Journal of Advanced Research 24 (2020) 91–98

Contents lists available at ScienceDirect

Journal of Advanced Research

journal homepage: www.elsevier.com/locate/jare

COVID-19 infection: Origin, transmission, and characteristics of human

coronaviruses
Muhammad Adnan Shereen a,b,1, Suliman Khan a,1,⇑, Abeer Kazmi c, Nadia Bashir a, Rabeea Siddique a
a
The Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China
b
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, PR China
c
College of Life Sciences, Wuhan University, Wuhan, PR China

g r a p h i c a l a b s t r a c t

a r t i c l e i n f o a b s t r a c t

Article history: The coronavirus disease 19 (COVID-19) is a highly transmittable and pathogenic viral infection caused by
Received 15 March 2020 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which emerged in Wuhan, China and
Accepted 15 March 2020 spread around the world. Genomic analysis revealed that SARS-CoV-2 is phylogenetically related to sev-
Available online 16 March 2020
ere acute respiratory syndrome-like (SARS-like) bat viruses, therefore bats could be the possible primary
reservoir. The intermediate source of origin and transfer to humans is not known, however, the rapid
Keywords: human to human transfer has been confirmed widely. There is no clinically approved antiviral drug or
Coronaviruses
vaccine available to be used against COVID-19. However, few broad-spectrum antiviral drugs have been
COVID-19
Origin
evaluated against COVID-19 in clinical trials, resulted in clinical recovery. In the current review, we sum-
Outbreak marize and comparatively analyze the emergence and pathogenicity of COVID-19 infection and previous
Spread human coronaviruses severe acute respiratory syndrome coronavirus (SARS-CoV) and middle east respi-
ratory syndrome coronavirus (MERS-CoV). We also discuss the approaches for developing effective vac-
cines and therapeutic combinations to cope with this viral outbreak.
Ó 2020 THE AUTHORS. Published by Elsevier BV on behalf of Cairo University. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction
Peer review under responsibility of Cairo University.
⇑ Corresponding author. Coronaviruses belong to the Coronaviridae family in the Nidovi-
E-mail address: [email protected] (S. Khan). rales order. Corona represents crown-like spikes on the outer sur-
1
Contributed equally (M.A.S and S.K). face of the virus; thus, it was named as a coronavirus.

https://doi.org/10.1016/j.jare.2020.03.005
2090-1232/Ó 2020 THE AUTHORS. Published by Elsevier BV on behalf of Cairo University.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
92 M.A. Shereen et al. / Journal of Advanced Research 24 (2020) 91–98

Coronaviruses are minute in size (65–125 nm in diameter) and nationals were diagnosed to be infected with another coronavirus.
contain a single-stranded RNA as a nucleic material, size ranging The detected virus was confirmed as a member of coronaviruses
from 26 to 32kbs in length (Fig. 1). The subgroups of coronaviruses and named as the Middle East Respiratory Syndrome Coronavirus
family are alpha (a), beta (b), gamma (c) and delta (d) coronavirus. (MERS-CoV). The World health organization reported that MERS-
The severe acute respiratory syndrome coronavirus (SARS-CoV), coronavirus infected more than 2428 individuals and 838 deaths
H5N1 influenza A, H1N1 2009 and Middle East respiratory syn- [8]. MERS-CoV is a member beta-coronavirus subgroup and phylo-
drome coronavirus (MERS-CoV) cause acute lung injury (ALI) and genetically diverse from other human-CoV. The infection of MERS-
acute respiratory distress syndrome (ARDS) which leads to pul- CoV initiates from a mild upper respiratory injury while progres-
monary failure and result in fatality. These viruses were thought sion leads to severe respiratory disease. Similar to SARS-
to infect only animals until the world witnessed a severe acute res- coronavirus, patients infected with MERS-coronavirus suffer pneu-
piratory syndrome (SARS) outbreak caused by SARS-CoV, 2002 in monia, followed by ARDS and renal failure [9].
Guangdong, China [1]. Only a decade later, another pathogenic Recently, by the end of 2019, WHO was informed by the Chi-
coronavirus, known as Middle East respiratory syndrome coron- nese government about several cases of pneumonia with unfamil-
avirus (MERS-CoV) caused an endemic in Middle Eastern countries iar etiology. The outbreak was initiated from the Hunan seafood
[2]. market in Wuhan city of China and rapidly infected more than
Recently at the end of 2019, Wuhan an emerging business hub 50 peoples. The live animals are frequently sold at the Hunan sea-
of China experienced an outbreak of a novel coronavirus that killed food market such as bats, frogs, snakes, birds, marmots and rabbits
more than eighteen hundred and infected over seventy thousand [10]. On 12 January 2020, the National Health Commission of China
individuals within the first fifty days of the epidemic. This virus released further details about the epidemic, suggested viral pneu-
was reported to be a member of the b group of coronaviruses. monia [10]. From the sequence-based analysis of isolates from the
The novel virus was named as Wuhan coronavirus or 2019 novel patients, the virus was identified as a novel coronavirus. Moreover,
coronavirus (2019-nCov) by the Chinese researchers. The Interna- the genetic sequence was also provided for the diagnosis of viral
tional Committee on Taxonomy of Viruses (ICTV) named the virus infection. Initially, it was suggested that the patients infected with
as SARS-CoV-2 and the disease as COVID-19 [3–5]. In the history, Wuhan coronavirus induced pneumonia in China may have visited
SRAS-CoV (2003) infected 8098 individuals with mortality rate of the seafood market where live animals were sold or may have used
9%, across 26 contries in the world, on the other hand, novel corona infected animals or birds as a source of food. However, further
virus (2019) infected 120,000 induviduals with mortality rate of investigations revealed that some individuals contracted the infec-
2.9%, across 109 countries, till date of this writing. It shows that tion even with no record of visiting the seafood market. These
the transmission rate of SARS-CoV-2 is higher than SRAS-CoV and observations indicated a human to the human spreading capability
the reason could be genetic recombination event at S protein in the of this virus, which was subsequently reported in more than 100
RBD region of SARS-CoV-2 may have enhanced its transmission countries in the world. The human to the human spreading of
ability. In this review article, we discuss the origination of human the virus occurs due to close contact with an infected person,
coronaviruses briefly. We further discuss the associated infectious- exposed to coughing, sneezing, respiratory droplets or aerosols.
ness and biological features of SARS and MERS with a special focus These aerosols can penetrate the human body (lungs) via inhala-
on COVID-19. tion through the nose or mouth (Fig. 2) [11–14].

Comparative analysis of emergence and spreading of

coronaviruses Primary reservoirs and hosts of coronaviruses

In 2003, the Chinese population was infected with a virus caus- The source of origination and transmission are important to be
ing Severe Acute Respiratory Syndrome (SARS) in Guangdong pro- determined in order to develop preventive strategies to contain the
vince. The virus was confirmed as a member of the Beta- infection. In the case of SARS-CoV, the researchers initially focused
coronavirus subgroup and was named SARS-CoV [6,7]. The infected on raccoon dogs and palm civets as a key reservoir of infection.
patients exhibited pneumonia symptoms with a diffused alveolar However, only the samples isolated from the civets at the food
injury which lead to acute respiratory distress syndrome (ARDS). market showed positive results for viral RNA detection, suggesting
SARS initially emerged in Guangdong, China and then spread that the civet palm might be secondary hosts [15]. In 2001 the
rapidly around the globe with more than 8000 infected persons samples were isolated from the healthy persons of Hongkong and
and 776 deceases. A decade later in 2012, a couple of Saudi Arabian the molecular assessment showed 2.5% frequency rate of anti-
bodies against SARS-coronavirus. These indications suggested that
SARS-coronavirus may be circulating in humans before causing the
outbreak in 2003 [16]. Later on, Rhinolophus bats were also found
to have anti-SARS-CoV antibodies suggesting the bats as a source of
viral replication [17]. The Middle East respiratory syndrome
(MERS) coronavirus first emerged in 2012 in Saudi Arabia [9].
MERS-coronavirus also pertains to beta-coronavirus and having
camels as a zoonotic source or primary host [18]. In a recent study,
MERS-coronavirus was also detected in Pipistrellus and Perimyotis
bats [19], proffering that bats are the key host and transmitting
medium of the virus [20,21]. Initially, a group of researchers sug-
gested snakes be the possible host, however, after genomic similar-
ity findings of novel coronavirus with SARS-like bat viruses
supported the statement that not snakes but only bats could be
the key reservoirs (Table 1) [22,23]. Further analysis of homolo-
gous recombination revealed that receptor binding spike glycopro-
tein of novel coronavirus is developed from a SARS-CoV (CoVZXC21
Fig. 1. Structure of respiratory syndrome causing human coronavirus. or CoVZC45) and a yet unknown Beta-CoV [24]. Nonetheless, to
 M.A. Shereen et al. / Journal of Advanced Research 24 (2020) 91–98 93

Fig. 2. The key reservoirs and mode of transmission of coronaviruses (suspected reservoirs of SARS-CoV-2 are red encircled); only a and b coronaviruses have the ability to
infect humans, the consumption of infected animal as a source of food is the major cause of animal to human transmission of the virus and due to close contact with an
infected person, the virus is further transmitted to healthy persons. Dotted black arrow shows the possibility of viral transfer from bat whereas the solid black arrow
represent the confirmed transfer. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Table 1
Comparative analysis of biological features of SARS-CoV and SARS-CoV-2.

Features SARS-CoV SARS-CoV-2 Reference

Emergence date November 2002 December 2019 [37,79–81]
Area of emergence Guangdong, China Wuhan, China
Date of fully controlled July 2003 Not controlled yet
Key hosts Bat, palm civets and Raccon dogs Bat [22,82,83]
Number of countries infected 26 109 [84]
Entry receptor in humans ACE2 receptor ACE2 receptor [22,55,85]
Sign and symptoms fever, malaise, myalgia, headache, diarrhoea, shivering, Cough, fever and shortness of breath [12,23,85]
cough and shortness of breath
Disease caused SARS, ARDS SARS, COVID-19 [85,86]
Total infected patients 8098 123882 [84]
Total recovered patients 7322 67051
Total died patients 776 (9.6% mortality rate) 4473 (3.61% mortality rate)

eradicate the virus, more work is required to be done in the aspects teins, and membrane proteins, such as RNA polymerase, 3-
of the identification of the intermediate zoonotic source that chymotrypsin-like protease, papain-like protease, helicase, glyco-
caused the transmission of the virus to humans. protein, and accessory proteins [30,31]. The spike protein of
SARS-CoV-2 contains a 3-D structure in the RBD region to maintain
the van der Waals forces [32]. The 394 glutamine residue in the
Key features and entry mechanism of human coronaviruses RBD region of SARS-CoV-2 is recognized by the critical lysine 31
residue on the human ACE2 receptor [33]. The entire mechanism
All coronaviruses contain specific genes in ORF1 downstream of pathogenicity of SARS-CoV-2, from attachment to replication is
regions that encode proteins for viral replication, nucleocapsid well mentioned in Fig. 3.
and spikes formation [25]. The glycoprotein spikes on the outer
surface of coronaviruses are responsible for the attachment and
entry of the virus to host cells (Fig. 1). The receptor-binding Genomic variations in SARS-CoV-2
domain (RBD) is loosely attached among virus, therefore, the virus
may infect multiple hosts [26,27]. Other coronaviruses mostly rec- The genome of the SARS-CoV-2 has been reported over 80%
ognize aminopeptidases or carbohydrates as a key receptor for identical to the previous human coronavirus (SARS-like bat CoV)
entry to human cells while SARS-CoV and MERS-CoV recognize [34]. The Structural proteins are encoded by the four structural
exopeptidases [2]. The entry mechanism of a coronavirus depends genes, including spike (S), envelope (E), membrane (M) and nucle-
upon cellular proteases which include, human airway trypsin-like ocapsid (N) genes. The orf1ab is the largest gene in SARS-CoV-2
protease (HAT), cathepsins and transmembrane protease serine 2 which encodes the pp1ab protein and 15 nsps. The orf1a gene
(TMPRSS2) that split the spike protein and establish further pene- encodes for pp1a protein which also contains 10 nsps [34–36].
tration changes [28,29]. MERS-coronavirus employs dipeptidyl According to the evolutionary tree, SARS-CoV-2 lies close to the
peptidase 4 (DPP4), while HCoV-NL63 and SARS-coronavirus group of SARS-coronaviruses [37,38] (Fig. 5). Recent studies have
require angiotensin-converting enzyme 2 (ACE2) as a key receptor indicated notable variations in SARS-CoV and SARS-CoV-2 such
[2,26]. as the absence of 8a protein and fluctuation in the number of
SARS-CoV-2 possesses the typical coronavirus structure with amino acids in 8b and 3c protein in SARS-CoV-2 [34] (Fig. 4). It is
spike protein and also expressed other polyproteins, nucleopro- also reported that Spike glycoprotein of the Wuhan coronavirus
94 M.A. Shereen et al. / Journal of Advanced Research 24 (2020) 91–98

Fig. 3. The life cycle of SARS-CoV-2 in host cells; begins its life cycle when S protein binds to the cellular receptor ACE2. After receptor binding, the conformation change in
the S protein facilitates viral envelope fusion with the cell membrane through the endosomal pathway. Then SARS-CoV-2 releases RNA into the host cell. Genome RNA is
translated into viral replicase polyproteins pp1a and 1ab, which are then cleaved into small products by viral proteinases. The polymerase produces a series of subgenomic
mRNAs by discontinuous transcription and finally translated into relevant viral proteins. Viral proteins and genome RNA are subsequently assembled into virions in the ER
and Golgi and then transported via vesicles and released out of the cell. ACE2, angiotensin-converting enzyme 2; ER, endoplasmic reticulum; ERGIC, ER–Golgi intermediate
compartment.

is modified via homologous recombination. The spike glycoprotein another suitable option to develop spike glycoprotein targeting
of SARS-CoV-2 is the mixture of bat SARS-CoV and a not known therapeutics against novel coronaviruses. Recently, mice models
Beta-CoV [38]. In a fluorescent study, it was confirmed that the and clinical isolates were used to develop any therapeutic strategy
SARS-CoV-2 also uses the same ACE2 (angiotensin-converting against SARS-CoV-2 induced COVID-19 [46,47]. In a similar study,
enzyme 2) cell receptor and mechanism for the entry to host cell artificial intelligence prediction was used to investigate the inhibi-
which is previously used by the SARS-CoV [39,40]. The single tory role of the drug against SARS-CoV-2 [48]. SARS-CoV-2 infected
N501T mutation in SARS-CoV-2’s Spike protein may have signifi- patients were also used to conduct randomized clinical trials
cantly enhanced its binding affinity for ACE2 [33]. [46,49,50]. It is now important that the scientists worldwide col-
laborate the design a suitable model and investigate the in vivo
The major obstacle in research progress mechanisms associated with pathogenesis of SARS-CoV-2.

Animal models play a vital role to uncover the mechanisms of Potential therapeutic strategies against COVID-19
viral pathogenicity from the entrance to the transmission and
designing therapeutic strategies. Previously, to examine the repli- Initially, interferons-a nebulization, broad-spectrum antibi-
cation of SARS-CoV, various animal models were used which otics, and anti-viral drugs were used to reduce the viral load
showed the symptoms of severe infection [43]. In contrast to [49,51,52], however, only remdesivir has shown promising impact
SARS-CoV, no MERS-CoV pathogenesis was observed in small ani- against the virus [53]. Remdesivir only and in combination with
mals. Mice are not vulnerable to infection by MERS-coronavirus chloroquine or interferon beta significantly blocked the SARS-
due to the non-compatibility of the DPP4 receptor [44]. As the CoV-2 replication and patients were declared as clinically recov-
entire genome of the 2019-novel coronavirus is more than 80% ered [46,50,52]. Various other anti-virals are currently being eval-
similar to the previous human SARS-like bat CoV, previously used uated against infection. Nafamostat, Nitazoxanide, Ribavirin,
animal models for SARS-CoV can be utilized to study the infectious Penciclovir, Favipiravir, Ritonavir, AAK1, Baricitinib, and Arbidol
pathogenicity of SARS-CoV-2. The human ACE2 cell receptor is rec- exhibited moderate results when tested against infection in
ognized by both SARS and Novel coronaviruses. Conclusively, patients and in-vitro clinical isolates [46,48,50,52]. Several other
TALEN or CRISPR-mediated genetically modified hamsters or other combinations, such as combining the antiviral or antibiotics with
small animals can be utilized for the study of the pathogenicity of traditional Chinese medicines were also evaluated against SARS-
novel coronaviruses. SARS-CoV has been reported to replicate and CoV-2 induced infection in humans and mice [46]. Recently in
cause severe disease in Rats (F344), where the sequence analysis Shanghai, doctors isolated the blood plasma from clinically recov-
revealed a mutation at spike glycoprotein [45]. Thus, it could be ered patients of COVID-19 and injected it in the infected patients
 M.A. Shereen et al. / Journal of Advanced Research 24 (2020) 91–98 95

Fig. 4. Betacoronaviruses genome organization; The Betacoronavirus for human (SARS-CoV-2, SARS-CoV and MERS-CoV) genome comprises of the 50 -untranslated region (50 -
UTR), open reading frame (orf) 1a/b (green box) encoding non-structural proteins (nsp) for replication, structural proteins including spike (blue box), envelop (maroon box),
membrane (pink box), and nucleocapsid (cyan box) proteins, accessory proteins (light gray boxes) such as orf 3, 6, 7a, 7b, 8 and 9b in the SARS-CoV-2 genome, and the 30 -
untranslated region (30 -UTR). The doted underlined in red are the protein which shows key variation between SARS-CoV-2 and SARS-CoV. The length of nsps and orfs are not
drawn in scale. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 5. Phylogenetic tree of coronaviruses (content in red is the latest addition of newly emerged SARS-CoV-2 and WSFMP Wuhan-Hu-1 is used as a reference in the tree); The
phylogenetic tree showing the relationship of Wuhan-Hu-1 (denoted as red) to selected coronavirus is based on nucleotide sequences of the complete genome. The viruses
are grouped into four genera (prototype shown): Alphacoronavirus (sky blue), Betacoronavirus (pink), Gammacoronavirus (green) and Deltacoronavirus (light blue).
Subgroup clusters are labeled as 1a and 1b for the Alphacoronavirus and 2a, 2b, 2c, and 2d for the Betacoronavirus. This tree is based on the published trees of Coronavirinae
[3,41] and reconstructed with sequences of the complete RNA- dependent RNA polymerase- coding region of the representative novel coronaviruses (maximum likelihood
method using MEGA 7.2 software). severe acute respiratory syndrome coronavirus (SARS- CoV); SARS- related coronavirus (SARSr- CoV); the Middle East respiratory
syndrome coronavirus (MERS- CoV); porcine enteric diarrhea virus (PEDV); Wuhan seafood market pneumonia (Wuhan-Hu-1). Bat CoV RaTG13 Showed high sequence
identity to SARS-CoV-2 [42]. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

who showed positive results with rapid recovery [54]. In a recent receptor-binding motif. CR3022 has the potential to be developed
study, it was identified that monoclonal antibody (CR3022) binds - as a therapeutic candidate, alone or in combination with other
with the spike RBD of SARS-CoV-2. This is likely due to the anti- neutralizing antibodies for the prevention and treatment of -
body’s epitope not overlapping with the divergent ACE2 COVID-19 infection [55].
96 M.A. Shereen et al. / Journal of Advanced Research 24 (2020) 91–98

Vaccines for SARS-CoV-2 Most importantly, human coronaviruses targeting vaccines and
antiviral drugs should be designed that could be used against the
There is no available vaccine against COVID-19, while previous current as well as future epidemics. There are many companies
vaccines or strategies used to develop a vaccine against SARS-CoV working for the development of effective SARS-CoV-2 vaccines,
can be effective. Recombinant protein from the Urbani (AY278741) such as Moderna Therapeutics, Inovio Pharmaceuticals, Novavax,
strain of SARS-CoV was administered to mice and hamsters, Vir Biotechnology, Stermirna Therapeutics, Johnson & Johnson,
resulted in the production of neutralizing antibodies and protec- VIDO-InterVac, GeoVax-BravoVax, Clover Biopharmaceuticals, Cur-
tion against SARS-CoV [56,57]. The DNA fragment, inactivated eVac, and Codagenix. But there is a need for rapid human and
whole virus or live-vectored strain of SARS-CoV (AY278741), sig- animal-based trails as these vaccines still require 3–10 months
nificantly reduced the viral infection in various animal models for commercialization. There must be a complete ban on utilizing
[58–63]. Different other strains of SARS-CoV were also used to pro- wild animals and birds as a source of food. Beside the development
duce inactivated or live-vectored vaccines which efficiently of most efficient drug, a strategy to rapidly diagnose SARS-CoV-2 in
reduced the viral load in animal models. These strains include, suspected patient is also required. The signs and symptoms of
Tor2 (AY274119) [64,65], Utah (AY714217) [66], FRA (AY310120) SARS-CoV-2 induced COVID-19 are a bit similar to influenza and
[59], HKU-39849 (AY278491) [57,67], BJ01 (AY278488) [68,69], seasonal allergies (pollen allergies). Person suffering from influ-
NS1 (AY508724) [70], ZJ01 (AY297028) [70], GD01 (AY278489) enza or seasonal allergy may also exhibit temprature which can
[69] and GZ50 (AY304495) [71]. However, there are few vaccines be detected by thermo-scanners, hence the person will become
in the pipeline against SARS-CoV-2. The mRNA based vaccine pre- suspected. Therefore, an accurate and rapid diagnostic kit or meter
pared by the US National Institute of Allergy and Infectious Dis- for detection of SARS-CoV-2 in suspected patients is required, as
eases against SARS-CoV-2 is under phase 1 trial [72]. INO-4800- the PCR based testing is expensive and time consuming. Different
DNA based vaccine will be soon available for human testing [73]. teams of Chinese doctors should immediately sent to Eurpean
Chinese Centre for Disease Control and Prevention (CDC) working and other countries, especially spain and Italy to control the over
on the development of an inactivated virus vaccine [74,75]. Soon spread of COVID-19, because Chinese doctors have efficiently con-
mRNA based vaccine’s sample (prepared by Stermirna Therapeu- trolled the outbreak in china and limited the mortality rate to less
tics) will be available [76]. GeoVax-BravoVax is working to develop than 3% only. The therapeutic strategies used by Chinese, should
a Modified Vaccina Ankara (MVA) based vaccine [77]. While Clover also be followed by other countries.
Biopharmaceuticals is developing a recombinant 2019-nCoV S pro-
tein subunit-trimer based vaccine [78].
Acknowledgments
Although research teams all over the world are working to
investigate the key features, pathogenesis and treatment options,
The authors acknowledge the Postdoctoral grant from The Second
it is deemed necessary to focus on competitive therapeutic options
Affiliated Hospital of Zhengzhou University (for S.K).
and cross-resistance of other vaccines. For instance, there is a pos-
sibility that vaccines for other diseases such as rubella or measles
can create cross-resistance for SARS-CoV-2. This statement of
Declaration of Competing Interest
cross-resistance is based on the observations that children in china
were found less vulnerable to infection as compared to the elder
The authors of this manuscript declare no conflict of interest.
population, while children are being largely vaccinated for measles
in China.
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