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Coronavirus Infections and Immune Responses

Article  in  Journal of Medical Virology · January 2020

DOI: 10.1002/jmv.25685

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Received: 21 January 2020 | Accepted: 22 January 2020
DOI: 10.1002/jmv.25685

REVIEW

Coronavirus infections and immune responses

Geng Li1,2 | Yaohua Fan3 | Yanni Lai3 | Tiantian Han3 | Zonghui Li2 |
1 2 1 4
Peiwen Zhou | Pan Pan | Wenbiao Wang | Dingwen Hu |
Xiaohong Liu5 | Qiwei Zhang1,6 | Jianguo Wu1,4

1
Guangdong Provincial Key Laboratory of
Virology, Institute of Medical Microbiology, Abstract
Jinan University, Guangzhou, China
2 Coronaviruses (CoVs) are by far the largest group of known positive‐sense RNA
Laboratory Animal Center, Guangzhou
University of Chinese Medicine, Guangzhou, viruses having an extensive range of natural hosts. In the past few decades, newly
China
evolved Coronaviruses have posed a global threat to public health. The immune
3
The First Clinical Medical College, Guangzhou
University of Chinese Medicine, Guangzhou, response is essential to control and eliminate CoV infections, however, maladjusted
China immune responses may result in immunopathology and impaired pulmonary gas
4
State Key Laboratory of Virology, College of
exchange. Gaining a deeper understanding of the interaction between Cor-
Life Sciences, Wuhan University, Wuhan, China
5
The First Affiliated Hospital, Guangzhou
onaviruses and the innate immune systems of the hosts may shed light on
University of Chinese Medicine, Guangzhou, the development and persistence of inflammation in the lungs and hopefully can
China
6
reduce the risk of lung inflammation caused by CoVs. In this review, we provide
School of Pubic Health, Southern Medical
University, Guangzhou, China an update on CoV infections and relevant diseases, particularly the host
defense against CoV‐induced inflammation of lung tissue, as well as the role of
Correspondence
Jianguo Wu, Guangdong Provincial Key the innate immune system in the pathogenesis and clinical treatment.
Laboratory of Virology, Institute of Medical
Microbiology, Jinan University, 510632 KEYWORDS
Guangzhou, China.
Email: [email protected] chemokine, coronavirus, cytokines, inflammation, interferon

Funding information
National Natural Science Foundation of China,
Grant/Award Numbers: 81730061, 81902066,
81471942

1 | INTRODUCTION respiratory syndrome coronavirus (MERS‐CoV) was first identified in

2012, bringing a total of 1401 MERS‐CoV infections, and 543 (~39%) of
During the end of 2019 and the beginning of 2020, multiple human cases which died.3‐5 All the infection cases and recent epidemics show that
of novel coronavirus infection were reported in relation to the Huanan coronaviruses impose a continuous threat to human beings and the
Seafood Wholesale Market (South China Seafood City Food Market) in economy as they emerge unexpectedly, spread easily, and lead to cata-
Wuhan, China. At 9 O'clock, 7 January 2020, the virus was identified as a strophic consequences.
novel coronavirus and officially named by the WHO as 2019‐nCoV, the Coronaviruses are enveloped, nonsegmented, positive‐sense
new coronavirus in 2019.1 On 22 January 2020, a total of 314 confirmed single‐stranded RNA virus genomes in the size ranging from 26 to
case have been reported, and 6 patients were reported to have died.2 On 32 kilobases, the largest known viral RNA genome. The virion has a
13, 16, and 21 January, respectively, Thailand, Japan, and Korea con- nucleocapsid composed of genomic RNA and phosphorylated
2
firmed the detection of a human infection with 2019‐nCoV from China. nucleocapsid (N) protein, which is buried inside phospholipid bilayers
In recent years, novel coronaviruses emerge periodically in different and covered by two different types of spike proteins: the spike
areas around the world. Severe acute respiratory syndrome coronavirus glycoprotein trimmer (S) that can be found in all CoVs, and
(SARS‐CoV) occurred in 2002, which reportedly infected 8422 people the hemagglutinin‐esterase (HE) that exists in some CoVs. The mem-
and caused 916 deaths worldwide during the epidemic. Middle East brane (M) protein (a type III transmembrane glycoprotein) and the

J Med Virol. 2020;1–9. wileyonlinelibrary.com/journal/jmv © 2020 Wiley Periodicals, Inc. | 1

2 | LI ET AL.

Although the pathologies of SARS and MERS are not yet fully un-
derstood, viral and host factors play a key role in SARS‐CoV and MERS‐
CoV infections. During virus infection, host factors trigger an immune
response against the virus. However, it should be noted that im-
munopathogenesis is associated with an immune response out of con-
trol, which may result in pulmonary tissue damage, functional
impairment, and reduced lung capacity. Chemotactic factors are essen-
tial to the immune responses against the virus infections, given their
regulatory effect on dilations and positions of leukocytes in the host
lungs. Therefore, spectral changes in chemotactic factors may lead to
severely maladjusted immune responses. Immune insufficiency or mis-
direction may increase viral replication and cause tissue damages. In
contrast, overactive immune responses may induce immunopathological
conditions. In this review article, we provide an analysis of the role of
cytokines secreted upon CoV infections and their potentially detrimental
contribution to the damages of the respiratory tract and other tissues.

F I G U R E 1 Coronavirus particle. Coronaviruses are enveloped,

nonsegmented, positive‐sense single‐stranded RNA virus genomes in the
size ranging from 26 to 32 kilobases. The virion has a nucleocapsid 2 | IN NA TE IMMU NE RESP ONSE
composed of genomic RNA and phosphorylated nucleocapsid (N) protein,
which is buried inside phospholipid bilayers and covered by the spike 2.1 | Pathogen‐recognition receptors
glycoprotein trimmer (S). The membrane (M) protein (a type III
transmembrane glycoprotein) and the envelope (E) protein are located
The host innate immune system detects viral infections by using pat-
among the S proteins in the virus envelope
tern recognition receptors (PRRs) to recognize pathogen‐associated
molecular patterns (PAMPs). At present, the known PRRs mainly in-
envelope (E) protein are located among the S proteins in the virus clude toll‐like receptor (TLR), RIG‐I‐like receptor (RLR), NOD‐like
envelope. CoVs were given their name based on the characteristic receptor (NLR), C‐type lectin‐like receptors (CLmin), and free‐molecule
crown‐like appearance. The structure of CoV virion is shown in receptors in the cytoplasm, such as cGAS, IFI16, STING, DAI, and so on.
Figure 1.
The coronavirus subfamily is genotypically and serologically di-
vided into four genera, the α, β, ɣ, and δ coronaviruses. The 2.2 | Toll‐like receptors
β‐coronavirus can be further classified into four viral lineages, namely
lineage A‐D. There are nearly 30 recognized CoVs that infect humans, PAMPs recognized by Toll‐like receptors (TLRs) include lipids, lipopro-
mammals, fowl, and other animals. Human CoV infections are caused teins, proteins, and nucleic acids of the bacterial, viral, parasite, and
by α‐ and β‐CoVs. CoVs are common human pathogens, and 30% to fungal origins.6 The recognition of PAMPs by TLRs also occurs in cell
60% of the Chinese population is positive for anti‐CoV antibodies. The membranes, endosomes, lysosomes, and endocytolysosomes and other
viral infections are generally associated with upper respiratory tract locations in cells.6 Different TLRs can induce different biological re-
infections, of which the signs and symptoms commonly include fever, sponses via subsequent activation of varied adapter proteins, such as
headache, and cough; some patients may have lower respiratory tract MyD88, TIRAP, TRIP, and TRAM, but these adapter proteins all share
infections. In contrast, SARS‐CoV and MERS‐CoV infections may the Toll/Interleukin‐1 receptor (TIR) structure.7 MyD88 is the first
remain asymptomatic in the early stage until severe pneumonia, dys- identified TIR family member, which acts as an adapter protein by almost
pnea, renal insufficiency, and even death (Figure 2). all TLRs except TLR3. It mainly activates the transcription factors NF‐kB
Histopathological observations of pulmonary lesions in SARS and mitogen‐activated protein kinases (MAPKs) pathways to induce in-
cases not only show nonspecific inflammatory responses such as flammatory factors' expression.6 Unlike MyD88, TRIF is an adapter
edema and inflammatory cell infiltration but also exhibit severe ex- protein of TLR3 and TLR4, which activates the transcription factors IRF3
foliation of alveolar epithelial cells, alveolar septal widening, damage and NF‐kB to induce the expression of type I interferon and immune‐
to alveolar septa, and alveolar space infiltration in a distinctly orga- inflammatory factors. The function of TRAM and TIRAP is to recruit
nized manner. Pathologically, inflammation includes degeneration TRIF molecules to the TLR4 receptor and MyD88 to the TLR2 and TLR4
(necrosis), infiltration, and hyperplasia. Thus, SARS‐CoV infection can receptors. Therefore, the TLR signaling pathways are classified as the
cause pathological changes, degeneration, infiltration, and hyperpla- MyD88‐dependent pathway, which functions to activate immune‐
sia. Damage to the pulmonary interstitial arteriolar walls indicates inflammatory factors, and the TRIF‐dependent pathway, which functions
that inflammatory response plays an important role throughout the to activate the type I interferons and inflammatory factors.6 After a TLR
course of disease in spites of the pathogenic effect of CoVs. is activated by the corresponding PAMP, MyD88 recruits the busy‐1
LI ET AL. | 3

F I G U R E 2 The innate immune response and adaptive immune responses of Coronaviruses (CoV) infection during an infection. A, CoV infects
macrophages, and then macrophages present CoV antigens to T cells. This process leads to T cell activation and differentiation, including the
production of cytokines associated with the different T cell subsets (ie, Th17), followed by a massive release of cytokines for immune response
amplification. The continued production of these mediators due to viral persistence has a negative effect on NK, and CD8 T cell activation. However,
CD8 T cells produce very effective mediators to clear CoV. B, Attachment of CoV to DPP4R on the host cell through S protein leads to the
appearance of genomic RNA in the cytoplasm. An immune response to dsRNA can be partially generated during CoV replication. TLR‐3 sensitized by
dsRNA and cascades of signaling pathways (IRFs and NF‐κB activation, respectively) are activated to produce type I IFNs and proinflammatory
cytokines. The production of type I IFNs is important to enhance the release of antiviral proteins for the protection of uninfected cells. Sometimes,
accessory proteins of CoV can interfere with TLR‐3 signaling and bind the dsRNA of CoV during replication to prevent TLR‐3 activation and evade the
immune response. TLR‐4 might recognize S protein and lead to the activation of proinflammatory cytokines through the MyD88‐dependent signaling
pathway. Virus‐cell interactions lead to the strong production of immune mediators. The secretion of large quantities of chemokines and cytokines
(IL‐1, IL‐6, IL‐8, IL‐21, TNF‐β, and MCP‐1) is promoted in infected cells in response to CoV infection. These chemokines and cytokines, in turn, recruit
lymphocytes and leukocytes to the site of infection. Red lines refer to inhibitory effects. Green lines refer to activating effects

receptor‐related kinases IRAK4, IRAKI, IRAK2, and IRAK‐M. IRAK4 of RNA viruses.12,13 They have a DExD/H‐box RNA helicase struc-
plays an important role in activating NF‐kB and MAPKs downstream of ture and a C‐terminal termination structure (CTD), while RIG‐I and
MyD88. IRAK interacts with TRAF6, which causes its K‐63 ubiquitina- MDA5 have an N‐terminal caspase recruitment structure (CARD), to
tion, and facilitates NEMO ubiquitination to activate NF‐kB. TRIF‐ interact with the downstream adapter MAVS. The C‐terminal RNA
8,9
dependent pathways activate IRF3 and NF‐kB. In addition to acti- helicase and CTD structure are considered to recognize RNA, and its
vating NF‐kB, TRIF‐dependent pathways, they also activate IRF3 and conformational change requires ATP to make the CARD structure
interferon‐β.10,11 interact with MAVS.14
RIG‐I is activated by a variety of RNA viruses' infections, in-
cluding Influenza A virus (IAV), Newcastle disease virus (NDV),
2.3 | RIG‐I‐like receptors Sendai virus (SeV), and Vesicular stomatitis virus (VSV), Measles virus
(MV), and Hepatitis C virus (HCV).15,16 The common features of the
RIG‐I‐like receptors (RLRs), including the H family members RIG‐I viral RNAs are short double‐stranded with a triphosphate structure,
(DDX58), MDA5 (IFIH), and LGP2, primarily recognize nucleic acids and complementary ends and/or poly‐U/UC‐rich structure. The viral
4 | LI ET AL.

nucleocapsid proteins containing triphosphine RNA at the 5′‐end can complex formation. At the same time, apoptosis‐related granule‐like
be recognized by RIG‐I.17 The double‐stranded RNA with double‐ proteins, including ASC, is acidified by SyK and JNK,30 and PKCS is
basic acid at the 5′‐end can be recognized by RIG‐I.18 When the viral also a key essential element in the pathway.31 The signaling pathways
5′‐terminal triphosphate end is recognized by the CTD structure, the activate downstream molecules, including NF‐kB and MAPKs, and
ATP‐dependent conformational change brings the CTD structure to trigger a variety of cellular responses, including cell phagocytosis,
form a complex with the double‐stranded RNA, and the CARD maturation of DC cells, and chemotaxis of cells.31
structure is then released from its self‐inhibition and interacts with
MAVS.19
MDA5 recognizes RNAs of picornaviruses, including poliovirus 2.6 | Cytoplasmic DNA receptor
(PV) and Encephalomyocarditis virus (EMCV). MDAS‐recognized
RNA is characterized by long double‐stranded RNA more than 1 Exogenous microbial DNAs are recognized by host DNA receptors. In
kbp. Crystal structure analysis shows that the helicase and CTD addition to TLR9 in the TLR family, Cytoplasmic DNA receptor (CDR)
structure of MDA5 are also surrounded by double‐stranded RNA, the can recognizes DNA CpG islands.32 More than 10 CDRs distributed
same as RIG‐I. However, the CTD structure of MDA5 does not have a in the cytoplasm have been identified, including AIM2‐like receptors
20
hat structure, and the hat structure is necessary to have a tri- (ALRs), DNA‐dependent activator of IFN‐regulatory factor (DAI), in-
phosphate RNA interaction at the 5′‐end. The CTD structure of terference stimulator of interferon gene (STING), leucine‐rich repeat
MDA5 directly interacts with the double‐stranded RNA, so that the flightless‐interacting protein 1 (LRRFIP1), DExD/H‐box RNA helicase
5′‐end RNA can be freely released.21 (DDX), Meiotic recombinant protein 11 Homolog A (MRE11), RNA
polymerase III (Pol III), DNA dependent protein kinase (DNA‐PK),
DNA repair‐related proteins Rad50, cyclic GMP‐AMP synthase
2.4 | Nucleotide‐binding and oligomerization (cGAS), and Sry‐related HMG box 2 (Sox2).4,32,33 DAI recognizes
domain‐like receptors Z‐type DNA and B‐type DNA, which does not depend on sequence
specificity, but on the length of DNA.34,35 AIM2 is mainly involved in
Nucleotide‐binding and oligomerization domain (NOD)‐like receptors the recognition of double‐stranded DNA. Exogenous microbial DNAs
(NLRs) are a class of pattern recognition receptors,22 which re- are also recognized by host DNA receptors. IFI16 and cGAS are re-
cognize components of pathogens and contain a conserved NOD ported to be novel DNA receptors that mediate cytosolic DNA re-
structure.23 NLR receptor family members are divided into three cognition and induce type I interferon.36
subclasses according to their functions. The first NLR subclass forms
complexes with a variety of proteins and these complexes are de-
fined as inflammasome that contains at least eight NLR proteins, 2.7 | Type I interferons
including NLRP1, NLRP3, NLRP6, NLRC4, NLRC5W, and AY2.24–26
The second subclass is essential to reproduction and embryo re- When a virus invades the host, PRRs initially recognize the viral
generation.27 The third subclass is comprised of regulatory NLRs. nucleic acid, collect the specific signal adapter protein, activate IRF3
These NLRs are positive or negative conditioned inflammatory sig- and IRF7 before being translocated to the nucleus and promote the
naling cascade pathways. synthesis of type I interferons (IFNs). Type I IFNs subsequently ac-
tivate the downstream JAK‐STAT signal pathway, promote the ex-
pression of IFN‐stimulated genes (ISGs).37,38
2.5 | C‐type lectin‐like receptor As the host's major antiviral molecules, IFNs limit virus spread,
and play an immunomodulatory role to promote macrophage pha-
C‐type lectin‐like receptor (CLRs) are a large family of soluble, trans- gocytosis of antigens, as well as NK cells restriction of infected target
membrane pattern recognition receptors with more than 1000 mem- cells and T/B cells. Thus, blocking the production of IFNs has a direct
bers, which are widely expressed in myeloid cells. Due to its motif effect on the survival of the virus in the host.39,40 So far, PRRs are
structure in the intracellular region with multiple signaling pathways, divided into three types according to their forms of existence41: the
the CLR receptor has a wide range of functions, including cell adhe- membrane type includes TLR2, TLR4, mannose receptor (MR), sca-
sion, induction of endocytosis, phage, tissue repair, platelet activation, venger receptor (SR); the secretory type comprises mannose‐binding
and natural immune responses. There are two main ways of CLR re- lectin (MBL) and C‐reactive protein (CRP); the cytoplasmic type
ceptor activation in the cells. The first type is direct activation, such as consists of TLR3, TLR7/8, and NLRs. Among them, the IFN
macrophage‐induced Mincle and CLEC4E receptors, and Dectin‐2 production‐related PRRs mainly include TLRs, RLRs, and NLRs. The
(CLEC6A) receptors. The second type is to activate the receptor by signaling pathways induce downstream IFNs production.42 Upon in-
activating HAM‐like motifs in the intracellular tail of the receptor, such fecting plasma‐like dendritic cells (pDCs), the viral nucleic acids are
as Dectin‐1 (CLEC7A) and DNGR‐1 (CLEC9A).28,29 Both mechanisms recognized by TLR7/TLR9 to induce the production of inflammatory
involve the recruitment of acidified spleen tyrosine kinases, which in cytokines and type I IFNs mediated by NF‐κB and IRF7.43,44 VSV
turn promotes CARD9, B‐cell lymphoid tissue 10 (BcL10), and Maltl infection induces miR‐146a expression in macrophages through the
LI ET AL. | 5

RIG‐I/NF‐κB‐dependent pathway45 and the disorder of the JAK‐ defensins have killing effects on bacteria, fungi, mycoplasma, chla-
STAT signaling pathway directly affects the spread of virus.46 mydia, spirochetes, tumor cells, and viruses.60,61
Although SARS‐CoV and other coronaviruses are sensitive to Defensins of human and rabbit neutrophils are mainly found in the
IFN‐a/b, these viruses remain highly pathogenic. Reportedly, the N eosinophilic granules of neutrophils. They are small molecular cationic
protein of SARS‐CoV acts as an antagonist of immune escape protein polypeptides composed of 29 to 34 amino acid residues, with a relative
and host interferon response.47–49 It is reported that EV71 infection molecular weight of 3500 to 4000 dolt and three intramolecular disulfide
downregulates JAK1, p‐JAK1, and p‐TYK2, inhibits p‐STAT1/2, and bonds. They are main components of the neutrophils independent of
blocks the JAK‐STAT signaling pathway mediated by type I IFNs, oxygen sterilization.62,63 Human α‐defensin HNP‐1 inactivates herpes
thereby hindering the function of IFNs and promoting EV71 simplex virus type I and type II (HSV‐1 and HSV‐2), cytomegalovirus
replication and proliferation in host cells.50 Ebola virus (EBOV) (CMV), VSV, and IAV.64,65 Purified defensins of guinea pigs, rabbits, and
promotes cytokine signal inhibitory factor‐1 (SOCS1) and blocks the rats have weak anti‐HIV‐1 activity.66,67
JAK‐STAT signal pathway by directly binding to phosphorylated JAK, However, some studies showed that purified human neutrophil
resulting in the inhibition of JAK activation.51 In addition, influenza A defensin (HNP1‐3) and rabbit neutrophil defensins (RNP1–5) could
virus can inhibit the IFN‐I downstream pathway by inducing the neither inhibit nor kill SARS‐CoV.68,69
expression of SOCS3.52

3 | ADAP TIVE IMMUNE RE SP ONSES

2.8 | Dendritic cells
3.1 | Immune response of T cells
Dendritic cells (DCs) play a key role in innate immune and adaptive
immune responses. As the strongest antigen‐presenting cells in the or- MERS‐CoV and SARS‐CoV are β‐coronaviruses that can cause fatal lower
ganism, they effectively stimulate the activation of T‐lymphocytes and respiratory tract infections and extrapulmonary manifestations.70–72
B‐lymphocytes, thus combining innate and adaptive immunity. Immature T cells, CD4+ T cells, and CD8+ T cells particularly play a significant
DCs have strong migration ability, and mature DCs can effectively antiviral role by balancing the combat against pathogens and the risk of
activate T cells in the central link of start‐up, regulation, and maintenance developing autoimmunity or overwhelming inflammation.73 CD4+
of immune responses. Thus, once the maturation process of DCs is T cells promote the production of virus‐specific antibodies by activating
blocked, it directly affects the initiation of subsequent adaptive immune T‐dependent B cells. However, CD8+ T cells are cytotoxic and can kill
53–55
responses. DC precursor cells differentiate into DCs by adding such viral infected cells. CD8+ T cells account for about 80% of total in-
inducers as GM‐CSF, IL‐4, and TNF‐α.56 However, DC precursor cells filtrative inflammatory cells in the pulmonary interstitium in SARS‐CoV‐
cannot differentiate into DCs if transfected with HIV‐1 Nef protein in the infected patients and play a vital role in clearing CoVs in infected cells
presence of the inducers, indicating that Nef blocks the differentiation of and inducing immune injury.74 In addition, by comparing T‐cell‐deficient
DC precursor cells into mature DCs. Both the core protein and NS3 BALB/c mice (transduced by ad5‐hdp4) with controls and B‐cell‐deficient
protein of HCV inhibit the expression of CD1a, CD1b, and DC‐SIGN mice, some researchers determined that T cells could survive in the in-
molecules on human peripheral blood mononuclear precursor cells fected lungs and destroy the infected cells.75 It emphasizes the important
(PBMCs), which play an important role in the development of peripheral role of T cells rather than B cells in the control of pathogenesis of MERS‐
57
blood mononuclear precursor cells to DCs. In addition, HIV‐1 attenu- CoV infection. A cross‐reactive T cell response leads to a decrease in
ates the major histocompatibility antigen I (MHC I) on the surface of DCs, MERS‐CoV.76 However, CD4+ T cells are more susceptible to MERS‐CoV
thereby reducing the ability of DCs to present the viral antigens. HIV‐1 infection. The depletion of CD8+ T cells do not affect and delay viral
infection enhances the expression of DC‐specific intercellular adhesion replication at the time of infection with SARS‐CoV.77,78 Depletion of
molecule‐3‐grabbing nonintegrity (DC‐SIGN), thus inhibiting CC chemo- CD4+ T cells is associated with reduced pulmonary recruitment of lym-
kine receptor 7 (CCR7) and MHC‐II, which are important receptors of DC phocytes and neutralizing antibody and cytokine production, resulting in
homing.58,59 These results indicate that virus infection interferes with a strong immune‐mediated interstitial pneumonitis and delayed clearance
the differentiation and function of DCs, hinders the subsequent adaptive of SARS‐CoV from lungs.79 Additionally, T helper cells produce proin-
immune response mediated by DCs, and makes the virus evade the flammatory cytokines via the NF‐kB signaling pathway.80 IL‐17 cytokines
adaptive immune response of the host successfully. recruit monocytes and neutrophils to the site of infection with in-
flammation and activate other downstream cytokine and chemokine
cascades, such as IL‐1, LL‐6, IL‐8, IL‐21, TNF‐β, and MCP‐1.81,82
2.9 | Defensins On the other hand, MERS‐CoV induces T cell apoptosis by acti-
vating the intrinsic and extrinsic apoptosis pathways. A novel BH3‐like
Defensins are a family of endogenous antibiotic peptide molecules, region located in the C‐terminal cytosolic domain of SARS‐CoV protein
which widely exist in human, animals, and plants, and are important mediates its binding to Bcl‐xL and induced T‐cell apoptosis.83 During the
for the host's innate defense system. Defensins have broad‐spectrum later stage of infection, depletion of T cells having antiviral effects may
antimicrobial activities. In vitro inhibition experiments show that prolong the infection and promote viral survival.84
6 | LI ET AL.

The reappearance of SARS‐CoV is still a noteworthy problem. is important to determine whether the antibodies are powerful in the
SARS‐CoV‐specific T cells have been screened in SARS convalescent adaptive immune responses to MERS‐CoV infection. Research from
patients. All the detected memory T cell responses are directed at all over the world have described more than 20 kinds of monoclonal
SARS‐CoV structural proteins. Two CD8+T cell responses to SARS‐ antibodies, most of which are human or humanized antibodies. The
CoV membrane (M) and Nucleocapsid (N) protein are characterized virus uses its spike proteins as an adhesion factor to facilitate host
by measuring their HLA restriction and minimal T cell epitope re- entry through a special receptor called dipeptidyl peptidase‐4
gions. Further, these reactions are found to last up to 11 years after (DPP4). This receptor is considered a key factor in the signal trans-
infection. Absence of cross‐reactivity of these CD8+T cell responses mission and activation of acquired and innate immune responses in
against the MERS‐CoV is also demonstrated.78 infected patients. Thus, compared with the time‐consuming vaccine
Results of the current research show that the T cell response to S preparation, the design of monoclonal antibodies against these pro-
protein and other structural proteins (including the M and N pro- teins has a better protective effect.
teins) is long‐lasting and persistent. This provides evidence for the Human monoclonal antibody (m336) isolated from the phage
design of the SARS vaccine composed of viral structural proteins, display library interacts with the receptor‐binding region of MES
which can induce dominant, effective, and long‐term memory cell coronavirus spike protein and displays strong neutralization activity
responses against the virus. to MES‐CoV in vitro.93 Human monoclonal antibody m336 shows
high neutralization activity to MERS‐CoV in vitro. m336 reduces the
RNA titer of lung by 40 000 to 90 000 folds.94 After infection with
3.2 | Humoral immune responses MERS‐CoV, monkeys were treated with high‐titer hyperimmune
plasma or monoclonal antibody m336. Both groups had relieved
B cell subsets with phenotypes characteristic of naive, non‐isotype‐ symptoms of clinical diseases, but the reduction of respiratory viral
switched, memory cells and antibody‐secreting cells accumulate in load was only found in the hyperimmune plasma group. Although
CoVs.85 The antigen stimulation of MERS‐CoV infection was clarified both super immune plasma and m336 therapy show to mitigate the
by using the specific 9‐mer peptide “CYSSLILDY”, which located at disease of the common marmoset, neither has the ability to prevent
85
position 437 to 445 within the region of the S glycoprotein. The the disease completely.95 Yet, HMab m336 is found to significantly
sequence has the highest B cell antigenicity plot and has the ability to reduce the viral RNA titers and viral‐associated pathological changes
form the greatest number of interactions with MHCI alleles in a in rabbit lung tissue.94 Mice inoculated with S nanoparticles pro-
computerized simulation.86 Reports show that humoral immunity is duced high‐level neutralizing antibodies against homologous viruses,
essential to control the persistent phase of CoV infection. More and these antibodies have no cross‐protection with heteroviruses.96
antibodies isolated from patients who have survived MERS‐CoV in- After being stimulated by SARS‐CoV, immunized ferrets produced
fection have been described, including MCA1, CDC‐C2, CSC‐C5, more rapid and stronger neutralizing antibody reaction than the
CDC‐A2, CDC‐A10, MERS‐GD27, and MERS‐GD33.87–89 control animals; however, the strong inflammatory reaction is ob-
The complement system plays a vital role in the host immune re- served in liver tissue. All this suggests that the expression of SARS‐
sponse to CoV infection. Primitively identified as a host‐sensitive and CoV S protein is associated with enhanced hepatitis.97 On the other
nonspecific complement to adaptive immune pathways, the complement hand, the time course of SARS‐CoV viremia and antibody response
system provides a way for the innate immune system to detect and has been studied.98 SARS‐CoV viremia is not detected in the blood
respond to foreign antigens.90 Given its potential to damage the host samples of convalescent patients. In the peak period of viremia, 75%
tissues, the complement system is tightly controlled by inhibiting proteins of the blood samples of patients diagnosed as SARS in the first 1 to 2
in the serum. Virus encoded proteins help them evade the detection of weeks before detection can detect virus RNA. The prolongation of
the complement system, suggesting that complements are vital to the IgG production may indicate the significance of IgG in both humoral
antiviral response. C3a and C5a have potent proinflammatory properties immune response to acute SARS‐CoV infection and clearance of the
and can trigger inflammatory cell recruitment and neutrophil activation. remaining virus sources during recovery. This is an important subject
C3a and C5a blockade acts as a treatment for acute lung injury, and anti‐ that needs further study.
C5a antibody shows to protect mice from infection with MERS‐CoV.91
SARA‐CoV infection activates the complement pathway and complement
signaling contributes to disease.92 4 | CON CLUSIONS

Since the emergence of SARS‐CoV in 2002 and its spread throughout

3.3 | Antibody responses to coronaviruses' 32 countries and areas, the world has experienced the outbreak of
infections MERS‐CoV and now, the 2019‐nCoV. All these viruses belong to the
subfamily Coronavirinae in the family Coronaviridae. Since CoVs
The antibody response in vivo is a dynamic and complex mixture of emerge periodically and unpredictably, spread rapidly, and induce
monoclonal antibodies (mAbs), which work together to target dif- serious infectious diseases, they become a continuous threat to hu-
ferent antigenic domains on the envelope glycoprotein of the virus. It man health. This is especially true when there are no approved
LI ET AL. | 7

vaccines or drugs for the treatment of CoV infections and there Wenbiao Wang http://orcid.org/0000-0003-4944-764X
exists a range of animal reservoirs for CoVs and recombinant CoVs. Dingwen Hu http://orcid.org/0000-0001-5062-459X
In recent years, profound understandings of the innate immune re- Xiaohong Liu http://orcid.org/0000-0003-4795-3039
sponse to viruses have been made. This type of immune response Qiwei Zhang http://orcid.org/0000-0003-0134-1985
inhibits virus replication, promotes virus clearance, induces tissue Jianguo Wu http://orcid.org/0000-0002-8326-2895
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