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 Table of Contents  
Year : 2020  |  Volume : 22  |  Issue : 3  |  Page : 10-15

Evolutionary origin and structure of SARS-CoV-2 – A brief narrative review

1 Professor and Head Microbiology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
2 Senior Resident, Microbiology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
3 Department of Psychiatry, NIMHANS, Bengaluru, Karnataka, India

Date of Submission22-Sep-2020
Date of Decision13-Oct-2020
Date of Acceptance15-Oct-2020
Date of Web Publication02-Nov-2020

Correspondence Address:
Dr Pratima Gupta
Department of Microbiology, All India Institute of Medical Sciences, Rishikesh - 249 203, Uttarakhand
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jmms.jmms_141_20

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Coronavirus disease 19 (COVID-19) outbreak occurred in Wuhan city, China, in December 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that belongs to the group of beta-coronaviruses (CoVs) and has created an unprecedented situation worldwide. Since the inception of this disease, the mystery about the origin still persists. Over 3200 types of CoVs can infect bats; therefore, finding out the susceptibility of CoVs to specific species of bats is always challenging. Similarities of pangolin-CoV with SARS-CoV-2 and bat CoV suggested pangolin as another intermediate host of SARS-CoV-2. Recombination mechanism is primarily crucial to understand the origin of CoVs as it creates genetic diversity, thus novel variants of viruses emerged. In this review, attention has been paid to understand the origin and structure of SARS-CoV-2. This will help prevent similar pandemics in the future as well as effective in discovering possible therapeutic targets and vaccines.

Keywords: Bats, coronavirus disease 19, recombination, SARS-CoV-2, zoonosis

How to cite this article:
Gupta P, Gairolla J, Varshney P. Evolutionary origin and structure of SARS-CoV-2 – A brief narrative review. J Mar Med Soc 2020;22, Suppl S1:10-5

How to cite this URL:
Gupta P, Gairolla J, Varshney P. Evolutionary origin and structure of SARS-CoV-2 – A brief narrative review. J Mar Med Soc [serial online] 2020 [cited 2021 Jan 20];22, Suppl S1:10-5. Available from: https://www.marinemedicalsociety.in/text.asp?2020/22/3/10/299800

  Introduction Top

Near the end of 2019, few clusters of cases with idiopathic pneumonia were reported in Wuhan city, China.[1] From 18 to 29 December, 2019, 5 patients were hospitalized in Wuhan Jinyintan Hospital, Hubei province, China. Later on, by January 2, 2020, 41 patients with pneumonia of unknown cause were hospitalized with comorbidities including hypertension, diabetes, and cardiovascular disease.[2] After sequencing analysis of samples obtained from the lower respiratory tract, the Chinese Center for Disease Control and Prevention declared on January 7 that this novel coronavirus pneumonia was caused by a novel coronavirus (2019-nCoV).[3]

The WHO on January 30, 2020, declared coronavirus disease 19 (COVID-19) as a global public health emergency and on March 11, 2020, COVID-19 as a pandemic (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen). The International Committee on Taxonomy of Viruses on February 11, 2020, named the novel coronavirus as “SARS-CoV-2” and the WHO on February 11, 2020, named the disease as “COVID-19” [Figure 1] showing the timeline events of COVID-19.[2],[4] Before the end of January 2020, a sum of 571 cases of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were confirmed in 25 provinces in China, and several exported cases were also reported from other countries such as Thailand, Malaysia, Taiwan, the UAE, Korea, Japan, and the USA.[2],[5],[6] Since the inception of COVID-19 to date, the global situation is worsening every day as the confirmed cases are rising and have brought the world to a standstill. According to the WHO, at present, there have been 2, 53, 27,098 infected cases of SARS-CoV-2, and 8, 48, 255 deaths have occurred across the globe. The United States of America is leading in COVID-19 case tally and over 13,596,877 cases have been confirmed by the 1st week of September 2020. As of September 3, 2020, there were 3.8 million cases of COVID-19 in India which is now the third most affected country after the USA and Brazil.[7] Till the time manuscript was being written, a total of 8,82,542 active cases were reported with a recovery rate having increased to 77%. The overall number of recovered patients is 3.61 times higher than the active cases.[8]
Figure 1: The timeline events of COVID-19

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The global case fatality rate of COVID-19 is estimated between 2.1% and 3.4% which is lesser than of Middle East respiratory syndrome (MERS) (34.4%) and SARS (9.5%),[9],[10] however, the number of cases, deaths, and affected countries has far surpassed comparatively to MERS-CoV and SARS-CoV.[11]

  Origin of Sars-Cov-2 Top

The issues concerning the origin of SARS-CoV-2 outbreak and evolutionary crossover of the source between animals and humans are still unclear.[12] Identification of the reservoir of infection is crucial to understand the phylogeny, limit the spread of the pathogen, and thus allow the authority to isolate humans from potential sources of infection. Initial reports on COVID-19 cases from China suggest its epidemiological association to an open-air seafood market in the city of Wuhan, China. Most of the infected had exposure and gave a history of eating seafood contaminated with bats or bat droppings which thus revealed the zoonotic origin of SARS-CoV-2.[13],[14] However, some individuals who developed the COVID-19 disease gave no record of visiting the seafood market; in these cases, the zoonotic source remained obscure. It might be possible that SARS-COV-2 originated elsewhere and the crowded seafood market of Wuhan only contributed to the spreading of this epidemic.[15]

The evolutionary and genomic analysis of pangolin-CoV with SARS-CoV-2 and bat CoV RaTG13 showed 91% and 90.5% similarity, respectively, which suggested pangolin as an intermediate host of SARS-CoV-2.[16] In general, due to ecological disruptions, the exposure of humans to wildlife is increasing which possibly allows coronaviruses (CoVs) to mutate their genetic component and becomes more adapted to infect human host which as a result may cause a threat to human health like the outbreak of SARS and MERS and the global pandemic of COVID-19. Over the last three decades, numerous cross-species transmission diseases have been reported. Till the emergence of COVID-2019, the most noteworthy events of cross-species transmission were SARS and MERS which were reported in late 2002–2003 and 2012 in Guangdong Province, China, and Saudi Arabia, respectively.[9],[17] SARS, an infection, is caused by SARS-CoV, a beta-CoV, and palm civets as well as raccoon dogs as a reservoir, whereas on the other hand, MERS is caused by other CoVs belongs to subgenus Merbecovirus known as MERS-CoV.[18] [Table 1] provides a brief overview of the comparative characteristics of COVID-19, MARS, and SARS.[11],[19],[20],[21],[22],[23],[24],[25]
Table 1: A brief overview of the comparative characteristics of coronavirus disease-19, middle east respiratory syndrome, and severe acute respiratory syndrome

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There are more than 1300 species of bats and over 3200 types of CoVs which can infect bat; therefore, finding out the susceptibility of CoVs to specific species of bats is always difficult.[12],[26] Recently, closely related sequences of SARS-CoV-2 were obtained from Malayan pangolins which further strongly evidenced its zoonotic origin.[27] Thus, pangolin as a missing link for SARS-CoV-2 transmission between wildlife and humans has been proposed.[16]

Ever since the COVID-19 global outbreak, a key question about its origin is hanging among the scientific communities. By the use of high throughput sequencing technology and sequence annotation, the characterization of SARS-CoV-2 was witnessed comparatively faster than ever[1],[28] after few weeks of incidence in Wuhan, China. In the month of February 2020, Hao et al. unsupported the conspiracy theory of the lab origin COVID-19 though a scientific rebuttal that strongly discredited the lab manipulation as they found that unique sequence (1378 bp) in spike gene of SARS-CoV-2 has high sequence identity with other CoVs, thus indicating natural existence.[29] Moreover, scientists and public health and medical professionals from various countries strongly condemned the conspiracy over lab origin and manmade manipulations in SARS-CoV-2 genome as they sequenced and published the validated scientific information that overwhelmingly concluded the wildlife origin of this CoV.[30]

  Structure of Sars-Cov-2 Top

CoVs form a major group of viruses (Arteriviridae, Roniviridae, and Coronaviridae) under the Nidovirales order. Orthocoronavirinae is the subfamily of Coronaviridae which consists of four genera: α-, β-, δ-, and γ-CoVs. The first two, α- and β-CoVs, are found in mammals, whereas δ- and γ-CoVs are primarily found in birds.[12],[31] SARS-COV-2 is a member of β-CoVs, and the size of virion ranges from 50 to 200 nm and possesses a single-strand positive-sense RNA genome of 29.9 kb length that encodes for 9860 amino acids.[32],[33] However, distinctive RNA-dependent RNA polymerase of SARS-CoV-2 has placed this virus in sarbecovirus subgenus. The family of CoVs consists of nucleic acid core surrounded by glycoprotein-spiked envelope which appears like a crown [Figure 2] depicts the structure of SARS CoV-2.
Figure 2: The structure of SARS -CoV-2

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Initial findings by Zhou et al. showed 96% sequence identity of novel SARS-CoV-2 with the CoVs of horseshoe bat origin, i.e., beta-CoV RaTG13 (Rhinolophus affinis).[28] SARS-CoV-2 binds to angiotensin-converting enzyme-2 (ACE-2) receptor present on epithelial cells and many other tissues including lungs, heart, kidneys, and facilitating viral entry.[34] Recently, more than 8000 point mutations have been found in the SARS-CoV-2 genome which directly affects the viral infectivity.[35] The receptor-binding domain (RBD) of SARS-CoV-2 is a mutated version of RaTG13 virus-bats (R. affinis) with increased RBD affinity to ACE-2 in humans.[36] Later on, the genome analysis in the samples obtained from COVID-19 patients showed 88% identity with bat CoVs. This also indicates that genetic sequences were distant from previously reported SARS (about 79%) and MERS (about 50%), respectively.[37] In addition, homology modeling revealed structural similarity of RBD between SARS-COV and SARS-COV-2.[37]

The genome annotation of the first three strains of SARS-COV-2 obtained from Wuhan, China, showed only 5 base pair differences in the genome of strains.[38] SARS-COV-2 possesses 14 open reading frames (ORFs) encoding 27 proteins. ORF1a and b regions constitute the major part encode polyproteins (pp1a and pp1ab) comprising most of the nonstructural proteins.[38],[39] 3'-UTR end of the genome encodes 8 accessory proteins including 3a, 3b, p6, 7a, 7b, 8b, 9b, and orf14 and four important structural proteins crucial for pathogenesis including spike (S) protein, envelope (E) protein, membrane (M) protein, and nucleocapsid (N) protein of the virus.[39],[40],[41] Notably, all known CoVs are similar in structural proteins (S, E, M, and N) and genetic makeup, hence crossover may occur due to recombination. [Figure 2] depicts the structure of SARS CoV-2.

Recombination is a primary mechanism that plays a crucial role in the origin of CoVs as it creates genetic diversity.[42],[43] A recent study by Li et al. on the emergence of SARS-CoV-2 has shown the recombination and purifying selection in RBD in the spike protein between pangolin, bat, and human CoV emergence of novel SARS-COV-2.[44] Although ACE-2 serves as a common target receptor for both SARS-CoV and SARS-CoV-2,[45] both the viruses have shown a high level of genetic divergence.[44]

  Updates on Possible Vaccines for Covid-19 Top

The current COVID-19 pandemic creates an unprecedented challenge for the scientists and health professionals to develop an imperative and effective treatment for its prevention. The genomic sequence of SARS-CoV-2 was made available on January 12, 2020, and uploaded on National Center for Biotechnology Information GeneBank database (https://www.ncbi.nlm.nih. Gov/labs/virus/vssi/. accessed on October 10, 2020). This has triggered the development of therapeutic targets including vaccine. Currently, the number of clinical trials is in progress, and some of those are in Phase 3 (https://clinicaltrials.gov/ct2/results?cond = COVID-19). As per the landscape document prepared by the WHO and released on October 2, 2020, there are 42 candidate vaccines for COVID-19 in clinical evaluation, and among those, mRNA-1273, Gam-COVID-Vac, Ad5-nCoV, AZD1222, CoronaVac, CureVac, and ChAdOx1 are in Phase 3 of clinical trials (https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines. accessed on October 10, 2020). The other therapeutic options proposed to cure COVID-19 include plasma and interferon-based therapies, monoclonal antibodies, and oligonucleotide-based therapies. The various antiviral drugs that are broad spectrum in nature such as HIV protease inhibitors and nucleoside have been repurposed.[46],[47] Viral proteins are the prime targets that could turn into a vaccine through inactivation or attenuation, therefore, restricting the fusion of virus or its entry into host cells.[48] Subunit vaccines based on spike proteins (S1, S2, and RBD) and nucleocapsid protein are also under development.[46],[49] [Table 2] shows the list of vaccines entered in Phase 3 of clinical trial.[50],[51],[52]
Table 2: Current status of vaccines which have entered in Phase 3 of clinical trial

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In addition, clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein nuclease (Cas) has also been proposed as an alternative and a promising antiviral approach that relies on virus recognition, and degradation of intracellular viral genome could be effective in eliminating viral infections.[53],[54] Recently, a bioinformatics-based study by Abbott et al. has shown that the group of CRISPR RNAs can target more than 90% of all CoVs, and this prophylactic antiviral CRISPR in human strategy could effectively degrade SARS-CoV-2 genome.[53] Recently Indian Council of Medical Research(ICMR) has approved a new rapid diagnostic test based on CRISPR-Cas9 technology to detect genetic material of SARS-CoV-2 virus.

  Conclusion Top

From the beginning of COVID-19 pandemic, the mystery about SARS-COV-2 origin persists on whether it was manmade in the lab or it was originated from natural selection. The emergence of COVID-19 through lab manipulation has been discredited and improbable as the facts are limited leading to a rebuttal to the claim of formation through lab recombination. From a public health perspective, there is a need for insight into the origin of SARS-CoV-2 and of how the virus entered the human population will be effective to prevent similar pandemic in the future, instrumental in discovering possible therapeutic targets and vaccine.

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  [Table 1], [Table 2]


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