|Year : 2020 | Volume
| Issue : 5 | Page : 65-74
A comparative study between the severe acute respiratory syndrome–Coronavirus-2, severe acute respiratory syndrome coronavirus, and the middle east respiratory syndrome coronavirus
Syed Abdullah Ibn Asaduzzaman, Amayna Zakaria, Ilora Shabnam Kheya, Nazmul Fahad, Yusra Binte Sikandar, Rashed Noor
Department of Microbiology, School of Life Sciences (SLS), Independent University, Bangladesh (IUB), Dhaka, Bangladesh
|Date of Submission||23-Jun-2020|
|Date of Acceptance||03-Jul-2020|
|Date of Web Publication||13-Aug-2020|
Dr. Rashed Noor
Department of Microbiology, School of Life Sciences, Independent University Bangladesh, Plot 16, Block B, Bashundhara, Dhaka 1229
Source of Support: None, Conflict of Interest: None
The ongoing COVID-19 pandemic caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is of public health emergency of international concern. Within the last two decades, the prevalence of the epidemics by the acute respiratory syndrome coronavirus (SARS-CoV) and by the Middle East respiratory syndrome coronavirus has also been observed. Therefore, regarding these three coronaviruses, certain critical issues have been focused in the current review concerning their evolution and transmission, genomic influence on the corresponding virulence, immunopathogenesis, and the preventive measures including the vaccination strategies and the antiviral therapies.
Keywords: COVID-19 pandemic, Middle East respiratory syndrome coronavirus, public health, SARS-CoV, severe acute respiratory syndrome-coronavirus-2
|How to cite this article:|
Asaduzzaman SA, Zakaria A, Kheya IS, Fahad N, Sikandar YB, Noor R. A comparative study between the severe acute respiratory syndrome–Coronavirus-2, severe acute respiratory syndrome coronavirus, and the middle east respiratory syndrome coronavirus. Biomed Biotechnol Res J 2020;4, Suppl S1:65-74
|How to cite this URL:|
Asaduzzaman SA, Zakaria A, Kheya IS, Fahad N, Sikandar YB, Noor R. A comparative study between the severe acute respiratory syndrome–Coronavirus-2, severe acute respiratory syndrome coronavirus, and the middle east respiratory syndrome coronavirus. Biomed Biotechnol Res J [serial online] 2020 [cited 2022 Jan 25];4, Suppl S1:65-74. Available from: https://www.bmbtrj.org/text.asp?2020/4/5/65/292090
| Introduction|| |
Currently, the whole world population is suffering from the COVID-19 pandemics caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), so far causing 465,740 deaths (official estimation) with 8,860,331 infected cases resulting in pneumonia, with the acute respiratory distress syndrome (ARDS) and others accompanied with the secondary infections.,,,, Along the last 20 years, the onset of severe acute respiratory syndrome-coronavirus (SARS-CoV) epidemic outbreak in 2002 and the onset of the Middle East respiratory syndrome-coronavirus (MERS-CoV) were noticed in 2012. Both SARS-CoV and MERS-CoV were found to originate from bats, and afterward, SARS-CoV was transmitted to humans from market civets, while the MERS-CoV from the dromedary camels., The transmission mode of SARS-CoV-2 is thought to be similar as in the case of SARS-CoV, and the circulation of SARS-CoV-2 is mediated by human-to-human transmission via sneezing or coughing. In addition, the worldwide traveling has been identified as the most potential risk for the global spread of SARS-CoV-2 virus causing the COVID-19 pandemics.
Although a high similarity between SARS-CoV-2 and the SARS-CoV remains in terms of their genomic and structural organizations, the reason for the pandemic outbreak of SARS-CoV-2 may be explained by the structural differences in the spike (S) proteins among these two coronaviruses (CoVs) as revealed by the study on the mechanisms of viral entry into the host cell utilizing the S protein. In terms of pathophysiological impact in the coronavirus-affected patients, the study of cytokines and chemokines upon the viral infection has been extremely beneficial to focus on the viral infectivity potential., An increased amount of interleukin (IL)-1β, interferon gamma (IFNγ), IP10, monocyte chemotactic protein 1 (MCP1), granulocyte-colony-stimulating factor (GCSF), IP10, macrophage inflammatory protein 1 (MIP1A), and tumor necrosis factor-alpha (TNF-α) was noticed in the case of SARS-CoV-2 infection, which is often termed the cytokine storm. The SARS-CoV-2 infection has also been noticed to account for the elevated levels of T-helper-2 cytokines (IL-4 and IL-10), thereby suppressing inflammation, which is a quite different trait from that observed in the SARS-CoV infection. However, the heightened levels of the pro-inflammatory cytokines (IL-1B, IL-6, IL-12, IFNγ, IP10, and MCP1) have been noticed in the case of the SARS-CoV-infected patients, whereas an increased concentration of IFNγ, TNFα, IL-15, and IL-17 has been observed among the MERS-CoV-infected patients., Indeed, the SARS-CoV-2 (causing COVID-19 pandemics) and the earlier SARS-CoV have been found to share many similarities regarding their modes of transmission and pathogenicity, and both have resulted in the cause of ARDS. Therefore, further studies on the events of viral pathogenesis depending on their genetic organizations to encode the respective virulence factors, and the corresponding activation of some common cytokine/chemokines as well as some distinguishing ones upon any of these three viral infection may impart significant viral infectivity potential which in turn may open the scope of developing both the viral diagnosis accuracy and the treatment strategies.
A plethora of reports on the SARS-CoV-2, SARS-CoV, and MERS-CoV have been published so far. Regarding the ongoing COVID-19 pandemic outbreak, certain critical issues have been raised regarding the similarities or dissimilarities between these three CoVs. The origin of each virus and the evolution, the mode of transmission and the infectivity potential, epidemiology, genomic organization and the escaping strategies of the host immunity, pathogenesis, diagnosis rate and accuracy, and the possible scope of the development of the anti-viral drugs along with vaccination strategies are mainly focused by the ongoing research on these CoVs around the world. The present review summarized these points in brief, which may add to the specific understanding on the fatality of coronavirus diseases which have been bringing the global public health at a risk.
| Coronaviruses|| |
CoVs :Family Coronaviridae, order Nidovirales, are the enveloped, nonsegmented, unusually long (up to 33.5 kb) positive-sense RNA viruses with the club-like spikes projecting from their surface. The coronavirus subfamily is grouped into the following four genera: alpha, beta, gamma, and delta CoVs, of which the beta-CoVs include the SARS-CoV-2, the SARS-CoV, and the MERS-CoV., Viruses falling in the order Nidovirales are unique because of their highly conserved genomic organization, consisting of a large replicase gene (encoding the nonstructural proteins, nsps) preceding the structural and the accessory genes; due to their capacity to express many of the nonstructural genes; through their unique enzymatic activities (encoded within the large replicase–transcriptase polyprotein); and by the expression of the downstream genes through the synthesis of 3′ nested subgenomic messenger RNAs (mRNAs). The coronavirus life cycle has the events of the attachment and entry into the host followed by the expression of the replicase protein, viral replication and transcription ending at the viral assembly, and release to cause the pathogenicity.,,,, Indeed, an intensive effort has been given to identify novel bat CoVs because these are the likely ancestors for SARS-CoV and MERS-CoV.
| Genomic Organization and Translated Proteins of Coronavirus|| |
As reported by Fehr and Perlman in 2015, the CoV genomic organization is arranged in the 5′ cap-leader-UTR (untranslated region)-replicase (around 20 kb)-S (spike)-E (envelope)-M (membrane)-N (nucleocapsid)-3′ UTR-poly (A) tail scheme, along with the accessory genes interspersed within the structural genes at the 3′ end of the RNA. The leader sequence and the UTR comprise multiple stem loop structures which are required for RNA replication and transcription [Figure 1]. The transcriptional regulatory sequences (TRSs) remain at the beginning of each structural (or accessory) gene, which are required for the corresponding expressions. The 3′ UTR consists of RNA structures needed for the replication and synthesis of viral RNA. The accessory proteins are important for the viral pathogenesis.,,,
|Figure 1: A comparative scheme of the genome sequence of the severe acute respiratory syndrome-coronavirus 2, severe acute respiratory syndrome-coronavirus, and the Middle East respiratory syndrome coronavirus|
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The 3′ end of the viral genome encodes the following four main structural proteins: spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins [Figure 1]. The S protein (which is N-linked glycosylated) has been shown to utilize an N-terminal signal sequence to gain access to the ER, and the homotrimers of the S protein (Class I fusion protein) result in the distinctive spike structure which mediates attachment to the host receptor. In most CoVs, S is cleaved by a host cell furin-like protease into two separate polypeptides: S1, making up the large receptor-binding domain (RBD), and S2, forming the stalk of the spike molecule., M protein (consisting of three transmembrane domains) imparts the viral shape and exists as a dimer in the virion along with adopting two different conformations, which allow it to promote the membrane curvature and to bind to the nucleocapsid. The E protein helps in the assembly and release of the virus, and its ion channel activity is required for pathogenesis especially in the SARS-CoV. The phosphorylation of N protein triggers a structural change enhancing the affinity for viral versus nonviral RNA. N protein can (1) detect the TRSs and the genomic packaging signal and (2) bind to nsp3, a key component of the replicase complex and the M protein. Such protein interactions help tether the viral genome to the replicase-transcriptase complex followed by the packaging of the encapsidated genome into the viral particles., The fifth structural protein, the hemagglutinin-esterase, can act as a hemagglutinin which binds sialic acids on the surface glycoproteins and possesses the acetyl-esterase activity which enhances the S protein-mediated viral entry and spread through the mucosa.
| Severe Acute Respiratory Syndrome-Coronavirus-2|| |
As stated earlier, the ongoing COVID-19 pandemics caused by SARS-CoV-2 originated from the Wuhan City, Hubei Province, China, in December 2019. Like the other b-CoVs, they are enveloped, positive-sense, single-stranded RNA viruses, consisting of the S, E, M, and N proteins with their respective functions as stated above., However, this is to be noted that N protein of SARS-CoV-2 is involved in other aspects of the CoV replication cycle (including assembly and budding) as well as the host response to viral infection. Within the viral envelope, polymers of S proteins remain embedded, which, in turn, imparts the virus a crown-like appearance, and hence the name coronavirus appeared.,, As shown in [Figure 1], there are 14 open-reading frames (ORFs) within the SARS-CoV-2: the first two ORFs at 5´ UTR (two-thirds of the viral RNA) encode polyprotein (pp1a/ab, which are required for virus replication) and 16 nonstructural proteins (required for the transcription and replication of the virus), followed by the structural proteins (encoded by the rest one-third portion of the genome) as mentioned above, while at the 3´ terminus, the accessory genes (3a, 3b, p6, 7a, 7b, 8b, 9b, and orf14) are located with flanking ORFs.,, There are hypervariable genomic hot spots within the genes encoding the spike (S) and in the other ORFs encoding the nonstructural proteins. Phylogenetic analyses unraveled that SARS-CoV-2 is closely related to two SARS CoVs of bat origin: Bat-SL-CoVZC45 and bat-SL-CoVZXC21; however, SARS-CoV-2 is quite distant from the SARS-CoV (79% sequence homology) and from the MERS (only 50% homology).
Evolution, mode of transmission, and the molecular epidemiology
Different animals such as bats, pangolins, and snakes could have been the intermediate hosts that facilitated the spillover of SARS-CoV-2 from bats to the human. Indeed, China has witnessed the emergence of avian influenza H5N1 in 1997, SARS-CoV in 2003, and the ongoing SARS-CoV-2. Human-to-human transmission through the respiratory droplets (sneezing and coughing) and international traveling have been pointed as the major routes for the worldwide spread of SARS-CoV-2. This is to be noted that the transmission of SARS-CoV-2 may remain unnoticed during the viral incubation period within the infected individuals (i.e., asymptomatic) who actually possess the potential to actively transmit the infection. The coding regions of SARS-CoV-2 showed the existence of a longer spike protein compared to those in the SARS-CoV and MERS-CoV., In addition, apart from the discussion about the SARS-CoV-2, this is to be mentioned that two novel bat SARS-related CoVs have been isolated which possess the strong similarity to the SARS-CoV than any other virus identified to date, and they were also noticed to employ the same angiotensin-converting enzyme 2 (ACE2) receptor as the human virus, providing further proof that SARS-CoV originated in bats.
As revealed from recent studies, the evolution of the virus might also take place by the successive mutations and recombination processes, and the probable evolutionary rate may be up to 104 base substitutions per site per year, resulting in the corresponding mutations at every replication cycle.,,, The antibody-dependent enhancement (ADE) of viral entry may also be associated with the epidemiology of the virus as well.
Escaping strategies of the host immunity by the severe acute respiratory syndrome-coronavirus-2 and subsequent pathogenesis
As stated earlier, the spike protein mediates the viral entry into the host by binding to host cell surface receptor, resulting in the fusion into the host membranes.,,, The spike protein of the SARS-CoV-2 binds to the ACE2 receptor of the human host., Upon the receptor engagement, the cellular surface serine protease TMPRSS2 (a plasma membrane-associated type II transmembrane serine protease) is also used by the SARS-CoV-2 to prime the spike protein (S) to facilitate the membrane fusion, which is essential to release the viral contents into the host cell cytosol. Indeed, the attachment of SARS-CoV-2 is facilitated by the interaction between the S1 region of the S protein (at the sites of receptor binding domains [RBD]) and its receptor., After that, virus enters the host cell cytosol by the acid-dependent proteolytic cleavage of the S protein by cathepsin, followed by fusion of the viral and cellular membranes within the acidified endosomes, and to the cell membrane to some extent. Eventually, the translation of the replicase gene takes place into two co-terminal polyproteins, pp1a and pp1ab, as shown in [Figure 1]. In addition, the ADE of viral entry may take place wherein a neutralizing monoclonal antibody (Mab, through the immunoglobulin G [IgG] Fc receptor) specifically targets the RBD of the spike, allowing it to undergo certain conformational changes to be activated proteolytically, which, in turn, is likely to showcase the viral entry into the IgG Fc receptor-expressing cells.,
The next step is the alteration of the intracellular membranes for the ease of SARS-CoV-2 RNA replication as well as the undisturbed transcription and translation. The viral RNAs avoids recognition by the innate immune RNA sensors by adding a cap-structure to its 5′-end, which helps them to be detected by the host translational machineries. During the transcription in nucleus, the viral nucleoprotein may impart a unique ability to steal the mRNA cap-structures, i.e., the short, 5′-capped transcripts produced by the cellular DNA-dependent RNA polymerase II from the host mRNAs, and such a process is called “cap-snatching” mechanism, which, in turn, helps the viral mRNA transcription.,, Furthermore, the 2'-O methylation to the viral cap-structures using the nsp16 (a result of the viral endoribonuclease activity encoded in one of the nonstructural genes) may also help to avoid recognition by the immune sensor MDA5 (melanoma differentiation-associated protein 5)., The viral endoribonuclease activity is also essential for the avoidance of the protein kinase R and the 2'-5' oligoadenylate synthetase/RNAse L system which is one of the IFN effector pathway machineries. Thus, the SARS-CoV-2 accelerates its own RNA during the infection processes with a concomitant avoidance of the host immune system. Besides, the N protein may also reduce the viral mRNA destruction through the efficient packaging of the viral RNAs.,
The pathological events are initiated in the nasopharyngeal tract following its movement across the bronchial tubes to the lungs, making the mucous membrane of the lungs inflamed and hard, which, in turn, results in the shortness of breath and ARDS.,, Subsequently upon the progression of the viral spread, cells of the innate defense machineries (alveolar macrophages, airway epithelial cells, innate lymphoid cells, and the dendritic cells) are avoided by the virus by the strategies described above. As stated earlier, the cytokine storm as well as the described strategies of immune-avoidance by ARS-CoV-2 together play significant roles in disease progression pathogenesis and the fatality. The immunopathogenecity principally involves the heightening of the levels of inflammatory chemokines and cytokines such as the GCSF, IP-10, MCP-1, MIP-1α, TNF-α, and other ILs, which, in turn, results in acute lung injury.
Significance of S genes in the evolution and pathogenicity of severe acute respiratory syndrome-coronavirus-2 over severe acute respiratory syndrome-coronavirus
Both SARS-CoV-2 and SARS-CoV can use human ACE2 (a metallopeptidase, and the key molecule in the renin–angiotensin system) as a cell entry receptor. However, the unique attributes of SARS-CoV-2 can be found within the genes (orf8 and orf3b) encoding the spike glycoproteins. The spike protein consists of two subunits: S1 domain containing the RBD and the S2 domain constitutive of highly conserved polypeptides linked with the viral envelope., However, the spike protein S1 subunits of SARS-CoV-2 and SARS-CoV share only approximately 70% amino acid identity. Significant amino acid differences between SARS-CoV-2 and SARS-CoV are noticed in the ectodomain of the spike protein. Moreover, the external subdomain of the S1 head possesses only 40% similarity with its counterparts in the bat- and human SARS-CoV-2. This portion (consisting of diversified amino acid substitutes) is accountable for the direct contact with the human ACEs receptor. The diversity within the amino acids might have evolved from the homologous recombinations between a bat CoV and another CoV from unknown origin.
Moreover, the binding affinity between the SARS-CoV-2 spike ectodomain and human ACE2 was calculated to be 10–20-fold higher than that of the SARS-CoV spike ectodomain and human ACE2; such higher receptor-binding ability facilitates the entry of the SARS-CoV-2 into the host as well as may lead to more efficient person-to-person transmission through the direct or indirect contact with the respiratory droplets from another SARS-CoV-2-infected individual (s). In addition, as mentioned above, the Orf3b protein encoded by the orf3b gene plays an essential role in the pathogenesis of SARS-CoV-2.
Phylogenetic analysis to detect the severe acute respiratory syndrome-coronavirus-2 variants with possible pathogenesis/epidemiology
Extensive genomic analysis of SARS-CoV-2 showed the ancestor (S) type and the emerging L type, which was prevalent during the early January this year; however, a gradual decrease of this L type was noticed in the following weeks. The phylogenetic analysis done by Tang et al. (in 2020) unraveled the following three subtypes SARS-CoV-2: S, G, and V; according to nucleotide variants resulting in the changes in the corresponding amino acid changes.
Another work revealed (1) at least two different viral variant (the S and G Chilean variants) entries to the Chilean territory from Europe and Asia and (2) the subclassification of the isolates into variants according to the punctual mutations in the genome. Thus, the phylogenetic analyses may contribute to the information on the SARS-CoV-2 transmission dynamics, which is really helpful for the specific preventive measures against the infection in specific zones around the world. Indeed, this is to be noted that the most related genomes to that of SARS-CoV-2 available in the public databases are the bat-SL-CoVZC45 with an 87.99% sequence identity and bat-SL-CoVZXC21 with an 87.23% sequence identity, followed by the human viruses SARS-CoV-Tor2 and MERS-CoV with a 79.0% and 51.8% of nucleotide identity, respectively. The genomic sequences of all SARS-CoV-2 viruses isolated from the infected individuals by Castillo et al. (in 2020) were noticed to share a sequence identity approximately to 99.9%, which is suggestive of the zoonotic infection (originating from bat) in Chile.
Another phylogenetic network analysis conducted by Forster et al. (in 2020) using 160 complete SARS-Cov-2 genomes revealed three central variants based on the amino acid changes, namely types A, B, and C, of which type A is considered the ancestral type according to the bat CoV. The A and C types are the most prevalent in the European countries and Americas, whereas type B is in the East Asia. Besides, their findings also indicated that the pangolin CoV genome sequences are poorly conserved with respect to the human SARS-CoV-2, whereas the bat CoV had the sequence similarity of 96.2%.
Symptoms, diagnosis, and treatment
After an incubation period of 5–14 days, SARS-CoV-2-infected people commonly manifest features of pneumonia, including fever, dry cough, dyspnea, myalgia, and fatigue. ARDS is a feature in severe cases. For the diagnosis purpose, the most appropriate laboratory test for SARS-CoV-2 is the real-time reverse transcriptase-polymerase chain reaction (RT-PCR) of the nasopharyngeal swabs., The suitable clinical specimens are the bronchoalveolar lavage fluid, nasopharyngeal swabs (not the throat swabs), fibrobronchoscope brush biopsy samples, pharyngeal swab, feces, and blood.
Till date, there are no Food and Drug Administration-approved vaccines neither the antiviral drugs against SARS-CoV-2 infection. However, according to the infectivity potential of the SARS-CoV-2, several drugs are under investigation, of which mostly are in use to treat other viral diseases such as malaria, Ebola, SARS, and MERS. Some potential drugs including saikosaponin, favipiravir, hydroxychloroquine, IDX-184, favipiravir, opinavir/ritonavir, ACE2, and cepharanthine have been found to be effective from different case studies.,
Preventive and control measures of the COVID-19 pandemic
Regarding the ongoing COVID-19 pandemic by the SARS-CoV-2, (1) the genomic analysis with the phylogenetic analysis to depict the origin, transmission, evolution, and the possible focus on epidemiology and the dynamics of pandemics and (2) the study of the clinical manifestations with the immunopathological research along with the diagnostic efficiency with the development of vaccines and appropriate antiviral drugs are progressing worldwide at an unprecedented speed.,,,,,,, The usage of the protective materials by the health professionals is extremely emphasized to reduce the nosocomial exposure of the virus. However, because no officially approved drugs are available till date, classical public health measures and control interventions such as the international lockdown strategies or the home quarantine practices are being applied together with the surveillance of the disease with possible treatment of the affected patients with the so-called underinvestigation drugs being applied.
| Severe Acute Respiratory Syndrome-Coronavirus|| |
As stated earlier, the SARS-CoV is a positive single-stranded RNA virus from the family Coronaviridae. Its taxonomical trait, physical profile, and genome organization are nearly similar to the other known CoVs. As shown in [Figure 1], the SARS-CoV genome also constitutes of the major genes encoding the proteins R (replicase), S (spike), E (envelope), M (membrane), and N (nucleocapsid) like all other well-understood CoVs including SARS-CoV-2., The 5' UTR contains a special segment of 65 and 90 nt depending on the different species of CoV (noted as leader) followed by the leader-mRNA junction segment, and both of them are important for the discontinuous mode of RNA transcription. As mentioned previously, both the SARS-CoV and MERS-CoV differ with the SARS-CoV-2 in the aspect of the length of the spike protein (S) because the SARS-CoV consists of a relatively longer spike protein than those of SARS-CoV and MERS-CoV.,
Evolution, transmission, and epidemiology of severe acute respiratory syndrome-coronavirus
As indicated above, two novel bat SARS-related CoVs showed extensive resemblance to the SARS-CoV than any other CoVs isolated till date, possessing to employ the similar type of ACE2 receptor as the other human CoVs, which actually proves that SARS-CoV originated in bats., Interestingly, closely related viruses were isolated from the Himalayan palm civets and raccoon dogs., In addition, a huge number of Chinese horseshoe bats were noticed to contain the genome sequences of SARS-related CoVs and also they possessed the serologic evidence for a prior infection with a related CoV. Transmission of SARS-CoV was only through the direct contact with infected individuals. Like the SARS-CoV-2, the SARS-CoV also spread from person to person through close contact with an infected person, especially through coughs and sneezes., SARS-CoV also spreads when a person touches a surface or object contaminated with the SARS-CoV saturated droplets and then touches his or her mouth, nose, or eye (s). Spreading by air has also been reported. One important point is to ponder that due to a very low transmission rate of SARS-CoV compared to that of the ongoing SARS-CoV-2, the SARS-CoV outbreak was controllable only by the quarantine strategy.,
The epidemic outbreak started in Hong Kong in 2003 (originated in bats) and then spread to more than two dozen countries in North America, South America, Europe, and Asia. Indeed, prior to the SARS-CoV epidemic outbreak in 2002–2003 in the Guangdong Province of China, CoVs were thought just to cause mild, self-limiting respiratory infections in humans. The human α-CoV, human coronavirus (HCoV)-229E, and the β-coronavirus, HCoV-HKU1 have been identified following the SARS-CoV outbreak, which are interestingly different in tolerance to genetic variability. The outbreak caused more than 8000 cases with approximately 800 deaths with a mortality rate of 9%, which was quite higher in the elderly individuals. This is to be mentioned that since 2004, no cases of SARS were found within the world. Indeed, during the 2003 global outbreak, most people who got infected were actually exposed to the virus in (1) the health-care facilities where an infected person was receiving care (2) or they got exposed in the household stuffs of a SARS-CoV-infected person.
Transmissibility dynamics between severe acute respiratory syndrome-coronavirus-2 and severe acute respiratory syndrome-coronavirus
A distinguishing factor between SARS-CoV and MERS-CoV may be drawn here that unlike SARS-CoV, MERS-CoV did not spread so easily in 2012; however, as stated earlier, the spread of SARS-CoV-2 is being noticed with an accelerated rate causing the COVID-19 pandemic.,,,,,, In an explanatory way, it can be said that within just 2 months, the number of COVID-19 cases by the SARS-CoV-2 worldwide exceeded the total number of SARS-CoV cases by nearly ten times. While the mean basic reproduction number (R0) of COVID-19 was found to be similar to that of SARS-CoV (roughly 3.0), at the epicenter of the outbreak in Hubei province, China, the R0 of COVID-19 was as high as nearly 6.5.
Immunopathogenesis of severe acute respiratory syndrome-coronavirus
SARS-CoV infection of macrophages, dendritic cells, and alveolar epithelial cells has been shown to induce a significant elevation of the pro-inflammatory chemokines, including the macrophage inflammatory protein-1α and activation and secretion of normal T cells, with a heightened level of IP-10, interleukin-8, and monocyte chemoattractant protein-1. Like SARS-CoV-2, SARS-CoV was also reported to primarily infect the epithelial cells within the lung with the potential to enter the macrophages and dendritic cells, and the infection of these cells induced the pro-inflammatory cytokines (i.e., the elevation of cytokines and chemokines with a concomitant reduction in the T-cell responses), ultimately resulting in the disease onset including an age-dependent severity of the disease unlike the SARS-CoV-2. Severe lymphocyte depletion and the concomitant decrease in the number of periarterial sheaths in the spleen are the major clinical features of SARS infection. Within the spleen, a decrease in the CD4+ lymphocytes, CD8+ lymphocytes, CD20+ lymphocytes, dendritic cells, macrophages, and natural killer cells was noticed upon SARS-CoV infection. Besides, the depletion of mucosal lymphoid tissue in the small intestines and appendix may take place with a subsequent decrease in lymphocytes too. Unlike the SARS-CoV-2 infection, several host factors including age and sex may have significant influence on the vulnerability to the SARS-CoV infection., Another difference in the pathogenesis of SARS-CoV with that SARS-CoV-2 pathogenesis can be pointed that has been found within a group of Taiwanese patients who were carrying the HLA-B*4601 haplotype.
Angiotensin-converting enzyme 2 and the pathogenesis of severe acute respiratory syndrome-coronavirus
Various etiological factors together with the intricate causes and clinical consequences especially regarding the respiratory and the immunological systems (including the elevated chemokines and cytokines), the insufficient IFN reaction, and a compromised host immune response may lead to the disease fatality. However, as stated above, the prime factor for the disease initiation and progression depends on the ACE2 receptor both in SARS-CoV-2 and in SARS-CoV.,,, The human autopsy studies showed that SARS-CoV S spike protein (that interacts with ACE2) and its RNA could only be detected in the ACE2-positive cells and not in the ACE2-negative cells, which in turn confirmed the suggestion that that only the ACE2-positive cells may be susceptible to the SARS-CoV infection. This is to be noted that the SARS-CoV infection of ACE2-expressing cells depends on the proteolytic enzyme cathepsin L which is not well discussed in the case of SARS-CoV-2 infection cases.,,, Experiments with animal model demonstrated that the binding of SARS-CoV S protein to ACE2 downregulates the expression of ACE2, which results in a weakened protective role of ACE2, triggering the acute respiratory failure; in humans too, the SARS-CoV-mediated downregulation of ACE2 elicits the progression to severe lung injury in SARS-CoV-infected individuals.
Symptoms, diagnosis, and treatment
Appearance of fever, chills, rigors, myalgia, headache, diarrhea, sore throat, and rhinorrhea is the indication of the early infection by SARS-CoV followed by the moderate illness characterized by the body temperature of >38°C, coughing, and shortness of breath, finally resulting in the onset of ARDS., The diagnosis principally involves the (1) detection of serum antibody to SARS-CoV by the enzyme immunoassay EIA; (2) isolation of SARS-CoV in cell culture from a clinical specimen, and (3) the detection of SARS-CoV RNA by a RT-PCR reaction. An X-ray of chest or its computed tomography scan may also show the signs of pneumonia characteristic of SARS.
There is not yet confirmed therapy of SARS-CoV infection and hence the treatment is mainly supportive with a partial effectiveness of the IFNs. However, several antiviral medicines are still under investigation. Supplemental oxygen or ventilation is prescribed if required. In severe cases, blood plasma from the SARS-infected individual who has already recovered may be administered., However, the SARS-CoV, MERS-CoV, and the SARS-CoV-2 outbreaks have stimulated research on the various antiviral strategies (detecting the antiviral targets using the viral proteases, polymerases, and entry proteins) for curing the infected patients., In addition, therapeutic SARS-CoV neutralizing antibodies were also generated, which could be retrieved and re-used in the case of another SARS-CoV outbreak.
| Middle East Respiratory Syndrome-Coronavirus|| |
As stated above, MERS-CoV, a 2c β-coronavirus (with the possible human-to-human transmission trait), emerged in the Middle East in 2012, causing a series of highly pathogenic respiratory tract infections in Saudi Arabia and the other Middle East countries with a high mortality rate of ~ 50% in the early stages of the outbreak. Although the MERS-CoV outbreak did not accelerate further in 2013, the sporadic cases kept continued throughout that year, causing nearly 900 infected cases with approximately 350 deaths. Hence, this is apparent that in contrast to the ongoing SARS-CoV-2 pandemic, the MERS-CoV epidemic apparently appeared with clinical insignificance. The genome structure is nearly similar to that of SARS-CoV and SARS-CoV-2 [Figure 1]; however, unlike these two, the MERS-CoV utilizes dipeptidyl peptidase 4 (DPP4) as its receptor [Table 1] from bats, humans, camels, rabbits, and horses instead of ACE2 receptor (utilized by SARS-CoV and the SARS-CoV-2) to inaugurate the viral infection.
|Table 1: Similarities and dissimilarities between the b-coronaviruses from Coronaviridae family - severe acute respiratory syndrome coronavirus 2, SARS-CoV, and the Middle East respiratory syndrome coronavirus|
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The MERS-CoV RNA (∼30 kb) has been shown to encode a total of ten proteins including two replicases (ORFs 1a and 1b) and the RNA-dependent RNA polymerase (RdRp) as shown in [Figure 1]; four structural proteins: envelope (E), M (membrane), N (nucleocapsid), and S (surface spike glycoprotein), and four nonstructural proteins (ORFs 3, 4a, 4b, and 5).,,,, In addition, this is to be noted that all the MERS-CoV genomes have been found to share more than 99% sequence identity, which is in fact indicative of a low mutation rate within the genomes, and this trait is quite distinguishing to that of SARS-CoV and SARS-CoV-2.
Evolution, mode of transmission, and epidemiology
The sixth HCoV isolate in 2012, namely the MERS-CoV, originated from bats, and it was found to be significantly related to two previously identified bat CoVs: HKU4 and HKU5., However, the virus had an intermediate host as humans too, and the human-to-camel spread triggered the epidemics. The most important point underlies the serological studies whereby the MERS-CoV antibodies were isolated in the dromedary camels in the Middle East, and it was noticed that the cell lines from those camels had been lenient for the replication of MERS-CoV particles, pondering that dromedary camels could be the natural host of that virus. When a study showed that the virus isolated from a MERS-CoV-infected patient was identical to that virus isolated from the camel, it was a clear proof that the MERS-CoVs in both camels and human cases were in nearby proximities in Saudi Arabia. Indeed, in 2012, a 60-year-old man died as a result of renal and respiratory failure triggered by MERS-CoV infection in Jeddah, Saudi Arabia. MERS-CoV has been reported in more than 27 countries across the Middle East, Europe, North Africa, and Asia, causing 712 deaths, mostly in the Arabian Peninsula up to 2017.
Escaping the host immunity by Middle East respiratory syndrome-coronavirus and the subsequent immunopathogenesis
As stated above, the route of entry for MERS-CoV into the host is the DPP4, which is also known as CD26, residing on the host cell surface, which is utilized by the RBD of the MERS-CoV spike (S) protein.,, Upon viral infection, the type I IFN-mediated innate immune response is activated through the production of type I IFNs including IFN-α and IFN-β. Evasion of host innate immunity through the IFN antagonism is an important means of viral pathogenesis, which is mediated by the MERS-CoV-encoded IFN antagonist proteins which block one or more key signaling proteins in the IFN and nuclear factor-κB pathways, which, in turn, accelerate the viral replication, expression of the virulence factors, and pathogenesis.,, Indeed, upon entry of the MERS-CoV, the IFN system is activated first, and then the activated IFNs induce the transcription of their target genes for mediating the antiviral action by the IFN-induced proteins., Then, the events relating to circumvent the IFN response start as also happened in the case of SARS-CoV and SARS-CoV-2.,,,, The MARS-CoV replication in human monocyte-derived macrophages has been reported with a concomitant threefold increased expression of the TNF-α; sixfold elevated expression of IL-6, IL-12, and IFN-γ; and the other chemokines; even some are expressed ten times more than those in the case of SARS-CoV infection.
The evasion strategies of the host innate immunity by MERS-CoV mainly involve (1) preventing the initial detection of virus by the host immune cells possibly through the impairment of the Toll-like receptors or the retinoic acid-inducible gene I-like receptors, or by circumventing the formation of the necessary ligands to be recognized by these receptors; (2) to impede the IFN production by the degradation of the transcription factors (IFN regulatory factor 3-RF3)/IRF7, nuclear factor-κB, or ATF-2/c-jun) required for the expression of the IFN; (3) opposing the IFN signaling by hindering the type I IFN receptor and by blocking the JAK/STAT signal transduction; (4) by interfering with the global expression of IFN-stimulated genes; and (5) by disrupting the IFN responses through co-opting the negative regulatory systems. Thus, there are defined consequences for all the three bhCoVs (i.e., SARS-CoV-2, SARS-CoV, and MERS-CoV) regarding the IFN response to regulate their persistence within the host; in all the three cases, distress of the IFN response has been noticed to lead to chronic disease onset.,,,, MERS-CoV has been reported to infect alveolar epithelial cells and macrophages, fibroblasts, and endothelial cells, resulting in alveolar damage, and also the virus can replicate within kidney and liver. It is to be mentioned that such replication was also noticed in goat, camel, and equid origin cell lines, but not in the cattle, sheep, or rodent cell lines.
Symptoms, diagnosis, and treatment
Within 5–7 days of the viral infection, a set of symptoms appear including fever, cough, shortness of breath, pneumonia, myalgia, diarrhea, vomiting, abdominal pain, chills or rigors, or malaise., Renal or pulmonary failure and even shock were also noticed in the case of severe infections. The principal diagnosis of the viral infection mostly relies on the detection of MERS-CoV RNA (RT-PCR either real time or conventional using the primer sets for the upstream of the E gene with ORF1a or ORF1b, or genes encoding RdRp, N, or S), and the serological means to some extent (using enzyme-linked immunosorbent assays and immunofluorescence assays).
For the most useful preventive measure, research on the MERS-CoV vaccine candidates is ongoing, and one candidate vaccine has been reported to undergo the Phase I human clinical trial. A replication defective full-length cDNA clone of the MERS-CoV genome was developed (using the MERS-CoV spike protein in a poxvirus vector) for identifying the future vaccine candidates. Indeed, the vaccine candidates for dromedary camels have been reported to elicit protective responses., As the antiviral chemotherapy, the combination of (1) ribavirin and IFN α2b therapy and (2) lopinavir/ ritonavir and IFN α1b (separately and in combination) has been noticed to be effective in mitigating the infection., Use of several monoclonal antibodies (mAbs) and conventional antibodies has also been found to be potent because they had demonstrated to be effective in targeting the viral entry points as well as suppressing the innate antiviral response. Indeed, as stated earlier, the dynamic invasive strategies of the host innate immune imposed especially by the ongoing SARS-CoV-2 are the major obstacles for designing the appropriate antiviral drugs, and hence elaborative case studies and trials are required.,,,,,
| Conclusion|| |
According to the current review which has been written based on the previously publish literature, the similarities and the dissimilarities between the SARS-CoV-2, SARS-CoV, and MERS-CoV have been discussed. While the genome organization of all these b-CoVs was noticed to be more or less similar in the perspective of the major structural genes, variations in the accessory genes were found. A major distinguishing point focused on the mechanism of viral entry because while SARS-CoV-2 and the SARS-CoV employed their spike protein to the RBD of the host ACE2 receptor, MERS-CoVs engaged their spike proteins to attach with the host DPP4 receptor. Again, SARS-CoV-2 was found to possess higher affinity for the ACE2 receptor than that of SARS-CoV, which may figure out the current COVID-19 pandemics caused by SARS-CoV-2. The mode of transmission of all the three viruses aligned ultimately to the human-to-human direct transmission, and even the origins for SARS-CoV-2 and SARS-CoV were identified as bats; however, regarding the MERS-CoV, the origin is still not sure. Nevertheless, the intermediate host for the MERS-CoV was camel as stated in this review. The pattern of pathogenesis was mainly dependent on escaping the host innate immunity by all the three viruses, especially regarding the IFN antagonism strategy and the event of the cytokine storm (especially in the case of SARS-CoV-2 and SARS-CoV). The onset of clinical manifestations was found nearly similar especially regarding the onset of ARDS in severe cases although renal failure was another major concern for the MERS-CoV infection. The treatment strategies as well as the research on vaccine development to mitigate all these viral infections are still in trial. This is to be mentioned that the target sites for the candidate antiviral drugs have been detected mainly as the viral entry points, the activity of the RNA dependent RNA polymerase, and the applications of the monoclonal antibodies. A major difference between SARS-CoV-2, SARS-CoV, and MERS-CoV epidemiology has already been apparent that the SARS-CoV-2 is pandemic all over the world, while the impact of SARS-CoV or the MERS-CoV was not that much in course of the global public health disaster. Ongoing computational research on the viral epidemiological dynamics aids a major insight into such dreadful impact of SARS-CoV-2.
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Conflicts of interest
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