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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 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-2transmission 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 present 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 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 traveling 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 its 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). 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).

b5458a3bdbf09093f413815c53e5b09872dd5c5aa847aba905c9d1594265784d2

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 4,644 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 ofcases, 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 (226,467 1) 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 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 2019are presented as a timeline in Fig. 5. Major events of current coronavirus COVID-19 disease outbreak 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, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-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 (originally 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 trimeric SI locates itself on top of the trimeric S2 stalk (45). Recently, structural analyses of the S proteins of COVID-19 have revealed 27 amino acid substitutions within a 1,273-amino-acid stretch (16). Six substitutions are located in the RBD (amino acids 357 to 528), while four substitutions are in the RBM at the CTD of the S1 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 is knowing how many differences would be required to change the host tropism. Sequence comparison revealed 17 nonsynonymous 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 ORFlab, ORF8 (4 substitutions), the spike gene (3 substitutions), and ORF7a (single substitution) (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 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-2E 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, 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 (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 nsps and Accessory Proteins Besides the important structural proteins, the SARS-CoV-2 genome contains 15 nsps, nsp1 to nsp10 and nsp12 to nspl6, 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 pó 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.

b5458a3bdbf09093f413815c53e5b09872dd5c5aa847aba905c9d1594265784d1

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 4,644 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 ofcases, 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 (226,467 1) 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 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 2019are presented as a timeline in Fig. 5. Major events of current coronavirus COVID-19 disease outbreak