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COVID-19
INTRODUCTION

Over the past 2 decades, coronaviruses (CoVs) have been associated with
significant disease outbreaks in East Asia and the Middle East. The severe acute
respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS)
began to emerge in 2002 and 2012, respectively. Recently, a novel coronavirus,
sever acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus
disease 2019 (C O V I D -19), emerged in late 2019, and it has posed a global health
threat, causing an ongoing pandemic in many countries and territories (1).

Health workers worldwide are currently making efforts to control further

disease outbreaks caused by the novel CoV (o r i g i n a l l y named 2019-nCoV),
which was first identified in Wuhan City, Hubei Province, China, on 12 December
2019. On 11 February 2020, the World Health Organization (WHO) announced the
official designation for the current CoV- associated disease to be COVID-19, caused
by SARS-CoV-2. The primary cluster of patients was found to be connected with
the Huanan South China Seafood Market in Wuhan (2).

CoVs belong to the family Coronaviridae (subfamily Coronavirinae), the members

of which infect a broad

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trimeric SI locates itself on top of the trimeric S2 stalk (45). Recently, structural
analysis of the S proteins of COVID-19 have revealed 27 amino acid substitution
within a 1,273-amino-acid stretch (16). Six substitutions are located in the RBD
(amino acids 375 to 528), while four substitutions are in the RBM at the CTD of the
SI domain (16). Of note, no amino acid change is seen in the RBM, which binds
directly to the angiotensin-converting enzyme-2 (ACE2) receptor in SARS- CoV (16,
46). At present, the main emphasis in knowing how many differences would be
required to change the host tropism. Sequence comparison revealed 17 non-
synonymous changes between the early sequence of SARS-CoV-2 and the later
isolates of SARS-CoV. The changes were found scattered over the genome of the
virus, with nine substitutions in ORF1ab, ORF8 (4 substitutions), the spike gene (3
substitutions), and ORF7a (single substitutions) (4). Notably, the same
nonsynonymous changes were found in a familial cluster, indicating that the viral
evolution happened during person-to-person transmission (4, 47). Such adaptive
evolution events are frequent and constitute a constantly ongoing process once the
virus spreads among new hosts (47). Even though no functional changes occur in
the virus associated with this adaptive evolution, close monitoring of the viral

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absence of this protein is related to the altered virulence of coronaviruses due to

changes in morphology and tropism (54). The E protein consists of three domains,
namely, a short hydrophilic amino terminal, a large hydrophobic transmembrane
domain, and an efficient C-terminal domain (51). The SARS -CoV-2 E protein reveals
a similar amino acid constitution without any substitution (16).

N Protein

The N protein of coronavirus is multipurpose. Among several functions, it

plays a role in complex formation with the viral genome, facilities M protein
interaction needed during virion assembly, and enhances the transcription
efficiency of the virus (55, 56) . It contains three highly conserved and distinct
domains, namely, an NTD, an RNA-binding domain or a linker region (LKR), and a
CTD (57). The NTD binds with the 3' end of the viral genome, perhaps via
electrostatic interactions, and is highly diverged both in length and sequence (58).
The charged LKR is serine and arginine rich and is also known as the SR (serine
and arginine) domain (59). The LKR is capable of direct interaction with in vitro
RNA interaction and is responsible for cell signaling (60, 61). It also modulates the
antiviral response of the host by working as an antagonist for interferon.

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NSPS and Accessory Proteins

Besides the important structural proteins, the SARS-CoV-2 genome contains.

15 NSPS, nsp1 to nsp10 and nsp12 to nsp16, and 8 accessory proteins (3a, 3b, p6,
7a, 7b, 8b, 9b, and ORF14) (16). All these proteins play a specific role in viral
replication (27). Unlike the accessory proteins of SARS-CoV, SARS-CoV-2 does not
contain 8a protein and has a longer 8b and shorter 3b protein (16). The nsp7,
nsp13, envelope, matrix, and p6 and 8b accessory proteins have not been detected
with any amino acid substitutions compared to the sequences of other
coronaviruses (16).

The virus structure of SARS-CoV-2 is depicted in

Fig. 2.

FIG 2 SARS-CoV-2 virus structure.

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Initially, the epicenter of the SARS-CoV-2 pandemic was China, which reported a
significant number of deaths associated with COVID-19, with 84,458 laboratory-
confirmed cases and 4644 deaths as of 13 May 2020 (Fig. 4). As of 13 May 2020,
SARS-CoV-2 confirmed cases have been reported in more than 210 countries apart
from China (Fig. 3 and 4) (WHO Situation Report 114) (25, 64). COVID-19 has been
reported on all continents except Antarctica. For many weeks, Italy was the focus
of concerns regarding the large number of cases, with 221,216 cases and 30,911
deaths, but now, the United States is the country with the largest number of
cases, 1,322,054, and 79,634 deaths. Now, the United Kingdom has even more
cases (226, 4671) and deaths (32, 692) than Italy. A John Hopkins University web
platform has provided daily updates on the basic epidemiology of the COVID-19
outbreak.

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COVID-19 has also been confirmed on a cruise ship, named Diamond Princess,
quarantined in Japanese waters (Port of Yokohama), as well as on other cruise
ships around the world (239) (Fig.3). The significant events of the SARS-CoV-
2/COVID-19 virus outbreak occurring since 8 December 2019 are presented as a
timeline in Fig. 5.

FIG 5
Timeline depicting the significant events that occurred during the SARS-CoV-
2/COVID-19 virus outbreak. The timeline describes the significant events during
the current SARS-CoV-2 outbreak, from 8 December 2019 to 13 May 2020.

At the beginning, China experienced the majority of the burden associated with
COVID-19 in the form of disease morbidity and mortality (65), but over time the
COVID-19 menace moved to Europe, particularly Italy and Spain, and now the
United States has the highest number of confirmed cases.

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another study, the average reproductive number of COVID-19 was found to be

3.28, which is significantly higher than the initial WHO estimate of 1.4 to 2.5 (77).
It is too early to obtain the exact R0 value, since there is a possibility of bias due
to insufficient data. The higher R0 value is indicative of the more significant
potential of SARS-CoV-19 transmission in a susceptible population. This is not the
first time where the culinary practices of China have been blamed for the origin of
novel coronavirus infection in humans. Previously, the animals presented in the
live- animal market were identified to be the intermediate hosts of the SARS
outbreak in China (78). Several wildlife species were found to harbor potentially
evolving coronavirus strains that can overcome the species barrier (79). One of the
main principles of Chinese food culture is that live-slaughtered animals are
considered more nutritious (5).

After 4 months of struggle that lasted from December 2019 to March 2020, the
COVID-19 situation now seems under control in China. The wet animal markets
have reopened, and people have started buying bats, dogs, cats, birds, scorpions,
badgers, rabbits, pangolins (scaly anteaters), minks, soup from palm civet,
ostriches, hamsters, snapping turtles, ducks, fish Siamese crocodiles, and other.

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as an entry receptor while exhibiting an RBD similar to that of SARS-CoV ( 17, 87,
254, 255). Several countries have provided recommendations to their people
travelling to China (88, 89). Compared to the previous coronavirus outbreaks
caused by SARS-CoV and MERS-CoV, the efficiency of SARS-CoV-2 human-to-
human transmission was thought to be less. This assumption was based on the
finding that health workers were affected less than they were in previous outbreaks
of fatal coronaviruses (2). Superspreading events are considered the main culprit
for the extensive transmission of SARS and MERS (90,91). Almost half of the
MERS-CoV cases reported in Saudi Arabia are of secondary origin that occurred
through contact with infected asymptomatic or symptomatic individuals through
human-to-human transmission (92). The occurrence of superspreading events in
the COVID-19 outbreak cannot be ruled out until it's possibility is evaluated. Like
SARS and MERS, COVID-19 can also infect the lower respiratory tract, with milder
symptoms (27). The basic reproduction number of COVID-19 has been found to be
in the range of 2.8 to 3.3 based on real-time reports and 3.2 to 3.9 based on
predicted infected cases (84).

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route warrants the introduction of negative fecal viral nucleic acid test results as
one of the additional discharge criteria in laboratory-confirmed cases of COVID-19
(326).

The COVID-19 pandemic does not have any novel factors, other than the
genetically unique pathogen and a further possible reservoir. The cause and the
likely future outcome are just repetitions of our previous interactions with fatal
coronaviruses. The only difference is the time of occurrence and the genetic
distinctness of the pathogen involved. Mutations on the RBD of CoVs facilitated
their capability of infecting newer hosts, thereby expanding their reach to all
corners of the world (85). This is a potential threat to the health of both animals
and humans. Advanced studies using Bayesian phylogeographic reconstruction
identified the most probable origin of SARS-CoV-2 as the bat SARS-like
coronavirus, circulating in the Rhinolophus bat family (86).

Phylogenetic analysis of 10 whole-genome sequences of SARS-CoV-2 showed

that they are related to two CoVs of bat origin, namely, bat-SL-CoVZC45 and bat-
SL-CoVZXC21, which were reported during 2018 in China (17). It was reported that
SARS-CoV-2 had been confirmed to use ACE2 as an entry receptor while exhibiting
an RBD similar.

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fever, cough, and sputum (83). Hence, the clinicians must be on the look-out for
the possible occurrence of atypical clinical manifestations to avoid the possibility
of a missed diagnosis. The early transmission ability of SARS-CoV-2 was found to
be similar to or slightly higher than that of SARS-CoV, reflecting that it could be
controlled despite moderate to high transmissibility (84).

Increasing reports of SARS-CoV-2 in sewage and wastewater warrants the

need for further investigation due to the possibility of fecal-oral transmission.
SARS-CoV-2 present in environmental compartments such as soil and water will
finally end up in the wastewater and sewage sludge of treatment plants (328).
Therefore, we have to reevaluate current wastewater and sewage sludge
treatment procedures and introduce advanced techniques that are specific and
effective against SARS-CoV-2. Since there is active shedding of SARS-CoV-2 in the
stool, the prevalence of infections in a large population can be studied using
wastewater-based epidemiology. Recently, reverse transcription-quantitative PCR
(RT-qPCR) was used to enumerate the copies of SARS-CoV-2 RNA concentrated
from wastewater collected from a wastewater treatment plant (327). The calculated
viral RNA copy numbers determine the number of infected individuals.

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The whole world is suffering from the novel SARS-CoV-2, with more than
4,170,424 cases and 287,399 deaths across the globe. There is an urgent need for
a rational international campaign against the unhealthy food practices of China to
encourage the sellers to increase hygienic food practices or close the crude live-
dead animal wet markets. There is a need to modify food policies at national and
international levels to avoid further life threats and economic consequences from
any emerging or reemerging pandemic due to close animal-human interaction
(285).

Even though individuals of all ages and sexes are susceptible to COVID-19,
older people with an underlying chronic disease are more likely to become severely
infected (80). Recently, individuals with asymptomatic infection were also found
to act as a source of infection to susceptible individuals (81). Both the
asymptomatic and symptomatic patients secrete similar viral loads, which
indicates that the transmission capacity of asymptomatic or minimally
symptomatic patients is very high. Thus, SARS-CoV-2 transmission can happen
early in the course of infection.
(82). Atypical clinical manifestations have also been reported in COVID-19 in
which the only reporting symptom was fatigue. Such patients may lack respiratory
signs, such as cough, fever, and sputum (83).

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Hence, the clinicians turtles, ducks, fish, Siamese crocodiles, and other animals
meat without any fear of COVID-19. The Chinese government is encouraging people
to feel they can return to Normalcy. However, this could be a risk, as it has been
mentioned in advisories that people should avoid contact with live-dead animals as
much as possible, as SARS-CoV-2 has shown zoonotic spillover.
Additionally, we cannot rule out the possibility of new mutations in the same virus
being closely related to contact with both animals and humans at the market (284).
In January 2020, China imposed a temporary ban on the sale of live-dead animals
in wet markets. However, now hundreds of such wet markets have been reopened
without optimizing standard food safety and sanitation practices (286).

With China being the most populated country in the world and due to it's
domestic and international food exportation policies, the whole world is now facing
the menace of COVID-19, including China itself. Wet markets of live-dead animals
do not maintain strict food hygienic practice. Fresh blood splashes are present
everywhere, on the floor and tabletops, and such food customs could encourage
many pathogens to adapt, mutate, and jump the species barrier. As a result, the
whole world is suffering from Novel SARS-CoV-2SARS-CoV-2.

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More than, from experience with several outbreaks associated with known emerging
viruses, higher pathogenicity of a virus is often associated with lower
transmissibility. Compared to emerging viruses like Ebola virus, avian H7N9,
SARS-CoV, and MERS-CoV, SARS-CoV-2 has relatively lower pathogenicity and
moderate transmissibility (15). The risk of death among individuals infected with
COVID-19 was calculated using the infection fatality risk (IFR). The IFR was found
to be in the range of 0.3% to 0.6%, which is comparable to that of a previous Asian
influenza pandemic (1957 to 1958) (73, 277).

Notably, the reanalysis of the COVID-19 pandemic curve from the initial cluster
of cases pointed to considerable human-to-human transmission. It is opined that
the exposure history of SARS-CoV-2 at the Wuhan seafood market originated from
human-to-human transmission rather than animal-to-human transmission (74);
however, in light of the zoonotic spillover in COVID-19, is too early to fully endorse
this idea (1). Following the initial infection, human-to-human transmission has
been observed with a preliminary reproduction number (R0) estimate of 1.4 to 2.5
(70, 75), and recently it is estimated to be 2.24 to 3.58 (76).

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In another study, the average reproductive number of possible origin of SARS-CoV-

2 and the first mode of disease transmission are not yet identified (70). Analysis of
the initial cluster of infections suggests that the infected individuals had a common
exposure point, a seafood market in Wuhan, Hubei Province, China (Fig.6). The
restaurants of this market are well-known for providing different types of wild
animals for human consumption (71). The Huanan South China Seafood market
also sells live animals, such as poultry, bats, snakes and marmots (72). This might
be the point where zoonotic (animal-to-human) transmission occurred (71).
Although SARS-CoV-2 is alleged to have originated from an animal host (zoonotic
origin) with further human-to-human transmission (Fig. 6), the likelihood of
foodborne transmission should be ruled out with further investigations, since it is a
latent possibility (1). Additionally, other potential and expected routes would be
associated with transmission, as in other respiratory viruses, by direct contact,
such as shaking contaminated hands, or by direct contact with contaminated
surfaces (fig. 6). Still, whether blood transfusion and organ transplantation (276),
as well as trans-placental and perinatal routes, are possible routes for SARS-CoV-2
transmission needs to be determined (Fig.6).

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The newly emerged SARS-CoV-2 is a group 2B coronavirus (2). The genome

sequences of SARS-CoV-2 obtained from patients share 79.5% sequence
similarities to the sequence of SARS-CoV (63).

As of 13 May 2020, a total of 4,170,424 confirmed cases of COVID-19 (with

287,399 deaths) have been reported in more than 210 affected countries worldwide
(WHO Situation Report 114)

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and deaths. The COVID-19 outbreaks have also been associated with severe
economic impacts globally due to the sudden interruption of global trade and
supply chains that forced multinational companies to make decisions that led to
significant economic losses (66). The recent increase in the number of confirmed
critically ill patients with COVID-19 has already surpassed the intensive care
supplies, limiting intensive care services to only a small portion of critically ill
patients (67). This might also have contributed to the increased case fatality rate
observed in the COVID-19 outbreak.

Viewpoint on SARS-CoV-2 Transmission, Spread, and

Emergence

The novel coronavirus was identified within 1 month (28 days) of the outbreak.
This is impressively fast compared to the time taken to identify SARS-CoV reported
in Foshan, Guangdong Province, China (125 days) (68). Immediately after the
confirmation of viral etiology, the Chinese virologists rapidly released the genomic
sequence of SARS-CoV-2, which played a crucial role in controlling the spread of
this newly emerged novel coronavirus to other parts of the world (69). The possible
origin of SARS-CoV-2 and the first mode of

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We assessed the nucleotide percent similarity using the MegAlign software

program, where the similarity between the novel SARS-CoV-2 isolates was in the
range of 99.4% to 100%. Among the other Serbecovirus CoV sequences, the novel
SARS-CoV-2 sequences revealed the highest similarity to bat-SL-CoV, with
nucleotide percent identity ranges between 88.12 and 89.65%. Meanwhile, earlier
reported SARS-CoVs showed 70.6 to 74.9% similarity to SARS-CoV-2 at the
nucleotide level. Further, the nucleotide percent similarity was 55.4%, 45.5% to
47.9%, 46.2% to 46.6%, and 45.0% to 46.3% to the other four subgenera,
namely, Hibecovirus, Nobecovirus, Merbecovirus, and Embecovirus,
respectively. The percent similarity index of current outbreak isolates indicates a
close relationship between SARS-CoV-2 isolates and bat-SL-CoV, indicating a
common origin. However, particular pieces of evidence based on further complete
genomic analysis of current isolates are necessary to draw any conclusions,
although it was ascertained that the current novel SARS-CoV-2 isolates belong to
the subgenus Sarbecovirus in the diverse range of beta-coronaviruses. Their

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We assessed the nucleotide percent similarity using the MegAlign software

program, where the similarity between the novel SARS-CoV-2 isolates was in the
range of 99.4% to 100%. Among the other Serbecovirus CoV sequences, the novel
SARS-CoV-2 sequences revealed the highest similarity to bat-SL-CoV, with
nucleotide percent identity ranges between 88.12 and 89.65%. Meanwhile, earlier
reported SARS-CoVs showed 70.6 to 74.9% similarity to SARS-CoV-2 at the
nucleotide level. Further, the nucleotide percent similarity was 55.4%, 45.5% to
47.9%, 46.2% to 46.6%, and 45.0% to 46.3% to the other four subgenera,
namely, Hibecovirus, Nobecovirus, Merbecovirus, and Embecovirus,
respectively. The percent similarity index of current outbreak isolates indicates a
close relationship between SARS-CoV-2 isolates and bat-SL-CoV, indicating a
common origin. However, particular pieces of evidence based on further complete
genomic analysis of current isolates are necessary to draw any conclusions,
although it was ascertained that the current novel SARS-CoV-2 isolates belong to
the subgenus Sarbecovirus in the diverse range of beta-coronaviruses. Their

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N Protein

The N protein of coronavirus is multi-purpose. Among several functions, it plays

a role in complex formation with the viral genome, facilitates M protein interaction
needed during virion assembly, and enhances the transcription efficiency of the
virus (55, 56). It contains three highly conserved and distinct domains, namely, an
NTD, an RNA-binding domain or a linker region (LKR), and a CTD (57). The NTD
binds with the 3' end of the viral genome, perhaps via electrostatic interactions,
and is highly diverged both in length and sequence (58). The charged LKR is serine
and arginine rich and is also known as the SR (s e r i n e and arginine) domain (59).

The LKR is capable of direct interaction with in vitro RNA interaction and is
responsible for cell signaling (60, 61). It also modulates the antiviral response of
the host by working as an antagonist for interferon (IFN) and (RNA) interference.
(62). Compared to that of SARS-CoV, the N protein of SARS-CoV-2 possess five
amino acid mutations, where two are in the intrinsically dispersed region (IDR;
positions 25 and 26), one each in the NTD (position 103), LKR (position 217), and
CTD ( position 334) (16).

NSPS and Accessory Proteins

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adaptive evolution, close monitoring of the viral mutations that occur during

subsequent human-to-human transmission is warranted.

M Protein

The M protein is the most abundant viral protein present in the virion
particle, giving a definite shape to the viral envelope (48). It binds to the
nucleocapsid and acts as a central organizer of coronavirus assembly (49).
Coronavirus M proteins are highly diverse in amino acid contents but maintain
overall structural similarity within different genera (50). The M protein has
three trans- membrane domains, flanked by a short amino terminus outside the
virion and a long carboxy terminus inside the virion (50). Overall, the viral
scaffold is maintained by M-M interaction. Of note, the M protein of SARS-CoV-2
does not have an amino acid substitution compared to that of SARS- CoV (16).

E Protein

The coronavirus E protein is the most enigmatic and smallest of the major
structural proteins (51). It plays a multifunctional role in the pathogenesis,
assembly, and release of the virus (52). It is a small integral membrane polypeptide
that acts as a viroporin (ion channel) (53).

The in-activation or coronavirus S protein is a large, multifunctional class 1 viral

trans-membrane protein. The size of this abundant S protein varies from 1,160
amino acids (IBV, infectious bronchitis virus, in poultry) to 1,400 amino acids
(FCoV, feline coronavirus) (43). It lies in a trimer on the virion surface, giving the
virion a corona or crown-like appearance. Functionally it is required for the entry
of the infectious virion particles into the cell through interaction with various host
cellular receptors (44).

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Furthermore, it acts as a critical factor for tissues tropism and the

determination of host range (45). Notably, S protein is one of the vital immuno-
dominant proteins of CoVs capable of inducing host immune responses (45). The
ectodomains in all CoVs S protein have similar domain organizations, divided into
two subunits, S1 and S2 (43). The first one, S1, helps in host receptor binding,
while the second one, S2, accounts for fusion. The former (S1) is further divided
into two subdomains, namely, the N-terminal domain (NTD) and C- terminal
domain (CTD). Both of these subdomains act as receptor-binding domains,
interacting efficiently with various host receptors (45). The S1 CTD contains the
receptor-binding motif (RBM). In each coronavirus spike protein, the turmeric S1
locates itself on the top of the turmeric S2.

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Cat and camels, respectively, act as amplifier hosts (40, 41).

Coronavirus genomes and sub-genomes encode six ORFs (31). The majority of
the 5' end is occupied by ORF1a/b, which produces 16 NSPS. The two poly-
proteins, pp 1a and pp 1ab, are initially produced from ORF1a/b by a -1 frame-
shift between ORF1a and ORF1b (32). The virus-encoded proteases cleave poly-
proteins into individuals NSPS (main protease [Mpro], chymotrypsin-like protease
[3CLpro], and papain-like proteases [PLPs]) (42). SARS-CoV-2 also encodes these
nsps, and their functions have been elucidated recently (31). Remarkable, a
difference between SARS-CoV-2 and other CoVs is the identification of a novel short
putative protein within the ORF3 band, a secreted protein with an alpha helix and
beta-sheet with six strands encoded by ORF8 (31).

Coronaviruses encode four major structural proteins, namely, spike (S),

membrane (M), envelope (E), and nucleocapsid (N), which are described in detail
below.

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S Glycol-protein

Coronavirus S protein is a large, multifunctional class 1 viral trans-

membrane protein. The size of this based on molecular characterization, SARS-
CoV-2 is considered a new Beta-coronavirus belonging to the subgenus
Sarbecovirus (3). A few other critical zoonotic viruses (MERS-related CoV and
SARS-related CoV) belong to the same genus. However, SARS-CoV-2 was identified
as a distinct virus based on the percent identity with other Beta-coronavirus;
conserved open reading frame 1a/b (ORF1a/b) is below 90% identity (3). An
overall 80% nucleotide identity was observed between SARS-CoV-2 and the
original SARS- CoV, along with 89% identity with ZC45 and ZXC21 SARS-related
CoVs of bats (2, 31, 36). In addition, 82% identity has been observed between
SARS-CoV-2 and human SARS-CoV Tor2 and human SARS-COV BJ01 2003 (31).
A sequence identity of only 51.8% was observed between MERS-related CoV and
the recently emerged SARS-COV-2 (37). Phylogenetic analysis of the structural
genes also revealed that SARS-CoV-2 is closer to bat SARS-related CoV. Therefore,
SARS-CoV- 2 might have originated from bats, while other amplifier hosts might
have played a role in disease transmission to humans (31). Of note, the other two
zoonotic CoVs (MERS-related CoV and SARS-related CoV) also originated from bats
(38, 39).
Nevertheless, for SARS and MERS, civet

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encircled with an envelope containing viral nucleocapsid. The nucleocapsid in CoVs

are arranged in helical symmetry, which reflects an atypical attribute in Positive-
sense RNA viruses (30). The electron micrographs of SARS-CoV-2 revealed a
diverging spherical outline with some degree of pleomorphism, virion diameters
varying from 60 to 140nm, and distinct spikes of 9 to 12nm, giving the virus the
appearance of a solar corona (3). The CoV genome is arranged linearly as 5'-leader-
UTR-replicase-structural genes (S-E-M-N) -3' UTR-poly(A) (32). Accessory
genes, such as 3a/b, 4a/b , and the hemagglutinin-esterase gene (HE), are also seen
intermingled with the structural genes (30). SARS-CoV-2 has also been found to be
arranged similarly and encodes several accessory proteins, although it lacks the HE,
which is characteristics of some Beta-coronaviruses (31). The Positive- sense
genome of CoVs serves as the mRNA and is translated to polyprotein 1a/1ab (pp
1a/1ab) (33). A replication-transcription complex (RTC) is formed in double-
membrane vesicles (DMVs) by non-structural proteins (nsps), encoded by the poly-
proteins gene (34). Subsequently, the RTC synthesizes a nested set of subgenomic
RNAs (sgRNAs) via discontinuous transcription (35).

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A pandemic situation in the worldwide population, leading to disease outbreaks

that have not been controlled to date, although extensive efforts are being put in
place to counter this virus (25). This virus has been proposed to be
designated/named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
by the International Committee on Taxonomy of Viruses (ICTV), which
determined the virus belongs to the severe acute respiratory syndrome-related
coronavirus category and found this virus is related to SARS-CoVs (26). SARS-CoV-
2 is a member of the order Nidovirales, family Coronaviridae, subfamily
Orthocoronavirinae, which is subdivided into four genera, viz., Alpha-
coronavirus, Beta-coronavirus, Gamma-coronavirus, and Delta-coronavirus
have evolved from bird and swine gene pools (24, 28, 29, 275).

Coronaviruses possess an unsegmented, single-stranded, positive-sense

RNA genome of around 30 kb, enclosed by a 5'-cap and 3'-poly (A) tail (30). The
genome of SARS-CoV-2 is 29,891 bp long, with a G+C content of 38% (31). These
viruses are encircled with an envelope containing viral.

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Some therapeutic options for treating COVID-19 showed efficacy in , in vitro

studies; however, to date, these treatments have not undergone any randomized
animal or human clinical trials, which limit their practical applicability in the
current pandemic (7, 9,19-21).

The present comprehensive review describes the various features of SARS-

CoV-2/ COVID-19 causing the current disease outbreaks and advance in diagnosis
and developing vaccines and therapeutics. It also provides a brief comparison with
the earlier SARS and MERS CoVs, the veterinary perspective of CoVs and this
emerging novel pathogen, and an evaluation of the zoonotic potential of similar
CoVs to provide feasible One Health strategies for the management of this fatal
virus (22 - 367).

THE VIRUS (SARS-CoV-2)

Coronaviruses are Positive-sense RNA viruses having an extensive

and promiscuous range of natural hosts and affect multiple systems (23,24).
Coronaviruses can cause clinical disease in humans that may extend from the
common cold to more severe respiratory diseases like SARS and MERS (17 ,

279). The recently emerging SARS-CoV-2 has wrought havoc in China and caused a
pandemic situation in the worldwide population leading to

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Furthermore, SARS-CoV-2 is genetically distinct from SARS-CoV (79% similarity)

and MERS-CoV (nearly 50%) (17). COVID-19 is associated with afflictions of the
lungs in all cases and generated characteristics chest computer tomography
findings, such as the presence of multiple lesions in lung lobes that appear as
dense, ground-glass opaque structures that occasionally coexist with consolidation
shadows (18).

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New targeted drugs, and prevention of further epidemics (13). The most
common symptoms associated with COVID-19 are fever, cough, dyspnea,
expectoration, headache, and myalgia or fatigue.

In contrast, less common signs at the time of hospital admission include

diarrhea, Hemoptysis, and shortness of breath (14). Recently, individuals with
asymptomatic infections were also suspected of transmitting infections, which
further adds to the complexity of disease transmission dynamics in COVID-19
infections (1). Such efficient responses require in-depth knowledge regarding the
virus, which currently is a novel agent; consequently, further studies are required.

Comparing the genome of SARS/SARS-like CoV revealed that the sequence

coding for the spike protein, with a total length of 1,273 amino acids, showed 27
amino acid substitutions. Six of these substitutions are in the region of the
receptor-binding domain (RBD), and another six substitutions are in the
underpinning subdomain (SD) (16). Phylogenetic analysis has revealed that
SARS-CoV-2 is closely related (88% similarity) to two SARS-like CoVs derived
from bat SARS-like CoVs (bat-SL-CoVZC45 and bat-SL-CoVZXC21) (Fig. 1).

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range of hosts, producing symptoms and diseases ranging from the common cold to
severe and ultimately fatal illnesses, such as SARS, MERS, and presently,
COVID-19. SARS-CoV-2 is considered one of the seven members of the CoV
family that infect humans (3), and it belongs to the same lineage of CoVs that
causes SARS; however, this novel virus is genetically distinct. Until 2020, six CoVs
were known to infect humans, including human CoV 229E (HCoV-229E), HCoV-
NL63, HCoV-OC43, HCoV-HKUI, SARS-CoV, and MERS-CoV have resulted in
outbreaks with high mortality, others remain associated with mild upper-
respiratory-tract illnesses (4).

Newly evolved CoVs pose a high threat to global public health. The current
emergence of COVID-19 is the third CoV outbreak in humans over the past 2
decades (5). It is no coincidence that Fan et al. Predicted potential SARs- or
MERS-like CoV outbreaks in China following pathogen transmission from bats (6).
COVID-19 emerged in China and spread rapidly throughout the country and,
subsequently, to other countries. Due to the severity of this outbreak and the
potential of spreading on an international scale, the WHO declared a global health
emergency on 31 January 2020; subsequently.

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on 11 March 2020, they declared it a pandemic situation. At present, we are not in

a position to effectively treat COVID-19, since neither approved vaccines nor
specific antiviral drugs for treating human CoV infections are available (7 - 9). Most
nations are currently making efforts to prevent the further spreading of this
potentially deadly virus by implementing preventive and control strategies.

In domestic animals, infections with CoVs are associated with a broad

spectrum of pathological conditions. Apart from infectious bronchitis virus, canine
respiratory CoV, and mouse hepatitis virus, CoVs are predominantly associated
with gastrointestinal disease (10). The emergence of novel CoVs may have
become possible because of multiple CoVs being maintained in their natural host,
which could have favored the probability of genetic recombination (10). High
genetic diversity and the ability to infect multiple host species are a result of high-
frequency mutations in CoVs, which occur due to the instability of RNA-dependent
RNA polymerases along with higher rates of homologous RNA recombination (10,
11). Identifying the origin of SARS-CoV-2 and the pathogen's evolution will be
helpful for disease surveillance (12).

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