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7162
European Review for Medical and Pharmacological Sciences 2021; 25: 7162-7184
A.A. RABAAN1,2,3, A.A. MUTAIR4,5,6, Z.A. ALAWI7, S. ALHUMAID8,
M.A. MOHAINI9,10, J. ALDALI11, R. TIRUPATHI12,13, A.A. SULE14, T. KORITALA15,
R. ADHIKARI16, M. BILAL17, M. DHAWAN18,19, R.K. MOHAPATRA20, R. TIWARI21,
S.A. SAMI22, S. MITRA23, M.K. PANDEY24, H. HARAPAN25,26,27,
T.B. EMR AN28, K. DHAMA29
1Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia
2Department of Public Health and Nutrition, The University of Haripur, Haripur, Pakistan
3College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
4Research Center, Almoosa Specialist Hospital, Al-Ahsa, Saudi Arabia
5College of Nursing, Princess Norah Bint Abdulrahman University, Riyadh, Saudi Arabia
6School of Nursing, Wollongong University, Wollongong, NSW, Australia
7Division of Allergy and Immunology, College of Medicine, King Faisal University, Al-Ahsa, Saudi Arabia
8Administration of Pharmaceutical Care, Al-Ahsa Health Cluster, Ministry of Health, Al-Ahsa, Saudi Arabia
9Basic Sciences Department, College of Applied Medical Sciences, King Saud bin Abdulaziz
University for Health Sciences, Al-Ahsa, Saudi Arabia
10King Abdullah International Medical Research Center, Al-Ahsa, Saudi Arabia
11Pathology Organization, Imam Mohammed Ibn Saud Islamic University, Riyadh, Saudi Arabia
12Department of Medicine Keystone Health, Penn State University School of Medicine, Hershey, PA, USA
13Department of Medicine Wellspan Chambersburg and Waynesboro Hospitals, Penn State
Chambersburg, PA, USA
14Department of Informatics and Outcomes, St. Joseph Mercy Oakland Pontiac, MI, USA
15Department of Internal Medicine, Mayo Clinic Health System Mankato, Mayo Clinic College of
Medicine and Science, MN, USA
16Department of Hospital Medicine, Franciscan Health Lafayette, IN, USA
17School of Life Science and Food Engineering, Huaiyin Institute of Technology, Huaian, China
18Department of Microbiology, Punjab Agricultural University, Ludhiana, India
19The Trafford Group of Colleges, Manchester, UK
20Department of Chemistry, Government College of Engineering, Keonjhar, Odisha, India
21Department of Veterinary Microbiology and Immunology, College of Veterinary Sciences,
Uttar Pradesh Pandit DeenDayal Upadhyaya PashuChikitsa Vigyan Vishwavidyalaya Evam Go
AnusandhanSansthan (DUVASU), Mathura, India
22Department of Pharmacy, Faculty of Biological Sciences, University of Chittagong, Chittagong,
Bangladesh
23Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka, Bangladesh
24Department of Translational Medicine Center, All India Institute of Medical Sciences, Bhopal,
Madhya Pradesh, India
25Medical Research Unit, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Aceh, Indonesia
26Tropical Diseases Centre, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Aceh, Indonesia
27Department of Microbiology, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Aceh, Indonesia
28Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, Bangladesh
29Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar
Pradesh, India
Corresponding Authors: Kuldeep Dhama, MVSc, Ph.D; e-mail: kdhama@rediffmail.com
Talha Bin Emran, Ph.D; e-mail: talhabmb@bgctub.ac.bd
Comparative pathology, molecular pathogenicity,
immunological features, and genetic
characterization of three highly pathogenic
human coronaviruses (MERS-CoV, SARS-CoV,
and SARS-CoV-2)
Comparative review of three human coronaviruses
7163
Abstract. – The last two decades have wit-
nessed the emergence of three deadly coronavi-
ruses (CoVs) in humans: severe acute respiratory
syndrome coronavirus (SARS-CoV), Middle East
respiratory syndrome coronavirus (MERS-CoV),
and severe acute respiratory syndrome corona-
virus 2 (SARS-CoV-2). There are still no reliable
and efcient therapeutics to manage the devas-
tating consequences of these CoVs. Of these,
SARS-CoV-2, the cause of the currently ongoing
coronavirus disease 2019 (COVID-19) pandem-
ic, has posed great global health concerns. The
COVID-19 pandemic has resulted in an unprec-
edented crisis with devastating socio-econom-
ic and health impacts worldwide. This highlights
the fact that CoVs continue to evolve and have
the genetic exibility to become highly patho-
genic in humans and other mammals. SARS-
CoV-2 carries a high genetic homology to the
previously identied CoV (SARS-CoV), and the
immunological and pathogenic characteristics
of SARS-CoV-2, SARS-CoV, and MERS contain
key similarities and differences that can guide
therapy and management. This review presents
salient and updated information on compara-
tive pathology, molecular pathogenicity, immu-
nological features, and genetic characterization
of SARS-CoV, MERS-CoV, and SARS-CoV-2; this
can help in the design of more effective vaccines
and therapeutics for countering these pathogen-
ic CoVs.
Key Words:
Pathology, Immunology, Genetic characterization,
Coronaviruses, MERS-CoV, SARS-CoV, SARS-CoV-2,
COVID-19.
Introduction
The devastating fact that zoonotic diseases at-
tributed to coronavirus (CoV) strains can result
in pandemics came to public attention in 2003
after a severe acute respiratory syndrome coro-
navirus (SARS-CoV) outbreak. Since this re-
alization, scientists and public health ofcials
have raised concerns over health threats posed
to the human population by the three coronavi-
ruses (CoVs) SARS-CoV, Middle East respira-
tory syndrome coronavirus (MERS-CoV), and
severe acute respiratory syndrome coronavirus
2 (SA R S - C oV- 2)1-7. Among at least six strains of
human-infecting CoVs that have been identied
by studies, these three have proved to be highly
pathogenic as they trigger severe pneumonia and
systemic symptoms in humans5,8 -13. CoVs are a
complex and diverse family of enveloped, posi-
tive-sense, single-stranded RNA viruses and are
divided into four genera: alpha, beta, gamma, and
delta CoV8,14,15. Of these, beta CoVs have drawn
the most attention due to their ability to cross an-
imal-human barriers and act as signicant global
infectious agents2, 6,8 ,16. SARS-CoV, SARS-CoV-2,
and MERS-CoV have been identied as the most
important and evolving beta CoVs, and their mo-
lecular biology and immunological features re-
main to be investigated in detail1,4,5,8 ,17-19. Seasonal
variations have been observed in the pattern of
these viruses: SARS-CoV-2 outbreak occurs in
the winter, in contrast to MERS-CoV and SARS-
CoV outbreaks and triggering severe pneumo-
nia18. Moreover, these three viruses show similar
genomic composition, clinical manifestations,
and route of transmission1,4, 20. The current pan-
demic of coronavirus disease 2019 (COVID-19)
caused by SARS-CoV-2 has apparent similari-
ties with SARS9,10, 21, including disease progres-
sion, escape from the host immune system, and
subsequent acute respiratory distress syndrome
(ARDS). The International Committee on Tax-
onomy of Viruses (ICTV) designated the causal
agent of COVID-19 as “SARS-CoV-2” due to its
similarities with SARS-CoV19,22-2 4.
During the COVID-19 pandemic, the world
has experienced unprecedented challenges, with
over 4.9 million deaths and more than 243 mil-
lion conrmed cases of SARS-CoV-2 infection in
over 225 countries with a fatality rate ranging be-
tween 1.5% and 5% as of October 26, 202117,22,25.
A high case fatality rate of about 49%9,26 has been
reported in patients with an acute disease requir-
ing ventilator support and Intensive Care Unit
(ICU) admission. There have been signicant
breakthroughs in vaccine development, with sev-
eral vaccines administered globally for protection
against SARS-CoV-2. In addition, many effective
drugs and therapeutic candidates are being eval-
uated, such as antivirals, monoclonal antibodies,
cytokine inhibitors, and immunosuppressants27-32 .
SARS-CoV-2, when observed under an electron
microscope, has a structure similar to a crown (co-
rona). The mechanism of virus entry into the host is
identical to that of SARS-CoV, which binds to the
human angiotensin-converting enzyme 2 (ACE2)
receptor via its protein receptor-binding domain
(R BD)33-3 5. In contrast, MERS-CoV binds to the
DPP4 receptor to enter host cells. Genomic analysis
data has revealed that the genome sequence simi-
larity of SARS-CoV-2 to SARS-CoV and MERS-
CoV is 80% and 50%, respectively21,36 . While ex-
ploring the evolutionary potential of SARS-CoV-2,
studies have found that its genome exhibits 96%
A.A. Rabaan, A.A. Mutair, Z.A. Alawi, S. Alhumaid, M.A. Mohaini, J. Aldali, R. Tirupathi, et al
7164
similarity to that of bat-derived CoV isolated in
201337,38 . SARS-CoV-2 and SARS-CoV have 380
amino acid (AA) substitution sites. It has been hy-
pothesized that any substitution in the AA sequence
could lead to a possible novel viral protein function
with unclear pathogenesis39. The spike (S) protein
and the nucleocapsid protein are linked to higher
transmission capability and lower pathogenicity
in SARS-CoV-2. However, the mutations in the S
protein are especially crucial because the S protein
is key for the rst step of viral transmission: entry
into the cell by binding to the ACE2 receptor40-44.
SARS-CoV-2 steadily mutates during continuous
transmission among humans, and naturally occur-
ring S mutations can reduce or enhance cell entry
via the ACE2 receptor44,45. According to a recent
study46, six AA residues (D480, T487, Y442, N479,
L472, and Y4911 for SARS-CoV, and Q493, S494,
L455, F486, Y505, and N501 for SARS-CoV-2) are
essential for binding to the human ACE2 receptor.
Among these six SARS-CoV-2 AA residues, the
lack of similarity of ve residues to those of SARS-
CoV may be attributed to the deletions, insertions,
or mutations in the S1 and S2 regions, which are
responsible for evolutionary changes4 6,47. The nov-
el strain has an evolutionary path different from
those of MERS-CoV and SARS-CoV, with lin-
eage similarity to previously evaluated bat-derived
CoV. However, there are proteomic and genomic
differences between the bat and human CoVs, in-
dicating a unique immune invasion mechanism
and a distinct immunopathology associated with
host response48. The common clinical symptoms
of COVID-19 are similar to those of SARS: dry
cough (67.7%), fever (87.9%), myalgia (34.8%), fa-
tigue (69.6%), hypoxia, and progressive dyspnea
followed by damage to multiple organs. In contrast
to SARS-CoV, SARS-CoV-2 is more transmissi-
ble, but the overall mortality rate is lower than that
for SARS-CoV infection. Like MERS and SARS,
COVID-19 is likely to be more severe in elderly
people and those suffering underlying comorbid-
ities, including many chronic health conditions.
Here, we present salient and updated information
on comparative pathology, molecular pathogenic-
ity, immunological features, and genetic charac-
terization of SARS-CoV, MERS-CoV, and SARS-
CoV-2. As the current pandemic remains ongoing,
this review can contribute to the design of more
effective vaccines and therapeutics.
Early Phase of Viral Infection
In the early stages, SARS infection causes
non-specic symptoms such as myalgia, fever,
headache, and severe fatigue49. These symptoms
tend to diminish in seven days. Sequential naso-
pharyngeal aspirate samples from SARS patients
indicate a direct relationship between clinical pro-
gression and viral load50. After its peak, viral load
usually decreases rapidly, with IgG seroconver-
sion serving as an indicator of specic immunity
development. However, some patients’ clinical
conditions can worsen during this period, creat-
ing inconsistencies with viral clearance observa-
tions. Delay in viral peak can indicate absence or
hindrance of host antiviral responses necessary to
enhance viral clearance51.
A retrospective study evaluating the cause of
worsening clinical condition after viral load re-
duction highlighted the underlying association be-
tween viral clearance, immune dysregulation, and
disease development52. The host hyper-inamma-
tory response, not the cytopathic effect of the vi-
rus, may be responsible for this phenomenon36 ,51.
To some extent, rapid viral load elevation could
be the contributing factor for disease pathology.
Clinical features such as diarrhea, oxygen desat-
uration, hepatic dysfunction, and fatality indicate
that high viral load may contribute to direct organ
dysfunction49,53. Clinical specimens of various
anatomic sites of organ dysfunction have yielded
virus. For instance, stool specimen was highly re-
lated to diarrhea, with viral particles detected in
ileum and colon biopsies observed under an elec-
tron microscope54. There is extensive evidence
regarding the relationship between pathological
effects, viremia, and viral loads from these nd-
ings. Strong evidence exists of high viral loads
associated with massive inltration of the inam-
matory immune cells being signicantly linked
to worse clinical outcomes in patients54. Patients
with elevated viral load at an early stage were also
likely to have higher mortality55 ,56. Therefore, it
is essential to address the molecular pathology,
immunological characteristics, pathogenicity,
and genetic sequence of MERS-CoV, SARS-CoV,
SARS-CoV-2, and other CoVs. A few of the gen-
eral characteristics of MERS-CoV, SARS-CoV
and SARS-CoV-2 are presented in Table I.
Genetic Similarities of MERS-CoV,
SARS-CoV, and SARS-CoV-2
Among the CoV subtypes, beta CoVs cause
severe and fatal diseases in humans, while al-
pha CoVs cause mild infections. The genom-
ic sequences of MERS-CoV, SARS-CoV, and
SARS-CoV-2 are quite similar, but SARS-CoV-2
displays signicant differences in genome com-
Comparative review of three human coronaviruses
7165
position compared to its predecessors57. Genom-
ic analysis suggests that SARS-CoV-2 is closely
related to pangolin CoV (86%-92%) and bat CoV
(96%), which further suggests bats as the prima-
ry reservoir43,58 -60. Furthermore, the outbreak of
SARS-CoV-2 is thought to be linked to trading
practices in Wuhan’s wet market, and due to
the genetic identities between SARS-CoV-2 and
BatCoV RaTG13 (a bat-CoV), it has been hy-
pothesized that bats could be the natural source
of S A R S - CoV-2 8, 43,61. A plethora of research ev-
idence shows that pangolins may be the inter-
mediate host—there is 99% homology between
SARS-CoV-2 and the CoV strain originating from
pangolins—but bats are the natural reservoir for
the virus62, 63. Bats are generally recognized as
potential primary reservoirs for most of the RNA
viruses64. The genome of SARS-CoV-2 showed
96.2% homology to that of the bat CoV (RaTG13)
collected in the Yunnan province of China43. The
SARS-CoV-2 genome is closely related (88%) to
zoonotic bat viruses, bat-SL-CoVZXC45, and bat-
S L- C oV Z XC 2165. The most commonly identied
sequence similarity between these bat and human
viruses is in the E gene, and the least common-
ly identied similarity is in the S gene. Multiple
SARS-CoV-2 proteins have the same sequence
as the bat-SL-CoVZC45 and bat-SL-CoVZXC21,
except for the S protein and protein 1366. A team
of researchers concluded that pangolin-CoV is a
highly associated descendant of SARS-CoV-2,
suggesting that pangolins could be the natural
reservoirs for SARS-CoV-2 and bat CoV67. The se-
quence similarity (89.2%) between SARS-CoV-2
and RaTG13, in terms of the RBD, is less than
the sequence similarity (97.2%) between SARS-
CoV-2 and pangolin-CoV. Additionally, the latter
contains six complete identical RBD residues,
whereas the former contains only one identical
amino acid residue43. Notably, pangolins in Chi-
na are categorized as endangered due to their
decreasing numbers, which are close to the point
of extinction; this reduces the likelihood of pan-
golins acting as an intermediate host of SARS-
CoV-2. The selling of pangolins is against the law,
and they have not been spotted in Wuhan’s wet
markets in recent times68. Through the use of the
optimized random forest model for human se-
quences of MERS-CoV and SARS-CoV, interme-
diate hosts (Camelids and Carnivores) were con-
rmed based on evolutionary signatures. With the
same method, SARS-CoV-2 evolutionary signa-
tures identied bats as hosts, further conrming
bats as the suspected origin of the present pan-
demic69. Furthermore, a recent study70 based on
genetic similarities proposed that snakes may be
intermediate hosts, as there are similarities in co-
dons among SARS-CoV-2, bat CoV, and a snake
virus. However, this analysis was insufcient to
reach a conclusive hypothesis, as several limita-
Table I. Characteristics of MERS-CoV, SARS-CoV and SARS-CoV-2.
Features MERS-CoV SARS-CoV SARS-CoV-2
Outbreak 2012, April 2002, November 2019, December
Location of the rst case Jeddah, Saudi Arabia Guangdong, China Wuhan, China
Key hosts Bat, camel Bat, palm civets,
raccoon dogs Bat, pangolin
Active cases conrmed 2519 (from 2012 until 8096 Over 243 million
January 31, 2020) (as of October 26, 2021)
Genome length (bp) 30,119 29,751 29,903
Mortality 34.40% 10% (6.8-16.1%) 2-5%
Days took to infect the rst 1000 persons 903 130 48
Incubation period (day) 5 to 6 2 to 7 7 to 14
Basic reproduction number (R0) 1 2-4 1.4-5.5
Receptor DPP4 ACE2 ACE2
Mode of transmission Touching or consumption Believed to have Human-to-human
of camel milk or meat. spread on close contact
There is limited human-to-human from bats. transmission occurs when
transmission despite close There is evidence there is close physical
physical contact of human-to-human contact (mainly
transmission through respiratory aerosols/
droplets). The transmissions
may be possible through
fecal-oral route
and contaminated
objects/ surfaces/fomites
A.A. Rabaan, A.A. Mutair, Z.A. Alawi, S. Alhumaid, M.A. Mohaini, J. Aldali, R. Tirupathi, et al
7166
tions were present in the study71. In any case, beta
CoVs are less likely to infect reptiles by crossing
over through mammals72. These ndings made
the natural reservoir of CoV a controversial topic,
and a contingent of groups embrace the idea that
different intermediate host species are yet to be
discovered, other than bats73 -75. The disease out-
break related to SARS-CoV-2 demonstrates con-
cealed virus reservoirs in animals that may spread
into human populations occasionally76. The lower
effective number of codons and the extreme co-
don usage bias of SARS-CoV-2 in S, envelop, and
matrix protein genes suggest higher gene expres-
sion efciency than that of SARS, bat SARS, or
MERS-CoV, which is similar to Pangolin beta
CoV77. In the human host, the SARS-CoV-2 dinu-
cleotide pair, UpG and CpA dinucleotides, were
highly preferred, and CpG dinucleotide was high-
ly avoided. This strategy might imply evasion of
the human immune system78. Multiple sequence
alignments of the ACE2 receptor proteins of hu-
mans with that of dogs, cats, tigers, minks, and
other animals revealed a high homology and full
conservation of the ve AA residues, 353-KGD-
FR-357, among the species, which may throw
light on the possibility of transmission of SARS-
CoV-2 from animals to humans78.
MERS-CoV is closely related to two bat CoV
(HKU4, HKU5); it has been suggested that it
may be isolated from bats, and dromedary camels
probably act as intermediate host, as evidenced
from serological studies79,80 . In Qatar, the pres-
ence of MERS-CoV RNA was reported in swabs
obtained from dromedary camels that shared a
correlation with two human cases of MERS81. A
comprehensive evolutionary relationship analysis
depicted the origin of MERS-CoV from bats due
to the occurrence of recombination events within
S and ORF1ab genes82,83. Recombination events
were also reported in SARS-CoV as regions for
putative recombination were detected via com-
putational genomic studies84. The MERS-CoV
strains isolated from humans and camels have
been reported to share over 99% identity with
variations located in the ORF3, ORF4b, and S
genes85. SARS-CoV-2 shows 80% similarity with
SARS-CoV and 51% with the MERS-CoV86.
Most of the coding areas of SARS-CoV-2 indi-
cate a similar genomic architecture to that of the
bat-originating CoVs and SARS-CoV. The twelve
coding regions predicted are; lab, 3, E, M, 7, 8, 9,
10B, N, S, 13, and 14. The proteins encoded by
all the three CoVs are mostly similar in length87.
However, there is a signicant variation in the S
protein of SARS-CoV-2, which is longer in com-
parison to the protein encoded in the bat CoVs,
SA RS- C oV, and MERS-CoV88.
SARS-CoV-2 shares many similarities in ar-
chitecture and pathogenicity with SARS-CoV
compared to MERS-CoV. Mathematical mod-
els such as decision-tree experiments have also
shown remarkable characteristics of an AA se-
quence of SARS-CoV-2, which is different from
M E RS - C oV 12. The CoVs use a similar S protein
for binding to their respective host cells and the
same cellular protease enzyme for the activation
of the S protein89. The S protein in SARS-CoV-2
has a sequence similarity of about 77% with that
of SARS-CoV, structural proteins are more than
90% similar to SARS-CoV, and 32.79% similar to
MERS-CoV counterparts. The receptor-binding
domain (S2) of SARS-CoV-2 has a sequence sim-
ilarity of 74% with the S2 domain in SARS-CoV
and an overall similarity of about 52% with that
of S A R S - CoV90. The E protein of SARS-CoV-2 is
96.00% similar to that of SARS-CoV and 36.00%
similar to that of MERS-CoV. The M protein of
SARS-CoV-2 is 89.59% similar to that of SARS-
CoV and 39.27% similar to that of MERS-CoV.
The SARS-CoV-2 N protein is 85.41% similar to
that of SARS-CoV and 48.47% similar to that of
MERS- C oV 91.
Accessory proteins are regarded as essential
for in vitro replication of viral particles; however,
some of these proteins are associated with viral
pathogenesis92,93. The 3CLpro (nsp5) and RdRp
(nsp12) proteins of SARS-CoV-2 are prime me-
diators of replication and new virion production,
and they share high sequence identity with SARS-
CoV and M ERS-CoV94. Recent reports95,96 have
demonstrated that ORF8b and ORF3a of SARS-
CoV catalyze the induction of proinammatory
cytokines and thus play a role in regulating che-
motaxis in macrophages. ORF8b of SARS-CoV
and MERS-CoV is also involved in suppressing
the induction of interferon (IFN-I)97,9 8. Another
study demonstrated that ORF8 of SARS-CoV-2
variant binds to major histocompatibility complex
(MHC) and regulates its degradation in cell cul-
ture, indicating that immune evasion may be me-
diated by ORF8. However, SARS-CoV-2 ORF8
shows low homology to SARS-CoV ORF899.
Generally, no homologous accessory proteins
are found in CoV genera. However, some simi-
lar kinds of proteins might be present in closely
associated CoVs. For instance, SARS-CoV-2 and
SARS-CoV show over 80% similarities in OR-
F3a, 6, 7a, 7b, and 9b protein sequences.
Comparative review of three human coronaviruses
7167
Comparative Molecular Pathology of
MERS-CoV, SARS-CoV, and SARS-CoV-2
Infection
SARS-CoV is considered a zoonotic virus
that was transmitted to humans from birds pri-
or to human-to-human transmission100 . However,
in humans, various risk factors including age,
underlying metabolic disease like diabetes, and
heart disease, lead to an increase in death risk101.
SARS starts with viral infection in the respiratory
tract of people of all ages via droplet transmis-
sion of virus present in the mucus or saliva102. It
was reported that viral loads of SARS-CoV de-
creased with increased severity of the disease.
On the contrary, a similar trend is still unclear
fo r M E R S - CoV103. Clinical symptoms associated
with SARS-CoV infection include fever, chills,
diarrhea, myalgia, and fatigue104. SA R S - C oV e n -
ters into the human cell through the attachment
of viral S glycoprotein (S protein) to the ACE2
receptor. ACE2 functions as a dominant host re-
ceptor, and the presence of two co-receptors, DC-
SIGN (CD209) and L-SIGN (CD209L), are also
reported105,106. In dendritic cells, viral infection
does not occur prior to DC-SIGN binding, but this
binding may enhance SARS-CoV infection and
dissemination substantially. On the other hand,
L-SIGN is considered an alternative receptor that
may bind with its spike protein and regulate cel-
lular entry of SARS-CoV107. Changes occur in the
S glycoprotein in the endosomal environment via
the serine protease cathepsins B and L to assist
in the union process108. The S glycoprotein is not
just an essential structural protein of CoVs; it per-
forms a vital role in the association of virus with
the host cell. The S- protein is made up of two
subunits: S1 and S210 9. The S1 subunit contains the
RBD, which is responsible for binding the virus
to the host receptor, while the S2 subunit controls
membrane fusion occurring during virus-host
membrane interactions. These interactions lead
to the penetration of the viral genome into the cy-
toplasm of the host cell110. SARS-CoV-2 encodes
a longer S protein compared to SARS-CoV and
MERS-CoV, as identied by phylogenetic analy-
sis20 ,76. The RBD of SARS-CoV, MERS-CoV, and
SARS-CoV-2 binds to functional receptors pres-
ent on the cellular surface, allowing penetration of
the virus into host cells111. SARS-CoV and SARS-
CoV-2 predominately utilize angiotensin-convert-
ing enzyme 2 (ACE2) as a host receptor105, 110,111.
Additionally, viral entry by antibody-depen-
dent enhancement (ADE) has been observed112.
Through ADE, the B cell producing antibodies
may also expedite viral infection113. Surprising-
ly, ACE2 exhibits stronger afnities for SARS-
CoV-2 compared to SARS-CoV114. For instance,
the interaction between host ACE2 and SARS-
CoV-2 spike ectodomain displayed 10- to 20-fold
higher binding afnity than that for SARS-CoV
in a recent study115. Another study speculated that
SARS-CoV-2 could use other cellular receptors
and proteins to bind with host cell receptors such
as integrins116. However, there is to date insuf-
cient evidence to corroborate this assumption.
CD147-SP can be considered another entry portal
of S A R S - CoV-2117. In addition to attachment of S
proteins to functional host receptors, priming of
S proteins is necessary for invading the cellular
machinery of the host118.
Apart from lung cells, the heart, kidney, liver,
and tongue also express ACE2 receptors on their
epithelial cells119,12 0. In fact, cilia could be the entry
gate of the virus121. Surprisingly, after the S gly-
coprotein attaches to ACE2, there is a signicant
cilia loss, squamous cell metaplasia, and elevated
macrophage migration into the alveoli, causing
notable damage to alveoli in the lungs. Addition-
ally, SARS-CoV generates 7a and 3a proteins that
lead to substantial programmed death of cells in
the lungs, liver, and kidney122. Host translation
elongation factor 1 (EF-1A) and serine protease
2 strongly bind to N protein of both SARS-CoV
and MERS-CoV, and subsequently induce local
or systemic inammatory responses94. TH1 acti-
vation also causes increased inammation in the
affected organs. MERS-CoV infection is more
common in males than females123, and SARS-
CoV and SARS-CoV-2 infection follow the same
order of gender prevalence8. Clinical presentation
of infection may range from being asymptom-
atic to massive organ damage. Notably, MERS
is closely associated with metabolic syndromes
such as diabetes mellitus, obesity, and cardiovas-
cular morbidities124. The developing metabolic
syndrome in most cases alters the immunological
function, exposing the infected person to further
risk of more infections.
Many previous investigations reported that
CoV infection leads to cytopathic effects, includ-
ing cell lysis and apoptosis. Cellular fusion is
caused by the virus and usually leads to syncytia
formation. These processes are observed in the
cell due to the mobilization of vesicles that form
the replication complex and cause disruption of
Golgi complexes at the time of viral replication94.
Unlike in SARS-CoV, DPP4 CD26 is the MERS-
CoV attachment site to lung and respiratory tract
A.A. Rabaan, A.A. Mutair, Z.A. Alawi, S. Alhumaid, M.A. Mohaini, J. Aldali, R. Tirupathi, et al
7168
epithelial cells125. Notably, MERS-CoV carries a
particular RBD in its S glycogen that binds DDP4
on the host cells. DPP4 plays a signicant role
in altering glucose metabolism, activating the
T cells, modulating cytotoxicity, and regulating
apoptosis126. SARS-CoV-2 infects both the lower
and upper respiratory systems and multiple other
organs and systems, thus causing multiple patho-
logical conditions, including neurological and
gastrointestinal manifestations and kidney dam-
age127-129. ACE2 receptors are abundant in oral
mucosa, nasal secretory and ciliated cells, lower
airways, lungs, cornea, ileum, and colon. Hence,
patients suffer from collapsed lung and symptoms
of diarrhea130,131. When spike D614 is replaced by
mutant G614, S protein possesses greater stability
and a potential to grow at a temperature of 37oC,
compared to early SARS-CoV-2 isolates, which
showed a preference for 33oC132. While SARS-
CoV-2 is less pathogenic than MERS-CoV or
SARS-CoV, its human-to-human transmission is
faster1,4,133. Underlying illnesses (comorbidities)
such as heart disease, diabetes, and hypertension
have a close association with the severe patho-
genesis of SARS-CoV-2 in affected patients134.
These disorders reduce the generation of IFN and
interleukin that leads to the downregulation of
the host’s innate immunity via blockage of lym-
phocyte and macrophage functions. In healthy
people, ACE2 alters the renin-angiotensin system
through angiotensin-II breakdown into angioten-
sin-17 to prevent the development of acute lung
failure135. Acute lung injury is directly related
to a deciency in ACE2 and an increase in Ang
II136,137. Postmortem analysis of SARS-CoV-2 pa-
tients has revealed pneumocyte hyperplasia and
partial brosis leading to thickening and collapse
of alveoli93,138
The sgRNAs are presumed to be translated into
accessory and structural proteins of CoV in the
cytoplasm. A recently concluded in vitro study
indicated that the enzymatic function of the nsp14
exoribonuclease (ExoN) is crucial for replication
of SARS-CoV-2 and MERS-CoV139. By enhanc-
ing degradation and interfering with host mRNA
translation, beta CoV nsp1 inhibits the expression
of host genes and thus serves as a potent virulence
factor140. MERS-CoV nsp1 inhibits mRNA trans-
lation and induces mRNA degradation by selec-
tively targeting nuclear mRNA translation and
avoiding cytoplasmic viral mRNAs141. Current
structural analysis and related studies have un-
veiled that SARS-CoV-2 nsp1 inhibits ribosomal
mRNA entrance14 2. The delta CoVs and gamma
CoVs cannot produce nsp1 due to lack of nsp1/
nsp2 cleavage sites, though the same host shutoff
is triggered by other mechanisms that have not
been explored well.
Clinical and Immunological Features of
MERS-CoV, SARS-CoV, and SARS-CoV-2
Infection
MERS is currently a common human corona-
virus (hCoV) infection. MERS-CoV infection has
lower transmissibility than the other two CoVs
but causes severe symptoms, leading to a high-
er case fatality rate40. Like SARS-CoV patients,
patients with MERS-CoV usually show milder
symptoms initially and later develop dyspnea and
complications leading to respiratory failure, with
most of the patients (63.4%) developing lethal
pneumonia25. Organ function later deteriorates,
leading to fatality within two weeks after infec-
tion48. Prominent comorbidities associated with
mortality among MERS-CoV patients are diabe-
tes and renal failure, which result in poor health
outcomes. To better understand the pathogenesis
and immunological features of MERS-CoV, it is
essential to undertand its comparative analysis
with SARS-CoV infection1,4.
Unlike the SARS-CoV abortive mechanism
of infection, MERS-CoV multiplies in lympho-
cytes, dendritic cells, and macrophages52,5 4,55,143.
Viral genomes, nucleoprotein expression, and vi-
ral particles are detectable in virus-infected cells.
Viral multiplication in macrophages and dendritic
cells indicates that host cells are the source of vi-
ral reservoirs thwarting host immunorecognition
of the virus55. MERS-CoV has been reported to
induce greater transcriptomic changes than those
induced by SARS-CoV88. Cells carrying the virus
facilitate systemic dissemination of the infection
to lymph nodes. Naïve T cells interact with the vi-
rus and trigger adaptive immune responses. This
leads to the release of massive amounts of cyto-
kines and chemokines. The diverse activation av-
enues that trigger production of cytokines during
MERS-CoV infection cause a distinct cytokine
prole compared to SARS-CoV infection88,14 4.
The reason for productive replication is the
high number of DDP4 receptors expressed in the
dendritic and monocyte cells compared to the
expression level of ACE2 receptors. This results
in differential infection outcomes. MERS-CoV
can infect cells from different human cell lines
in ex-vivo studies36, 145. DDP4 receptors are identi-
able in endothelial and epithelial cells present in
the prostate, liver, kidney, and intestines41, 42. Dis-
Comparative review of three human coronaviruses
7169
semination of the virus throughout the body was
observed in patients with MERS-CoV infections,
explaining the high incidence of systemic events
like multi-organ failure and septic shock. Another
important immunopathological feature is the an-
tibody-dependent enhancement (ADE) conrmed
in MERS- C oV146. The underlying mechanism is
linked to the enhanced membrane fusion pro-
cess. The interactions of antibodies and RBD of S
protein tend to elevate proteolytic susceptibility,
leading to conformational changes in the target
host cells55. The binding Ab enhances virus entry
via canonical receptor-dependent pathways.
Only three cytokines (IL-6, IP-10, and IFN-γ)
display a marked increase in SARS-CoV, MERS-
CoV, a nd S A R S - CoV-2 35. SARS-CoV shows sig-
nicant IFNantagonism, while the MERS-CoV
has minor antagonist characteristics that lead to
enhanced sensitivity to IFN-I antiviral respons-
es147. Furthermore, due to differences in the vi-
ral proteins among these human CoVs, SARS-
CoV-2 is more sensitive to IFN-I-dependent
antiviral response compared to other CoVs. In
fact, the levels of IFN-I and IFN-III in patients
with SARS-CoV-2 infections are reduced, un-
like that in patients infected by SARS-CoV and
other respiratory viruses144. MERS-CoV shares
similar viral evasion strategies and IFN antago-
nism with SARS-CoV. As a result, MERS-CoV
tends to decrease upregulation of antiviral inter-
feron-stimulated gene (ISG) responses through a
novel approach, resulting in the induction of re-
pressive histone modications in the host cells.
Similar histone modications, which mediate
several biological events such as gene regulation,
were identied in patients with H5N1 u infec-
tion52 . Inhibition of transcription factor binding
is controlled by modifying the basal state of
host chromatin, where genes are packed. This
mechanism is linked to low ISG expression in
IFN-administered MERS40. As in patients with
SARS-CoV infection, levels of IFN-I in MERS-
CoV infected patients are attenuated, and their
rate of increase is slowed. The absence of IFN-I
resulted in a lack of marked lung immunopa-
thology in studies. It also improved the clinical
outcomes compared to the delayed IFN-1 group,
suggesting an atypical IFN-I effect linked to
SARS infection36 ,37, but there were adverse out-
comes linked to MERS-CoVinfection. In this
respect, early IFN administration improved the
protection of mice from severe infection, irre-
spective of down-regulation of cytokine-related
genes and ISG.
In seriously ill patients with MERS-CoV, the
inability to activate Th1 cells reduces IFN-γ
production, leading to activated natural killer
(NK) cells and CD8+ T cells. This generates an
uncontrolled immune response and attenuates
viral clearance36,4 3,148 ,149. Extensive CD8+ T-cell
responses were noted in critically ill patients
during the acute phase, indicating no benet as-
sociated with hyper-activated T-cell responses150.
The acute-phase T-cell response for SARS-CoV
corresponds to that for MERS-CoV. The absence
of T-cell response activation during the innate re-
sponse provided sufcient enhancement of host
survival and improved disease outcome. Addi-
tionally, the adaptive immune response against
MERS-CoV infection showed positive effects
relative to those observed against SARS-CoV in-
fection151.
Concentration of certain inammatory cyto-
kines and chemokines (CXCR3, SOCS5, IL-1β,
IL-8, IL-15, IL-17, CCR2, IL-1α, IP-10, TNF-α,
and IFN-γ) was reported to increase during
MERS-CoV infection144,1 52. In terms of cytokines,
MERS-CoV-associated IL-17 expression demon-
strated signicant upregulation compared to that
associated with SARS-CoV. Secretion of IL-17 by
CD4+ T cells can produce extensive pro-inam-
matory effects on host cells54 ,153. IL-17 expression
is known to aggravate respiratory syncytial virus
(RSV). In MERS-CoV, IL-17 expression tends to
induce immune-mediated pathology, resulting in
an elevated mortality rate143. Patients with MERS-
CoV infection exhibit higher and more prolonged
production of cytokines compared to those with
SARS-CoV infection20.
The SARS-CoV-2 pandemic has resulted in
devastating outcomes in the 21st century because
of high transmissibility and viral-shedding prop-
erties6,22. COVID-19 patients show clinical symp-
toms that resemble u during the onset of the dis-
ease, including myalgia, fever, and dry cough128 ,154.
Symptoms such as rhinorrhoea, pharyngalgia, al-
veolar edema, amblygeustia, shortness of breath,
dry mouth, nausea, and vomiting have also been
recorded in a small number of COVID-19 pa-
tients4,155-157. The laboratory ndings obtained
from patients infected by SARS-CoV, MERS-
CoV, and SARS-CoV-2 are markedly similar; the
most common abnormal ndings include throm-
bocytopenia and lymphocytopenia. Additionally,
signicant elevation in serum levels of alanine
aminotransferase, lactate dehydrogenase, aspar-
tate aminotransferase, and C-reactive protein
have been recorded158-16 0. In severely affected pa-
A.A. Rabaan, A.A. Mutair, Z.A. Alawi, S. Alhumaid, M.A. Mohaini, J. Aldali, R. Tirupathi, et al
7170
tients, coagulation disorders, where D-dimer lev-
el is elevated and prothrombin time is prolonged,
are commonly observed161. Meanwhile, elevation
in the creatine kinase and serum creatinine lev-
el were reported in some patients, largely those
infected with MERS-CoV158- 160. Furthermore, a
large number of COVID-19 cases with gastroin-
testinal symptoms such as extreme diarrhea have
been recorded in numerous laboratories, imply-
ing that the virus is replicating in the digestive
system and viral particles are shed via stool162,16 3.
In addition, the sheer volume of ACE2 recep-
tors in the bile duct relative to the alveolar cells
contributes to the hypothesis that infection with
SARS-CoV or SARS-CoV-2 causes serious liv-
er damage164 -166. SARS-CoV-2 infection has also
been linked to neurological symptoms in several
recent studies. Moreover, in some cases, SARS-
CoV-2-RNA has been reported in cerebrospinal
uid167,16 8. The involvement of ACE2 receptors in
the central nervous system (CNS) has been con-
nected to neurological symptoms such as stroke,
polyneuropathy, acute encephalitis, anosmia, age-
usia169, 170, and brain inammation associated with
COV ID-19168 ,171. In previous studies, patients with
COVID-19 were evaluated for symptoms such as
anosmia and dysgeusia, and a high percentage
(approximately 75%) revealed alteration in the
senses of smell and taste172 ,173.
Cerebral arteriopathies and ischemic vascular
stroke have been attributed as the direct effects
of SARS-CoV-2 on ACE2 receptors of endothelial
cells and as indirect effects of misdirected host
immune response174. Neuro-opthalmic manifes-
tations of COVID-19 syndrome are also increas-
ingly recognized175,176 . SARS-CoV-2 has recently
been shown to infect different cells of the renal
system, including tubular epithelial cells and
podocytes, through direct tropism and indirect
action by induction of cytokine storm and other
mechanisms, resulting in a variety of renal ab-
normalities, including acute kidney damage, and
higher mortality177- 180. Several studies have linked
COVID-19 to impaired kidney function during
the course of COVID-19 progression. In seriously
ill patients with COVID-19, numerous renal dis-
orders such as proteinuria, hematuria, and acute
kidney failure (AKF) have been identied181-184.
According to current observational evidence,
AKF is one of the most important causes of ill-
ness and death in SARS-CoV-2 patients, second
only to ARDS185.
Secondary bacterial and fungal infections ob-
served in patients infected with COVID-19 have
been implicated to further complicate the severity
of the disease, constituting an important factor,
especially for high-risk patients186,18 7. Even the
microbiota, such as the bacterial microbiome,
virome, and fungal microbiome, are found to af-
fect the natural course of SARS-CoV-2 infection,
along with comorbidities such as diabetes and hy-
pertension188-19 0. Additional manifestations under-
stated during the COVID-19 epidemic, including
psychological illnesses such as depression, anxi-
ety, and sleep disorders191 and skin disorders such
as urticaria, rashes, erythema, and acro-ischemic
lesions, also should be considered192. All the
above COVID-19 manifestations are either the di-
rect results of SARS-CoV-2 multiplication or of
the indirect hyperinammatory condition known
as macrophage activation syndrome or cytokine
storm. This syndrome leads to increased produc-
tion of IL6, IL7, and TNF-alpha and inammato-
ry chemokines such as CCL2, CC13, and CXC10,
as well as elevated amounts of serum ferritin,
D-dimer, and chronic reactive protein; however,
evidence for inammasome activation is not pres-
ent as IL1β production is not elevated193-195.
Chronic cough is common in long COVID
(post-COVID syndrome) after SARS-CoV-2 in-
fection and may be associated with the vagal
sensory neurons and/or neuroinammatory re-
sponse. Mechanisms of post-COVID-19 chronic
cough and optimal management are still unclear.
New anti-inammatory drugs or neuromodula-
tors (gabapentin or opioids) could be considered
for treatment; however, randomized studies are
highly recommended to analyze the safety and
efcacy of these potential treatments196. Gunst
et al197 have performed a randomized trial to un-
derstand the safety and efcacy of TMPRSS2
inhibitors in COVID-19 patients and found that
TMPRSS2 inhibitors or camostat mesylate may
be effective in the early phase of the disease and
lowers the risk of disease progression; howev-
er, this treatment is not effective for severely ill
and hospitalized patients. According to another
recent study, saliva and nasal swabs offered the
best diagnostic performance and may be used as
an alternative specimen collection method for di-
agnosing SARS-CoV-2 infection198,199.
An overview of comparative clinical mani-
festations in patients with MERS, SARS, and
COVID-19 is presented in Table II.
Pathological studies on SARS-CoV-2 demon-
strate increased inltration into an infected per-
son’s lung tissues154,206 . Viral particles/macro-
phages/inammatory cells have been identied in
Comparative review of three human coronaviruses
7171
the bronchoalveolar uid (BALF) of COVID-19
patients103,207,208. SARS-CoV-2 also targets both
types of pneumocytes (I and II), similar to SARS-
CoV20 9. Monocyte-derived macrophages are pres-
ent at high levels in the BALF, constituting 80%
of the inltrated cells observed in severely sick
patients210. Various forms of activation of mono-
cyte-originating macrophages have been noted211.
ACE2 receptor expression on the surface revealed
that entry-binding receptors for SARS-CoV-2
could be detected in alveolar macrophages, indi-
cating the possibility of this path in the entry of
SARS-CoV-2. From these ndings, there is suf-
cient evidence that monocytes are essential in
the cytokine storm and lung pathology103,212 . The
pro-inammatory classically activated phenotype
(M1) identied in wound-healing can activate the
phenotype (M2) that leads to inammatory tissue
injuries and the development of brotic lesions in
ARDS patients213, 214. These results indicate fea-
tures of SARS research ndings that are common
to those observed for SARS-CoV-2.
Studies211,214 evaluating chemokines and cy-
tokines in SARS-CoV-2 infection would aid in
clarifying the full cytokine proles of patients
with severe infection during the acute phase. This
would help elucidate the pathogenic mechanisms
that result in worse health outcomes. SARS-
CoV-2 patients demonstrate increased concen-
tration of pro-inammatory cytokines, including
IL1β, IL-2, IL-6, IL-8, IL-17, TNF-α, IP-10, MCP-
1, GM-CSF, and G-CSF215 , which may be attribut-
ed to Th-1-cell responses216. Signicant cytokine
elevation was identied in patients with severe
symptoms, and Th-1-cell and Th-2-cell-related
cytokines were detected simultaneously217. Pre-
vious investigations conrmed that the increased
level of certain pro-inammatory cytokines (e.g.,
IFN-γ, IL1β, IL-6, IL-12) in serum positively
correlated with severe lung damage and pulmo-
nary inammation in SARS-CoV patients218. T
cell-related CD molecules and lymphocyte levels
showed a negative correlation with changes in cy-
tokines in patients with SARS-CoV-2 infection.
Therefore, there is a potential correlation between
cytokine storms and adaptive immunity. In pa-
tients with mild symptoms, lymphocyte levels
are usually normal during the convalescent phase
and are undetectable later as the infection pro-
gresses219, 220. In acute stages in mild cases, lym-
phocyte elevation was not linked to elevation in
cytokines. This could be due to cellular immune
response initiation that tends to accelerate viral
clearance during the early phases, inhibiting cy-
tokine production through innate immune activa-
tion, thus alleviating disease severity221. In severe
cases, cytokine hyperactivation during the acute
phase of SARS-CoV-2 resulted in dysregulated
systemic disease inammation and deterioration,
as shown by CRP, ferritin, D-dimers, and procal-
citonin elevation217 ,22 0. Cytokine storms generate
pathogenic effects instead of protective effects
against SARS-CoV-2 infection of host cells222-225.
Excessive cytokine and chemokine activation by
macrophages has similar outcomes, as reported
in macrophage activation syndrome (MAS) and
hemophagocytic lymphohistiocytosis. In particu-
lar, many proinammatory cytokines, IL-1, IL-6,
and TNF-α, are involved in COVID-19 pathogen-
esis226. Single-cell RNA sequencing has revealed
Table II. Comparative analysis of clinical manifestations in patients with MERS, SARS, and COVID-19.
MERS-CoV SARS-CoV SARS-CoV-2
Clinical symptoms/manifestations 8,157,200 8,157,160 8,201–205
Fever 63.5-83.5% 93-97.6% 67.7-90.8%
Cough 51-70% 49-59% 45.5-62.9%
Fatigue 21-35% 31.2% 23.3-38.1%
Dyspnoea 51% 32% 21-40%
Sputum 22-43% 16-27% 21.2-37.2%
Sore throat ≤ 25% 11-25% 14.6-31.0%
Headache 11-20% 30-46% 7.9-15.2%
Gastrointestinal symptoms
(like diarrhoea) ≤ 30% ≤ 32% 3-17%
Bilateral pneumonia N.A. N.A. 58.2-81.0%
Acute respiratory dist ress syndrome (ARDS) 20–30% 20% 18–30%
Neurological manifestations such as stroke 17.4 % N.A. 17- 30%
Acute kidney injury 41–50% 7% 3-20%
N.A.* (Not Available).
A.A. Rabaan, A.A. Mutair, Z.A. Alawi, S. Alhumaid, M.A. Mohaini, J. Aldali, R. Tirupathi, et al
7172
potent interactions between immune and epithe-
lial cells, with inammatory macrophages that
express multiple cytokines in samples with criti-
cal COVID-19 conditions130. Amongst these, IL-8
and IL-6 are detected at elevated concentrations
in individuals with critical or severe COVID-19.
These high levels of both cytokines indicate lym-
phocytopenia that predicts disease progression227.
During the initial stages of SARS-CoV-2 infec-
tion, the lymphocyte count decreases in patients
with severe symptoms associated with a dramat-
ic decrease in NK cells, B cells, CD4+, CD8+ T,
and CD3+ cells228. Mild cases of SARS-CoV-2
infection demonstrate a moderate increase in
these lymphocytes220, 221. These ndings further
reveal that lymphocytes can reach comparable
levels along with only slight variation in notice-
able lymphocyte count214, 221. Changes in adaptive
immunity occur due to imbalanced activation of
Th1/Th2, and alteration of T lymphocyte func-
tion causes adverse effects on host cells, wors-
ening the course of disease. Reduced function of
CD8+ T cells serves as a predictor of the severity
of SARS-CoV-2 infection208. Moreover, the pro-
duction of endogenous IFNβ in the nasal mucosa
of critical patients can be considered a prognostic
tool of IFN therapy for managing COVID-19, as it
predicts clinical outcomes229. The eosinophil level
in COVID-19 patients was related to the reduced
anticoagulant effect and therefore may be consid-
ered for determining the prophylactic anticoagu-
lant administration strategy2 30. The high eosino-
Figure 1. Coronaviruses infect human lung epithelial cells via the ACE2 receptor. TLR3/7 and MAVS, endosomal and cyto-
plasmic sensors, respectively, are activated by viral R NA. Interferon Regulator y Factors (IR Fs) and NFkB are activated by these
receptors, which trigger the cytokine storm by inducing inammatory cytokines such as interferons (IFNs) and proinammatory
cytokines. These lead to the recruitment of many immune cells into the lungs and cause a hypersecretion of cytokines i.e., cyto-
kine storm by activated immune cells. The cytokine storm causes cytotoxic and immunological disruption in host cells, as well as
ARDS and other clinical manifestations. Moreover, to prime the adaptive immunity, dendritic cells (DCs) sample antigen moves
towards lymphoid organs. After recognising antigen on DCs or infected cells, CD8+ T cells cause apoptosis.
Comparative review of three human coronaviruses
7173
phil count is also associated with lower activity
of anti-factor Xa230. Liu and coworkers have also
suggested the importance of familial cluster (FC)
and non-familial (NF) patients during the treat-
ment of COVID-19 patients231.
An overview on pathology and pathobiology of
SARS-CoV-2 is presented in Figu re 1.
Immunocompetent infected individuals usual-
ly present mild manifestations or become asymp-
tomatic232. However, the immunocompromised,
the elderly, and individuals with underlying con-
ditions such as cardiovascular disease, diabetes,
and cancer, develop severe symptoms and clinical
disease134. A recent study linked renal, cardiovas-
cular, and respiratory diseases with greater ICU
admission and fatality rate in COVID-19 patients.
Cancer and diabetes conditions also showed a
strong correlation with severe disease outcomes
in SARS-CoV-2 infected patients. Male patients
and older people showed higher ICU admission
and mortality. The risk of COVID-19 was dra-
matically increased in older patients233. In another
report, hypertension, cardiovascular disease, and
diabetes were closely associated with severe out-
comes in COVID-19-infected individuals across
all age groups. In contrast to elderly patients,
young patients exhibited a varied prevalence
of cardiovascular comorbidities234. The De Ri-
tis ratio has been associated with poor survival
in SARS-COV-2 infected patients and is an im-
portant prognostic factor. Moreover, the De Ritis
ratio on admission was signicantly associated
with in-hospital mortality in COVID-19 patients.
However, since the sample size in the clinical
study was considerably smaller, additional inves-
tigations are needed to validate the ability of this
parameter to independently predict death in hos-
pitalized patients235. Obesity is strongly associat-
ed with immune cells, including MAIT and NK
cells236-238. Hence, it may be considered a factor
for increased risk of severe COVID-19. Popkin
et al239 have recently conducted a meta-analysis
and found 48% higher mortality in COVID-19
patients with obesity. In a recent cohort study,
Gao et al240 found a linear increase in the risk
of severity in patients with COVID-19 leading
to hospitalization and death with an increase in
body mass index. This excess risk was observed
particularly in younger people and also in black
individuals. According to another cross-sectional
study, Lega et al241 found that COVID-19 patients
with a severe psychiatric disorder (schizophre-
nia and others) died at a younger age compared
to those without any psychiatric disorder. Addi-
tionally, the vulnerability of COVID-19 patients
with psychiatric disorders may reduce the chance
of recovery. Pregnant women were affected more
by COVID-19, particularly in the second wave
of infections, which may be associated with the
emergence of increasing numbers of pathogenic
strains242. Moreover, people with physical disabil-
ities are particularly at risk and need additional
support from mental health services243. In a simi-
lar report, authors have mentioned that older peo-
ple with disabilities have been neglected during
the COVID-19 pandemic244.
Conclusions
Three highly pathogenic coronaviruses (SARS-
CoV, MERS-CoV, and SARS-CoV-2) have been
reported in humans in the last two decades. Al-
though these CoVs exhibit several similar features
in their infection process, distinctive features and
characteristics are observed in the immunopa-
thology and clinical outcomes of each. Recurrent
outbreaks of infectious and pathogenic strains of
CoVs have posed a signicant burden and danger
to humankind, such as the current COVID-19
pandemic that has resulted in an unprecedented
crisis with devastating social, health, and eco-
nomic impacts worldwide. All three CoVs share
immunological aspects that affect pathological
characteristics. The viral agents undergo rep-
lication in the host immune cells and set off an
innate immune response that leads to induction
of pro-inammatory cells and cytokines. This cy-
tokine storm can be life-threatening. Finally, the
body responds by producing protective antibodies
that clear the viral infection and also confer im-
munity against future infection with the same vi-
rus. In vit ro studies have been particularly helpful
for understanding the immunological and patho-
logical aspects of the viruses and in conducting
drug trials against these agents. However, there is
a need to advance clinical research since these vi-
ral agents can undergo further mutations and may
give rise to viral species with enhanced patho-
genicity in the future. Collaborative and intense
efforts by scientists worldwide have resulted in
advanced discoveries related to many aspects of
SARS-CoV-2 and COVID-19. In addition, eluci-
dating the immunopathology and clinical features
of CoVs will help in developing better and more
effective drugs, medicines, and vaccines to count-
er the emergence and re-emergence of pathogenic
CoVs. Prospective outcomes from clinical inves-
A.A. Rabaan, A.A. Mutair, Z.A. Alawi, S. Alhumaid, M.A. Mohaini, J. Aldali, R. Tirupathi, et al
7174
tigations of different vaccines and antiviral can-
didates provide hope to end this pandemic soon.
Continuous research efforts to better understand
the pathogenesis, molecular biology, and immu-
nological characteristics of SARS-CoV-2 and oth-
er CoVs will help to stem the tide of the ongoing
COVID-19 pandemic and formulate prevention
plans for future pandemics.
Conflicts of interest
All authors declare that there exist no commercial or
nancial relationships that could, in any way, lead to a
potential conict of interest.
Author Contributions
All the authors substantially contributed to the con-
ception, compilation of data, checking and approving
the nal version of the manuscript, and agree to be ac-
countable for its contents.
Acknowledgements
All the authors acknowledge and thank their respec-
tive Institutes and Universities.
Funding
This is a review article written by its authors and re-
quired no substantial funding to be stated.
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