Volume 8, Issue 6, December Issue - 2020, Pages:683-708 |
Authors: Sonam Tripathi, Megha Katare Pandey, Yashpal Singh Malik, Muhammad Bilal, Kuldeep Dhama, Wanpen Chaicumpa, Ram Chandra |
Abstract: The novel coronavirus (CoV), earlier named 2019-nCoV, and later as severe acute respiratory syndrome coronavirus - 2 (SARS-CoV-2) has now created havoc and panic across the globe by its severe ongoing pandemic. This virus has to date as of 23rd November 2020, killed nearly 1.4 million persons out of more than 59 million confirmed positive cases, while spreading rapidly in more than 215 countries and territories. Taxonomically, SARS-CoV-2 has been characterized in genus Betacoronavirus, which contains non-segmented positive-sense, single-stranded (ss) RNA genome of ~30 kb. The first two open reading frames (ORFs), ORF1a and ORF1b, of SARS-CoV-2, encode 16 non-structural proteins (nsp1-nsp16), whereas other ORFs encodes four main structural proteins (sp) [spike (s) by ORF2, envelope (E) by ORF4, membrane (M) by ORF5, nucleoprotein (N) by ORF9], and accessory proteins essential for the virus fitness, pathogenesis and host immunity evasion. Sequence alignments of SARS-CoV-2 with genomes of various coronaviruses showed 58% identity in the non-structural protein (nsp)-coding region, 43% with the structural protein (sp)-coding region and 54% with the whole genome. The full-length genome sequence of the 2019-nCoV sample showed only up to 79.60% similarity with SARS CoV, but up to 96% similarity with bat coronavirus (bat coronavirus RaTG13). This gives strong evidence that 2019-nCoV has originated from the bat. The genomic and evolutionary evidence of another coronavirus species from pangolins also show higher similarity to SARS-CoV at the whole-genome level. Apart from RaTG13, Pangolin-CoV is the most closely related CoV to SARS-CoV-2. During infection, the viral S protein interacts with the receptor protein of the human cell membrane, known as angiotensin-converting enzyme II (ACE2). Presently, SARS-CoV-2 vaccines and drugs are not available, for which researchers are trying hard to develop to tackle rising tide of COVID-19- pandemic. Early diagnosis, contact tracing, strict prevention and control measures, biosecurity, personal biosafety, disinfection and sanitization practices, social distancing are aiding in prevention with SARS-CoV-2 infection. Boosting immunity by intaking the balanced and nutritious food, nutraceuticals, herbs, and following physical exercises along with avoiding stress conditions enhance the fighting power of the body against SARS-CoV-2 infection and limiting the severity of COVID-19. The present article describes salient knowledge on SARS-CoV-2 structure, genomic organization, pathogenesis, pathobiology, and advances and progress being made to treat COVID-19 patients. |
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Full Text: The 21st Century suddenly witnessed a new emerging virus - novel coronavirus 2019 (2019-nCoV) in December 2019 from Wuhan city of China, later named as severe acute respiratory syndrome coronavirus - 2 (SARS-CoV-2). The virus caused coronavirus disease 2019 (COVID-19) pandemic that has posed high challenges to the survival of the humans (Barbuddhe et al., 2020; Ciotti et al., 2020; Dhama et al., 2020a; Malik et al., 2020). This is the worst pandemic after the Spanish Flu pandemic of the year 1918 during which 20-50 million people lost their lives. In a short period of ten months, this virus rapidly got spread to many countries across the globe, affecting 215 countries and territories, while posing huge panic and fear among the entire population of the world owing to its severe clinical manifestations and associated mortality (Dhama et al., 2020b). COVID-19 has claimed the lives of nearly 1.4 million persons with more than 59 million confirmed cases as of 23rd November 2020 (https://www.worldometers.info/coronavirus/). The ongoing COVID-19 pandemic has implicated severe public health concerns, created high socio-economic negative impacts and substantial monetary losses along with putting millions of people under forced locked down states in their homes (Ahmad et al., 2020a; Ayittey et al., 2020; Nicola et al., 2020; Lenzen et al., 2020; Yamin, 2020). Due to the non-availability of any effective vaccine or drug, SARS-CoV-2 is continuously affecting many countries with daily rising numbers of positive cases and deaths. Researchers and pharmaceutical companies worldwide are trying their best to develop effective vaccines, drugs, therapies and immuno-modulators for tackling COVID-19, few of these have reached to clinical trials and are presently being evaluated under different phases of clinical trials. However, this may take few months still to get the market and to be practically available for the end-users vaccination (Ciotti et al., 2020; Dhama et al., 2020a; Dhama et al., 2020c; Felsenstein et al., 2020; Keam et al., 2020; Keni et al., 2020; Vellingiri et al., 2020; Yatoo et al., 2020). More recently, Russia has claimed to develop the COVID-19 vaccine, and vaccines being developed by other countries (USA, UK, India, and others) are in the pipeline. Under such scenario, timely diagnosis, increasing diagnostic capabilities, contact tracing, adaptation of appropriate strict disease prevention, control and mitigation strategies including follow-ups of bio-security, personal biosafety measures with wearing face masks, frequent washing of hands with water, soap and applying hands sanitizers, social distancing, and proper disinfection, hygiene and sanitization practices, are the promising options to circumvent SARS-CoV-2 infection and limit its spread (Ahmad et al., 2020b; Chu et al., 2020; Dhama et al., 2020a; Rodriguez-Morales et al., 2020). Due to the currently increasing trends of SARS-CoV-2 spreading within many countries, and specifically massively spreading in three countries viz., the United States of America, Brazil and India, affecting others like Russia, South Africa, Mexico and various countries, COVID-19 may further be affecting many more millions along with killing millions of people if its spread is not halted shortly. Understanding the genomic organization, molecular biology, pathogenesis, pathobiology, and immunobiology of the SARS-CoV-2 in an in-depth manner with better knowledge gains will pave ways to design effective vaccine candidates and drug targets. The present review highlights a few of the salient information on this pandemic virus while mainly focusing on SARS-CoV-2 structure, genome composition, pathogenesis, pathobiology, and advances and progress being made to treat COVID-19 patients. 2 Coronaviruses Coronaviruses (CoVs) are positive-sense, single-stranded RNA viruses. The RNA genome is encased by a nucleoprotein (N) to form a helically symmetric helix. They cause various diseases in human and different animals, indicating their broad host range that includes livestock, companion (dogs, cats), and other domestic animals, including cows, pigs, chicken and birds (Fehr & Perlman, 2015), which leads to significant researches on these viruses in the last 20 years. The viruses infect the hepatic, respiratory, gastrointestinal, brain and nervous systems of mammals, birds, bats, mice, and several other feral species (Ge et al., 2013; Roujian et al., 2020). A high-prevalence and wider spread nature of CoVs and their broad genetic diversity have been observed. The probability of the human-to-human and animal-to-human transmissions of the viruses might be due to the result of newly emerging coronaviruses, for which one approach needs to be adopted for effective control (Bonilla-Aldana et al., 2020; Tiwari et al., 2020). The severe acute respiratory syndrome (SARS) was noticed in Guangdong province of China in 2002, which spread in more than 26 countries till 2003. Further, the Middle East respiratory syndrome (MERS) in Saudi Arabia in 2012 has shown the changing properties of coronaviruses for their new hosts (Roujian et al., 2020). These two diseases infect the lower respiratory tract of human, which causes death due to the failure of respiratory function. In December 2019, an epidemic in Wuhan, China, of mystery pneumonia brought widespread concern to people around the world, due to severe clinical symptoms among patients, i.e., fever, headache, dry cough, dyspnoea, and pneumonia (Zhou et al., 2020a; Zhou et al., 2020b). The mortality rate was 10% for SARS, 37% for MARS, while the mortality rate in the case of COVID-19 was 2.9% as per the initial data of China. The initial illness can be quickly identified with clinical features of a rise in the body temperature, dyspnea, pneumonia, and a significant reduction in the white blood cells count, particularly lymphocytes. Taxonomically, coronaviruses belong to the Coronavirinae subfamily, Coronaviridae family, and order Nidovirales, which contain viruses of both medical and veterinary importance. At present, coronaviruses are categorized into four major genera, including Alphacoronavirus, Betacoronavirus, Gammacoronaviruses and Deltacoronavirus (Woo et al., 2012; de Groot et al., 2013; Tekes & Thiel, 2016). There is currently a total of 15 known strains of CoVs within different species. Only six species cause human diseases and chronic disorders; they are human coronavirus (HCoV)-229E, HCoV-OC43, HCoV-NL63, HKU1, SARS-CoV and MERS-CoV (Fehr & Perlman, 2015). Of the four coronavirus genera, members of the Alphacoronavirus and Betacoronavirus genera infect mammalian species (Fehr & Perlman 2015), whereas the Gammacoronaviruses and Betacoronavirus infect birds, fish and only a few of them can infect mammals as the detail is listed in Figure 1. In some cases, human coronaviruses (such as HKU1) only create minor upper respiratory diseases in infants, small children, and the elderly, while in other cases, they may induce severe morbidity. Patients infected with MERS-CoV and SARS-CoV at the lower respiratory tract suffer severe respiratory syndrome (Su et al., 2016). Many CoVs can also affect livestock, such as bovine coronavirus of cattle, porcine epidemic diarrhoea virus (PEDV) and porcine hemagglutinating encephalomyelitis virus (PHEV) of pigs and may cause major financial losses (Simas et al., 2015). Coronaviruses could be found in other animals, including bees, bats, moose, and other wildlife (Watanabe et al., 2010; Monchatre-Leroy et al., 2017; Menachery et al., 2020). In 2016, the HKU2-related bat CoV triggered swine-acute diarrhoea in Southern China, with over 24,000 deceased piglets (Zhou et al., 2018). This was the first report of bat CoV spillage, causing severe animal disease (Cui et al., 2019). 3 SARS-CoV-2 Reported data revealed the connection of SARS-CoV-2 infection with the Seafood Wholesale market in Wuhan, China, which has been regarded as the epicentre of the 2019-nCoV outbreak (Huang et al., 2020a; Huang et al., 2020b; Guan et al., 2020a). However, it should be noted that many other animal species are also sold at the Wuhan Seafood market. At the earliest outset of the outbreak, six clinical samples were collected from seven sellers/food delivers of the market, which was admitted to an intensive care unit in Wuhan Jin Yin-Tan Hospital with severe pneumonia (Chen et al., 2020a). The causative viruses could be isolated from five out of the six samples and later identified at the Wuhan Institute of Virology (WIV) as coronavirus. These early cases of the outbreak were from their direct contact with the seafood, but as the disease spread further, those who were not visited the Wuhan Seafood market were also infected, indicating human-to-human transmission of the virus. Metagenomic analysis of next-generation sequencing data of one of the five virus isolates (WIV04) revealed that it was only 79.60% similarity with the previously reported SARS-CoV BJ01, but 96% identity with the bat coronavirus (Zhou et al., 2020a; Zhou et al., 2020b). This genome sequence has been submitted to the Global Initiative on Sharing All Influenza Data (GISAID) accession numbers (EPIISI402127-402130) (Zhou et al., 2020a; Zhou et al., 2020b). Full-length genome sequences of the remaining four isolates (WIV03, WIV05, WIV06, and WIV07) showed more than 99.98% resemblance to each other (Zhou et al., 2020a; Zhou et al., 2020b). On 12th January 2020, the World Health Organization (WHO) has named the causative virus as 2019-nCoV. On January 20th, 2020, it was established that the SARS-CoV-2 belongs to the genus Betacoronavirus based on genome sequence analysis of 291 isolates (Chen et al., 2020a), although they cause different clinical symptoms than the antecedent SARS and MERS. On 1st March 2020, a total of 79,968 COVID-19 cases were recognized in mainland China with 2873 deaths. The COVID-19 becomes an epidemic in China and spread further rapidly to 27 other countries in different parts of the world due to the lack of specific preventive and therapeutic measures (Letko et al., 2020). The rapid disease transmission of human-to-human was due to direct contact (Millet & Whittaker, 2015; Tarar et al., 2020). Therefore, government management authorities restricted travel from Wuhan to other countries soon after. Currently, the COVID-19 has affected people across the world with severe conditions, particularly the USA, Brazil, India, Russia, and other many countries. Consequently, across the globe, the travelling restriction was imposed, social distancing was suggested, and the lockdown was implemented as an immediate control measure of the infection to all the affected countries. While the risk of animal-to-human transmission for the 2019 n-CoV has been noted, it was necessary to identify their natural host from the market. Also, due to several unknown features and properties of SARS-CoV-2, it is necessary to make a global awareness among the scientific societies that are not directly associated with the biological phenomena of the coronaviruses. Coronavirus is recognized to circulate in birds and mammals. Past examinations unveiled the zoonotic origin of both MERS-CoV and SARS-CoV, initially originating from bats (Guan et al., 2003; Lau et al., 2005). SARS-CoV spread from bats to palm civets to humans (Song et al., 2005), whereas bats to camels to humans is the route for MERS-CoV (Muller et al., 2014; Chu et al., 2014; Song et al., 2018). The current pandemic caused by SARS-CoV-2 is also considered to be originated from bats, based on the similarity of the genetic sequences to other coronaviruses (Li et al., 2020a; Zhou et al., 2020a; Zhou et al., 2020b). However, the intermediate animal host may have played a role in transmitting SARS-CoV-2 (Lu et al., 2020a). The identity of the intermediate animal host between bat reservoir and human remains unknown. The virus data obtained from pangolins sample reveals more closeness to the SARS-CoV-2, and further investigations of mammals consumed or handled by humans can uncover more closely related viruses (Liu et al., 2019). 4 SARS-CoV-2 structure, genome composition and salient characteristics Cryoelectron tomography and cryoelectron microscopy have revealed that CoVs are spherical with a diameter of about 125 nm (Neuman et al., 2006; Barcena et al., 2009). Coronaviruses are primarily distinguished by their club-shaped spike projections on the virion. Such spikes describe the virion surface morphology and give its appearance of the solar corona, which is responsible for its name “Coronavirus”. The nucleocapsid/ ribonucleoprotein (RNP) of CoVs have helical symmetry that is not a typical feature of RNA viruses, although the coronaviruses have positive-sense, single-stranded RNA genomes. Initial reports of SARS-CoV-2 comparison reveal 79% similarity with SARS-CoV at the nucleotide level. However, the similarity patterns are different among genes, like the spike (S) protein of SARS-CoV-2 and SARS-CoV display only 72% similarity. The close evolutionary relationships suggest the resemblance of SARS-CoV-2 genomic structure with other beta coronaviruses in the gene order as 5’- replicase ORF1ab-S-envelope (E)- membrane (M)-N-3’ (Zhang et al., 2020a). The unsegmented, positive-sense RNA genome of CoVs is approximately 30 kb. The genome has a 5′-cap configuration and a 3′-polyadenylated (polyA) tail. The organization of the CoV genome is as follows: 5′-leader-UTR followed by replicase genes (ORF1a and ORF1b for polyprotein production)-ORF2 for S (spike protein)- ORF 4 for E (envelope protein)- ORF5 for M (Membrane protein)- ORF9 for N (nucleoprotein)-3′ UTR-polyA tail, with additional genes scattered within the structural genes at the 3′-one-third of the genome (Snijder et al., 2006; Sawicki et al., 2007). On the genome 5′- end, an untranslated region (UTR) and leader sequence comprise several loops needed for genome replication and transcription. Transcriptional Regulatory Sequences (TRSs) to be required for the gene expressions are often presented at the start of each structural or accessory gene of the virus. The 3′-UTR also includes the RNA structures necessary for viral RNA synthesis and replication. The accessory proteins are virtually unessential in tissue culture for replication, but some of them have proven to play an essential role in causing neuroinflammation. In general, CoVs produce 120 to 160 nm (27-32 kb) particles that are the largest RNA genomes among the positive-sense, one-stranded RNA viruses as shown in Figure 2a and 2b. The diameter of the helical nucleocapsid is approximately 9-11 nm in size. In contrast to RNA coding for the structural, functional and accessory proteins that comprise just about 10 kb of the virus genome (one-third of the 3¢-end), the replicase genes (ORF1a and ORF1b) that encode nonstructural proteins (nsps) 1-16, take up about 20 kb of the genome (Chen et al., 2020a). Usually, RNA virus mutation rates are far higher than DNA virus replication rates. However, CoVs have several enzymes that carry out RNA processing, like the 3′-5′ exoribonuclease or nsp14, which can remove the incorrectly added nucleotide to the growing RNA strand. This is a unique feature of a CoV reverse transcription complex (RTC). Among all RNA viruses, the 3′-5′ exoribonuclease is very inimitable to CoVs, possibly having RTC proofreading feature. Sequence analysis has demonstrated that the 2019-nCoV belonging to the genus Betacoronavirus has a standard CoV genomic structure and includes Bat-SARS, like Bat-SL ZXC21, (SSL)–ZC45, MERS-CoV, and SARS-CoV. The CoVs phylogenetic tree found a close resemblance of SARS-CoV-2 with bat-SL-CoV ZXC21 and farther distant to SARS-CoV (Chen et al., 2020a; Zhou et al., 2020a; Zhou et al., 2020b). Four major types of structural proteins are identified in coronavirus particles. These are the membrane (M) protein, spike (S) protein, Envelope (E) protein and nucleoprotein (N). Some coronaviruses have hemagglutinin-esterase as another structural protein. Genes coding for these proteins are located at the 3′-one-third of the viral genome (Fehr & Perlman, 2015). 4.1 Spike (S) protein The S protein [~150 kDa, 1273 amino acids comprise a signal peptide of 1–13 amino acids located at the N-terminus, the S1 subunit (14–685 residues), and the S2 subunit (686–1273 residues] forms club-shaped homotrimeric projections on the surface of coronavirus virion (Delmas et al., 1990; Beniac et al., 2006). The trimeric S protein is a class I viral fusion protein (Bosch et al., 2003). Each molecule of S protein encompasses three parts: a relatively large N-glycosylated ectodomain, a single-pass transmembrane portion and a short endosegment. At the initial phase of infection, host furin-like protease cleaves S protein into two distinct polypeptides known as S1 and S2 subunits. The S1 contains two domains, i.e., C-terminal domain (S1-CTD) and N-terminal domain (S1-NTD) that can serve as a receptor-binding ligand for coronaviruses, e.g., SARS-CoV uses S1-CTD to bind to human ACE2, while murine hepatitis coronavirus uses S1-NTD to interact with CEACAM1 (colon embryonic antigen cell adhesion molecule 1) (Kubo et al., 1994; Cheng et al., 2004; Li et al., 2005; Lu et al., 2013). The S1-CTD has two subdomains, namely the receptor-binding motif (RBM) and the core structure (Li, 2015). The RBM of the S1-CTD of SARS-CoV-2 binds to human ACE2 receptor on the membrane of host cell; thus, the S1-CTD functions as RBD of the SARS-CoV-2 (Wang et al., 2020a; Li, 2015). The heptad repeat is a repetitive heptad peptide, HPPHCPC, where H is hydrophobic residue, P is hydrophilic residue and C is a charged residue. Under the acidic pH within the endosome, the S2 acquires conformational change and inserts the FP into the endosomal membrane and together with the HR1 and HR2 bring about the fusion of the viral and endosomal membranes resulting in the viral genome released into the cytoplasm for further translation and replication (Baranov et al., 2005; Belouzard et al., 2009; Huang et al., 2020a; Huang et al., 2020b). The S protein contains major neutralizing epitopes and is the target of vaccine and therapeutic development. The S gene of SARS-CoV-2 encoding 22 N-linked glycan sequences per promoter plays an imperative role in protein folding, and immune evasion (Watanabe et al., 2020) reported the glycan structures on a recombinant SARS-CoV2 S immunogen using the mass spectrometric method. The SARS-CoV-2 S glycan was different from the host glycan and may have a high impact on vaccine design and viral pathobiology (Watanabe et al., 2020). 4.2 Membrane (M) protein The M protein is a relatively small protein (~25–30 kDa) which is the main structural protein of the coronavirus virion. This protein has a tiny glycosylated N-terminal ectodomain, three transmembrane domains and a relatively long C-terminal endodomain (de Haan et al., 1998; Nal et al., 2005). Although most of the nascent M proteins are introduced in the endoplasmic reticulum (ER) membrane by the co-translational pathway (because the nascent M-protein does not contain the signal sequence for the translation), experimental data have shown that M protein in the virion adopt two conformations, i.e., long (MLONG) and compact (MCOMPACT), which each of them contains two copies of M protein (Neuman et al., 2011). The elongated M protein interacts with nucleocapsid, but the compact M does not (Neuman et al., 2011). Coronavirus M protein plays a key role in viral assembly, through M-M, M-nucleocapsid, and M-spike (S) interactions via the highly conserved cytoplasmic domain of the M protein (Arndt et al., 2011). 4.3 Envelope (E) protein E protein of coronaviruses is a small (~8–12 kDa; 76-109 amino acids) integral membrane protein that inserts once through the viral membrane. This small protein exhibits a C-terminal endodomain and N-terminal ectodomain. Although the endodomain of the E protein has ion channel activity but this protein is not necessary for virus proliferation. However, it is necessary for pathogenesis by interacting with the host proteins and causing the host cell stress (Nieto-Torres et al., 2011). E protein is a chaperone that facilitates interactions between M protein monomers (Boscarino et al., 2008). 4.4 Nucleoprotein (N) Coronavirus N is a phosphoprotein that encapsidates the viral RNA forming nucleocapsid. N protein consists of two distinct domains, an N-terminal domain (NTD) and the C-terminal domain (CTD), which binds RNA in vitro. N protein has been proposed to cause a shift in structure to improve the virus resistance to nonvirative RNA with specific mechanisms for binding RNA and phosphorylation process. In beads-to-string confirmation, N protein binds specifically to the viral genome. Two different RNA substrates of the N protein have been recognized including Translation Regulatory Sequences (TRSs) and the RNA Packaging signal (Ps) which is located at the 69-nucleotide (nt) stem-loop structure at the 3'-end of ORF1b (Molenkamp & Spaan, 1997). The N protein uses the N3 domain in the C-terminal to bind to the Ps; this N3 also interacts with the M protein (Kuo & Masters, 2013). N protein also binds to nsp3, the main component [papain-like protease of the replication complex (ORF1a and ORF1b)] and the M protein (Hurst et al., 2009; Hurst et al., 2013; Nikhra. 2020). Such protein interactions are effective to link the virus genome to the reverse transcription complex (RTC), and ultimately compress the enclosed genome into the viral proteins, as shown in Figure 3a and 3b. 4.5 Hemagglutinin-esterase (HE) Hemagglutinin-esterase (HE) is a fourth structural protein that forms short dimeric spike on the virion surface in some members of the genus Betacoronavirus. The protein has both receptor binding and receptor destroying activities. HE de-O-acetylates N-acetyl-4-O-acetylneuraminic acid, probably for preventing self-aggregation and help the virus spread through mucus (Cornelissen et al., 1997). HE of the murine hepatitis virus (MHV) encourages neuro-virulence of the virus (Kazi et al., 2005), although explanations for this process is unclear (Lissenberg et al., 2005). The roles of non-structural proteins (nsp1-16) of CoVs have been reviewed elsewhere (Yoshimoto, 2020). |
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