cells are
outfitted with layers of invulnerable antiviral
instruments. Nitric oxide produced following
contamination has intense antiviral activity and
Hudu SA. J Mol Virol Immunol 2021; 2(3): 75-85.
83
adjusts excessive cytokine articulation to prevent
irritation. Type I and type III IFN-reinforced
qualities, as well as meddling with viral replication
additionally limit infection instigated favourable to
incendiary cytokines to forestall unreasonable
aggravation.
Notwithstanding uncertain, a few
investigations associated diminished IFN
articulation with higher viral load in patients with
asthma. Despite new advances in the field of
inborn resistant reactions to HRV, the
fundamental components of HRV-related
exacerbations in patients with persistent lung
diseases are not yet fully understood. While
patients with COPD regularly show Th1 irritation,
the majority patients with asthma have Th2
aggravation in light of viral diseases.
Consequently, significant factors underlying
HRV-related aggravation in asthma and COPD
may be completely different, and this should be
considered when evaluating discoveries to foster
new treatments.
Conflict of interest: The author declares that there is no conflict of interest. The author alone is responsible
for the content and writing of the paper.
Financial disclosure: There is no financial support to this study.
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