**Analysis for Treatment** :

The treatment approaches for treating Covid-19 showed productiveness in laboratory based
studies; however these treatments have not been undertaken any haphazard any animal or
human clinical trials yet, which limit their practical validity in current pandemic (7, 9, 19-21)
The current comprehensive review reveals the various features of SARS-CoV-2/COVID-19 which is
the cause of the current disease outbreaks and progress in diagnosis and evoluting vaccines and
remedies. It also provides a comparison in brief with the ultimate SARS and MERS CoVs, the
veterinary outlook of CoVs and this appearing novel microbe, and an assessment of the zoonotic
potential of similar CoVs to give feasible One Health plans for the management of this lethal
virus (22-367).
* **
*THE VIRUS (SARS-CoV-2)
**Introduction**:
Corona viruses are positive-sense RNA viruses having an ample and dissolute range of natural
hosts and affect numerous systems (23, 24). Corona viruses can cause infection in humans that
may grow from the common cold to more severe respiratory diseases like SARS and MERS (17,
279). The recently appearing SARS-CoV-2 has created desolation in China and caused a pandemic
situation in the global population, leading to uncontrollable disease breakout, although
considerable resources are being allocated to counter this virus (25). The International
Committee on Taxonomy of Viruses (ICTV) has proposed naming the virus Severe Acute
Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). According to the ICTV, this virus belongs to
the category of Severe Acute Respiratory Syndrome-related coronaviruses and is closely related
to [Link]-CoV-2 belongs to the order Nidovirales, family Coronaviridae, and subfamily
Orthocoronavirinae. This subfamily is further classified into four genera: Alphacoronavirus,
Betacoronavirus, Gammacoronavirus, and Deltacoronavirus. The genera Alphacoronavirus and
Betacoronavirus comes from bats, while Gammacoronavirus and Deltacoronavirus have came
out from bird and swine gene pools (24, 28, 29, 275). Corona viruses have an intact, single-
stranded,positive-sense RNA genome, approximately 30 kilobases (kb) in length, which is flanked
by a 5'-cap and a 3'-poly(A) tail (30). The length of genome of SARS-CoV-2 is 29,891 bp, with a G+C
content of 38% (31). These viruses are enclosed in an envelope containing nucleocapsid. The
nucleocapsids in CoVs have helical symmetry, which shows an atypical attribute in positive-sense
RNA viruses (30). The electron micrographs of SARS-CoV-2 shows a radiating spherical form with
some degree of pleomorphism, the diameter of virion varies from 60 to 140 nm, and distinct
spikes of 9 to 12 nm, due to which the virus appears as a solar corona (3). The arrangement of
CoV genome is 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
intermixed with the structural genes (30). Similar arrangement has been observed in SARS-CoV-2
and it also encodes several accessory proteins, although HE is absent in it, which is feature of
some Betacoronaviruses (31). The positive-sense genome of CoVs works as the mRNA and is
translated to polyprotein la/lab (ppla/lab) (33). A replication-transcription complex (RTC) forms
within double-membrane vesicles (DMVs) through nonstructural proteins (nsps) encoded by the
polyprotein gene. This RTC then produces a nested set of subgenomic RNAs (sgRNAs) through
discontinuous transcription (35).
SARS-CoV-2 is classified as a new Betacoronavirus within the Sarbecovirus subgenus (3).
Although it shares similarities with other zoonotic viruses like MERS-related CoV and SARS-
related CoV, SARS-CoV-2 is distinct, showing less than 90% identity in the conserved ORF1a/b
region (3). It has about 80% nucleotide identity with the original SARS-CoV and 89% identity with
bat SARS-related CoVs like ZC45 and ZXC21 (2, 31, 36) . SARS-CoV-2 also shows 82% identity with
human SARS-CoV strains Tor2 and BJ01 2003 (31). In contrast, it has only 51.8% identity with
MERS-related CoV (37). Phylogenetic analysis suggests SARS-CoV-2 likely originated from bats,
with possible involvement of amplifier hosts in transmission to humans (31). Similar to SARS and
MERS, which also originated from bats, SARS-CoV-2's transmission dynamics may involve
intermediate hosts, such as civet cats for SARS and camels for MERS (38, 39) .Coronavirus
genomes contain six open reading frames (ORFs) (31), with ORF1a/b occupying most of the 5' end
and encoding 16 nonstructural proteins (nsps) (32). These nsps are produced as two polyproteins,
pp1a and pp1ab, which are cleaved by viral proteases into individual proteins, including main
protease (Mpro), chymotrypsin-like protease (3CLpro), and papain-like proteases (PLPs) (42).
SARS-CoV-2 shares these features, with recent studies elucidating the functions of these nsps (31).
Notably, SARS-CoV-2 has distinct features, including a novel short protein within ORF3 and a
secreted protein with an alpha helix and beta-sheet encoded by ORF8 (31). The virus also encodes
four major structural proteins: spike (S), membrane (M), envelope (E), and nucleocapsid (N).
**S glycoprotein** :

The coronavirus S protein, also known as the spike glycoprotein, is a large, multifunctional class
I viral transmembrane protein. Its size varies from 1,160 amino acids (in infectious bronchitis
virus, IBV) to 1,400 amino acids (in feline coronavirus, FCoV) (43). The S protein forms a trimer
on the virion surface, giving it a crown-like appearance. It plays a crucial role in viral entry into
host cells by interacting with cellular receptors (44) and determines tissue tropism and host
range (45). The S protein is also a key immunodominant protein that induces host immune
responses (45). The ectodomains of S proteins are divided into two subunits: S1, which helps with
host receptor binding, and S2, which facilitates fusion (43). The S1 subunit is further divided into
the N-terminal domain (NTD) and C-terminal domain (CTD), both of which can act as receptor-
binding domains (45). The CTD contains the receptor-binding motif (RBM), and the trimeric S1
sits atop the trimeric S2 in the spike protein [Link] evolution highlights the need for
close monitoring of viral mutations during human-to-human transmission.
**M protein** :
The M protein is the most abundant protein in the virion, shaping the viral envelope (48). It binds
to the nucleocapsid, organizing coronavirus assembly (49). Despite diversity in amino acid
content, M proteins maintain structural similarity across genera (50). The M protein features
three transmembrane domains, with a short amino terminus outside and a long carboxy
terminus inside the virion (50). M-M interactions maintain the viral scaffold. Notably, the SARS-
CoV-2 M protein has no amino acid substitutions compared to SARS-CoV (16).
**E protein** :
The E protein, the smallest major structural protein, is enigmatic (51). It plays multiple roles in
pathogenesis, assembly, and release (52) and acts as a viroporin (ion channel) (53).
* : protein*
**N
As the virus evolves, tracking genetic shifts during interpersonal transmission is crucial.
The structural framework of the virus relies heavily on a specific protein, which dictates the
morphology of its outer layer (48). This protein interacts with the genetic material, orchestrating
the assembly process (49). Despite variations in composition, this protein's overall architecture
remains consistent across different viral strains (50). Its configuration includes three membrane-
spanning segments, with a brief sequence exposed externally and a longer sequence internally
(50). Protein-protein interactions maintain the virus's structural integrity. Interestingly, this
protein in the current virus exhibits no sequence deviations compared to its predecessor (16).

Another protein, shrouded in mystery, plays a pivotal role in the viral lifecycle (51). Its
multifaceted nature influences disease progression, particle formation, and release (52),
functioning as a molecular gateway (53).
**nsps and accessory proteins**:
Our analysis utilized the Megalign software to evaluate nucleotide similarity, revealing a 99.4%
to 100% similarity range among the novel SARS-CoV-2 isolates .When compared to other
Serbecovirus the novel SARS-CoV-2 sequences exhibited the highest similarity to bat-SL-CoV,
with a nucleotideidentity range of 88.12% to 89.65%. In contrast, previously reported SARS-CoVs
displayed a lower similarity range of 70.6% to 74.9% to SARS-CoV-2. Furthermore, the
nucleotide similarity was 55.4 % for Hibecovirus, 45.5% to 47.9% for Nobecovirus, 46.2% to 46.
6% for Merbecovirus, and 45.0% to 46.3% for Embecovirus. The high similarity index between
SARS-CoV-2 isolates and bat-SL-CoV suggests a recent common ancestry. Exhaustive
examination of viral genomes may
reveal the intricacies of this relationship and potentially pinpoint the natural reservoir of the
virus.

**Splits tree phylogeny analysis** :

Phylogenetic analysis using SplitsTree revealed distinct clustering patterns among

Betacoronaviruses based on S protein sequences, with different subgenera forming separate
groups. SARS-CoV-2 sequences from Wuhan and other countries exhibited a close relationship
and appeared in a single cluster. The Sarbecovirus subgenus appeared jointly inSplitsTree and
divided into three subclusters, namely, SARS-CoV-2, bat-SARS-like-CoV (bat-SL-CoV), and SARS-
CoV. In other subgenera, like Merbecovirus, sequences grouped in a singlecluster, whereas
Embecovirus sequences from different species, including canine, bovine,equine, and human
CoV strain (OC43), grouped in a common cluster. Isolates in the subgenera Nobecovirus and
Hibecovirus were found to be placed separately away from other reportedSARS-CoVs but shared
a bat origin.

**CURRENT WORLDWIDE SCENARIO OF SARS-CoV-2** :

The COVID-19 outbreak has had severe economic impacts globally due to the sudden
interruption of global trade and supply chains that forced multinational companies to make
decisions leading to significant economic losses (66). The recent increase in confirmed critically
ill patients with COVID-19 has surpassed intensive care supplies, limiting services to only a small
portion of critically ill patients (67). This might have contributed to the increased case fatality
rate observed in the COVID-19 outbreak.
*The Spread of SARS-CoV-2: A Comprehensive Review ** :
The novel coronavirus was identified remarkably quickly, within 28 days of the outbreak,
compared to the 125 days it took to identify SARS-CoV in 2003 (68). Chinese virologists swiftly
released the SARS-CoV-2 genomic sequence, which was crucial in controlling the global spread of
the virus (69). However, the exact origin and initial transmission mode of SARS-CoV-2 remain
unknown (70). Analysis of early cases suggests a possible link to the Huanan Seafood Market in
Wuhan, where wild animals were sold for human consumption (71, 72). This market may have
been the point of zoonotic transmission (71). While SARS-CoV-2 is believed to have originated
from an animal host with subsequent human-to-human transmission (Fig. 6), the possibility of
foodborne transmission cannot be ruled out without further investigation (1). Other potential
transmission routes, such as direct contact and contaminated surfaces, are also being explored
(Fig. 6). Additionally, the potential for transmission through blood transfusion, organ
transplantation, transplacental, and perinatal routes requires further determination (Fig. 6).
Experience with previous viral outbreaks suggests that higher pathogenicity often correlates
with lower transmissibility. SARS-CoV-2 exhibits relatively lower pathogenicity and moderate
transmissibility compared to viruses like Ebola, avian H7N9, SARS-CoV, and MERS-CoV (15). The
infection fatality risk (IFR) for COVID-19 is estimated to be 0.3% to 0.6%, comparable to the 1957-
1958 Asian influenza pandemic (73, 277). Human-to-human transmission is evident, with some
studies suggesting that the initial outbreak may have originated from human-to-human
transmission rather than animal-to-human transmission at the Wuhan seafood market (74).
However, the zoonotic origin of COVID-19 cannot be ruled out (1). The basic reproduction
number (Ro) estimates range from 1.4 to 3.58, indicating moderate to high transmissibility (70,
75, 76). A higher Ro value suggests greater potential for transmission in a susceptible population.
China's culinary practices, particularly the sale of live animals, have been linked to previous
outbreaks, including SARS (78, 79). The cultural preference for live-slaughtered animals may
contribute to the emergence of novel coronaviruses (5).
After four months of intense efforts to control COVID-19, China appears to have brought the
situation under control, and life seems to be returning to normal. However, the reopening of wet
markets, where live animals such as bats, pangolins, and other exotic species are sold, raises
concerns about the potential for future outbreaks. Despite warnings from health experts to avoid
contact with live or dead animals, many markets have resumed operations without
implementing proper food safety and sanitation practices. China's temporary ban on the sale of
live animals in these markets, imposed in January 2020, has been lifted, and hundreds of markets
have reopened. This move may increase the risk of zoonotic spillover and the emergence of new
mutations in the SARS-CoV-2 virus.

**Reopening of China's wet markets** :

The reopening of China's wet markets, where live animals are sold for human consumption, has
sparked widespread concern among health experts and scientists. Despite the initial temporary
ban on the sale of live animals in these markets, many have now resumed operations without
implementing adequate measures to ensure food safety and sanitation. This move is feared to
potentially reignite the cycle of animal-to-human transmission of diseases, particularly given the
role that such markets are believed to have played in the emergence of the COVID-19 pandemic.

**Lack of stringent hygiene** :

The lack of stringent hygiene practices in these markets creates an environment conducive to the
spread of pathogens. Fresh blood splashes and unsanitary conditions are commonplace,
increasing the risk of zoonotic spillover and the emergence of new viral mutations. The global
community has been grappling with the devastating consequences of the COVID-19 pandemic,
which has resulted in millions of cases and hundreds of thousands of deaths worldwide. The
reopening of these markets without proper oversight and regulation may undermine efforts to
prevent future pandemics and protect global health.

There is an urgent need for policymakers to reassess the risks associated with these markets and
consider implementing stricter regulations to mitigate the potential for future outbreaks. This
may involve enforcing strict hygiene and sanitation standards, restricting the sale of certain
animal species, or even permanently closing markets that pose a significant risk to public health.
The international community must work together to address the complex challenges posed by
the intersection of human, animal, and environmental health, and to develop sustainable
solutions that prioritize both public health and animal welfare.
Healthcare professionals should be aware of unusual symptoms of COVID-19 to prevent
misdiagnosis. The transmissibility of SARS-CoV-2 in its early stages is similar to or slightly higher
than SARS-CoV, indicating that it can be controlled despite moderate to high contagiousness. The
detection of SARS-CoV-2 in sewage and wastewater necessitates further investigation due to the
potential for fecal-oral transmission. SARS-CoV-2 in environmental sources like soil and water
can ultimately contaminate wastewater treatment plants. Therefore, it is essential to reassess
current wastewater treatment procedures and implement advanced techniques specifically
designed to combat SARS-CoV-2. The active shedding of SARS-CoV-2 in stool enables the use of
wastewater-based epidemiology to study the prevalence of infections in large populations.
Recently, RT-qPCR was utilized to quantify SARS-CoV-2 RNA in wastewater, allowing for the
estimation of infected individuals based on viral RNA copy numbers.
The COVID-19 pandemic underscores the importance of incorporating negative fecal viral nucleic
acid test results as a supplementary discharge criterion for laboratory-confirmed cases (326).
This pandemic doesn't introduce novel factors beyond the genetically distinct pathogen and
potential reservoir. The underlying causes and likely future outcomes mirror previous
encounters with lethal coronaviruses. The timing and genetic uniqueness of the pathogen are the
primary distinguishing features. Mutations in the receptor-binding domain of coronaviruses
have enabled them to infect new hosts, thereby expanding their global reach (85). Research
suggests that SARS-CoV-2 likely originated from bat SARS-like coronaviruses, with phylogenetic
analysis revealing relationships to bat-origin coronaviruses (86, 17). SARS-CoV-2 utilizes ACE2 as
an entry receptor, exhibiting a receptor-binding domain similar to that of SARS-CoV (17, 87, 254,
255). In response, several countries have issued travel advisories for individuals traveling to
China (88, 89).
The efficiency of SARS-CoV-2 human-to-human transmission was initially thought to be lower
compared to previous outbreaks of SARS-CoV and MERS-CoV. This assumption was based on the
observation that healthcare workers were less affected than in previous outbreaks of fatal
coronaviruses (2). However, superspreading events have been a significant factor in the
extensive transmission of SARS and MERS, and it is possible that similar events may have
contributed to the spread of COVID-19 (90, 91).

In the case of MERS-CoV, nearly half of the cases reported in Saudi Arabia were secondary
infections resulting from human-to-human transmission, often through contact with infected
individuals who were either asymptomatic or symptomatic (92). Given the similarities between
COVID-19 and other coronaviruses, it is essential to evaluate the possibility of superspreading
events in the COVID-19 outbreak.

Like SARS and MERS, COVID-19 can infect the lower respiratory tract, often presenting with
milder symptoms (27). The basic reproduction number of COVID-19, which measures the
potential for transmission, has been estimated 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). These estimates suggest that COVID-
19 has a moderate to high transmission potential, highlighting the need for continued vigilance
and public health measures to control its spread.
*Key Considerations:*

- *Superspreading Events:* The role of superspreading events in the COVID-19 outbreak requires
further evaluation to inform public health strategies.
- *Transmission Dynamics:* Understanding the transmission dynamics of COVID-19, including
the potential for human-to-human transmission, is crucial for developing effective control
measures.
- *Public Health Measures:* Continued vigilance and public health measures, such as contact
tracing and isolation, are essential to control the spread of COVID-19.