Abstract
There are seven types of coronaviruses appeared till now and they are different in their pathogenicity and the degree of the severity of the symptoms they cause. Phylogenetic analysis should be conducted in order to know the origin of the lethal viruses to be able to find treatments for them. In this essay, what have been found so far about the evolutionary origins of SARS-CoV-1, MERS-CoV and SARS-CoV-2 will be discussed. Furthermore, the animal hosts that are similar to each one of them will be mentioned according to the phylogenetic analysis conducted on their genomes.
Introduction
The spreading of SARS-CoV-2 worldwide and the large number of death cases occurred in the past few months lead to put a great attention on the virus’s evolution and origin in order to find a treatment for it. The first appearance of SARS-CoV-2 case was in Wuhan city, China in 31st December 2019. Although it was confirmed that SARS-CoV-2 belongs to the same family (Coronaviridae) of SARS-CoV and MERS-CoV, it appears to be less pathogenic than those two viruses. Those viruses use single‐stranded positive‐sense mRNA for replications inside the host cells and their viral envelops contain glycoprotein spikes and are derived from the host cells they infected [1,2].
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The structure of SARS-CoV-2
According to the International Committee on Taxonomy of Viruses, coronaviruses are classified to be members of Coronaviridae family, Coronavirinae subfamily with Nidovirales order. It has been known that according to the viruses’ phylogenetic relationships and genomic structures, Coronavirinae subfamily is divided into four genera which are alpha, beta, gamma, delta coronavirus [3]. Before the appearance of the new coronavirus, SARS-CoV-2, six coronaviruses which are HCoV‐229E, HCoV‐OC43, HCoV‐NL63, and HKU1, SARS-CoV and MERS-CoV are well known and understood. The first mentioned four coronaviruses and the last two viruses can cause mild respiratory diseases and severe respiratory disease in humans, respectively [4].
The HCoV-OC43 and HCoV-HKU1 genomes include genes that encode for five proteins which are spike, membrane, envelope, nucleocapsid, and hemagglutinin-esterase structural proteins while SARS-CoV-2, SARS-CoV, HCoV-229E, and HCoV-NL63 genomes include genes that encode for only spike, membrane, envelope and nucleocapsid structural proteins. The trimming of spike protein, which is found on the viral surface, mostly by the furin-like protease in the host cell gives two domains of the protein S1 and S2 domains. S1 facilitates the receptor binding process because it is considered a fusion protein while S2 provides structural support. The hemagglutinin-esterase protein facilitates the entry of the virus inside the host through its interaction with sialic acid while the nucleocapsid protein helps in the packaging of the RNA viral genome inside the virus. Finally, the most important function of the envelope protein, which is found in the virion, is that it plays an important role in the assembly and the release of the virus [1].
Genetic diversity and mutations play a vital role in the transmission and pathogenicity of coronaviruses. Coronaviruses can transmit across species and undergo genetic recombination and evolutionary status inside their hosts and through their transmission from one species to another leading to deadly viruses to humans. Two recent mutations occur in SARS-CoV-2 in the spike and nucleocapsid proteins and it is suggested that those two mutations are responsible for the zoonotic transmission of SARS-CoV-2 [6].
During the pandemic status of SARS-CoV, it has been shown that almost all of the patients with this virus had a previous exposure to animals before developing the disease. From the studies conducted on SARS-CoV, it was revealed that the causative agents of SARS-CoV was identified in masked palm civets and that SARS-CoV was transmitted to farmed civets from other animals. After further investigations about the origin of SARS-CoV and the discovery of the presence of SARS-like coronavirus in bats, it was suggested that bats are the natural reservoir of SARS-CoV which transmit the virus to civets and civets transmit the virus to humans, so civets is considered an intermediate host. After that, the results of the analysis of bats in one cage in Yunnan province, China suggested that the recombination of bat SARSr-CoVs leads to the emergence of SARS-CoV. Frequently, the recombination occurs in the receptor binding domain (RBD), which binds to the angiotensin-converting enzyme 2 (ACE2) receptor in the host cell, of the spike protein and the upstream region of orf8 [3,7]. Another important survey conducted to know the animals that carried SARS-CoV during the pandemic outbreak in 2002 and 2003, 485076513854600showed that cats, civets, raccoon dogs, and ferret badgers from wet markets were carriers for SARS-CoV [8].
According to [9], SARS-CoV showed a unique structure and internal organization of its small ORFs in the 3′-proximal region and the nonstructural protein 3 (nsp3) replicase subunit, respectively indicating that SARS-CoV is distantly related to the other three groups of coronaviruses and forms a new fourth group. According to figure (3A), to show when SARS-CoV was emerged relative to the other three groups of coronaviruses, it was placed in a new group with its origin placed next to the ancestor of other coronaviruses. According to figure (3B), analysis on the most conserved part in the coronaviruses’ genomes, replicase ORF1b region, with equine torovirus used as an outgroup was conducted. The results revealed that in the late stage of SARS-CoV, it splitted off early from group 2 and also, group 3 (including the avian coronavirus) is splitted off early from the mammalian ancestors of coronaviruses. These results proposed that group 2 should be splitted into 2 subgroups, MHV and BCoV included in one subgroup while SARS-CoV included in the other subgroup. Although the majority of the published unrooted trees on coronaviruses showed that SARS-CoV is originated in group 2, many debates were originated about what is the best scenario for the evolutionary origin of SARS-CoV [9].
A phylogenetic analysis and relationship of SARS-CoV and related viruses, to study the S, M, N and PP1ab replicase polyprotein, was conducted using split decomposition phylogenetic method in figure (4). The analysis shown the descendent of M and N proteins from an avian-like coronavirus ancestor. In the N protein graph, it is cleared that the SARS N protein diverges and forms a clade with avian coronavirus, but there is no evidence on the recombination events that occurred between them. Also, in the M protein graph, it is cleared that SARS M proteins forms a clade with avian-coronavirus and the reticulations part in the SARS-avian clade in this graph showed that there was a recombination that occurred between them. In the PP1ab section in figure (4), it is shown that SARS PP1ab was derived from a mammalian ancestor and it is located between the avian and the murine and bovine coronaviruses. In the S section in the graph, it is shown that SARS S protein involves in a clade with group 1 coronavirus (including feline and canine) and avian-coronavirus with high number of recombination events occurred in this clade leading to change in the host specify of the S protein and the emergency of SARS-CoV infections in humans [10].
The spike structural protein of SARS-CoV is divided into two domains as mentioned previously, S1 and S2. The S1 domain, which is responsible foe receptor binding, hence entry of the virus, is divided into two domains: the amino-terminal domain (S1-NTD) and the carboxy-terminal domain (S1-CTD). It has been found that the 479 and 487 amino acid residues located in the S1-CTD are responsible for the transmission of SARS-CoV from civets to humans. Also, orf8 has acquired several modifications during its transmission form animals to humans and this leads to the adaptation of the virus to inhibit interferon responses in host cells and induce apoptosis with unclear mechanism [3].
The evolutionary origins of MERS coronavirus
The first appearance of MERS occurred in 2012 when fatal respiratory infection was detected in a patient in Saudi Arabia. After phylogenetic analysis of MERS-CoV, it was shown that it belongs to clade c of Betacoronavirus which termed as HKU4 and HKU5 and found in bats. Neoromicia capensis bat coronavirus found in South Africa. There are two clades to which MERS-CoV genomes are divided: clade A and clade B. The most strains are found in clade B while clade A contains few strains. The 3’ one-third of MERS genome encodes the aforementioned structural proteins (spike, membrane , nucleocapsid and envelop structural proteins) in addition to other accessory proteins while the 5′ two-thirds of its genomes encodes ORF1a and ORF1b, which are used in replication as a complex [11].
Whereas SARS-CoV early patients appeared to have a previous contact with civets in markets, MERS-CoV early patients showed to have a previous contact with dromedary camels. After several phylogenetic analysis, the sequence of MERS-CoV obtained from dromedary camels appeared to be almost identical to the sequence of MERS-CoV obtained from humans. Also, the presence of MERS-CoV present in the collected camels’ serums from 1983, revealed that MERS-CoV was present in camels for more than 30 years. Although two genomic sequences of Tylonycteris bat coronavirus HKU4 and Pipistrellus bat coronavirus HKU5 that showed some similarity to the sequence of MERS-CoV, the spike protein in the two sequences showed variability which was occurred due to positive selection and recombination events [3].
The receptor used by MERS-CoV to enter the host cell is dipeptidyl peptidase 4 (DPP4, CD26) which binds to the receptor binding domain of the spike protein. Also, this host receptor is used by Bat CoV-HKU4 which allows for the clustering of MERS-CoV to the same group of bat CoV-HKU4. In contrast to what happened in SARS-CoV-1, the recombination events and positive selection targets the heptad repeats of MERS-CoV, which are repeats important in the entry of the virus. Furthermore, point mutations that happened in the RBD of MERS-CoV allows the virus to spread more with increasing the affinity to the human host receptor [12,13].
87% nucleotide sequence of MERS-CoV are homology with bat CoV-HKU25, the closest animal to MERS-CoV indicating that bat CoV-HKU25 is not the natural reservoir of MERS-CoV. Although some patients with MERS-CoV showed prior exposure to dromedary camels, others showed no prior exposure to them which indicates that the transmission to those patients was due to human to human transmission or due to another animal which is not recognized yet [13]. The same two amino acid substitutions at the C terminal of the spike protein are found in both MERS-CoV and HKU4 which facilitates and changes the capability for their entry into the human host cell. It has been reported that MERS-CoV is found in five different species which are two species of bats, dromedary camel, and human and the hedgehog from Europe. Phylogenetic analysis of MERS-CoV obtained from these species was conducted through preforming ML tree. The results showed that MERS-CoV obtained from the hedgehog considered the ancestor to the other species while the two species of bat are considered the ancestor of the camel and the human MERS-CoV [14].
The evolutionary origins of SARS-CoV-2
The first appearance of SARS-CoV-2 was detected in patient in December 2019 in Wuhan city, China. It was reported that RaTG13, SARS-like coronavirus obtained from the bat Rhinolophus affinis, showed approximately 96% similarity in all genomic regions of SARS-CoV-2 with diversity in the RBD region. Furthermore, it has been reported that pangolins are considered intermediate hosts for SARS-CoV-2 due to its similarity to the RBD region of SARS-CoV-2 [15].
Upon further studying of the phylogenetic relationship between SARS-CoV-2 and other related coronaviruses from bats and pangolins, the conserved ORFs in their genomes, which are orf1ab, E, M, N, ORF3a, S, ORF7a, ORF6, and ORF7b, were used for building the phylogenetic trees according to the synonymous regions. From figure (5), it has been shown that RaTG13 is the closest one to SARS-CoV-2 and it is followed by GD Pangolin SARSr-CoV while BM48-31 is considered the distantly related coronavirus to SARS-CoV-2 [16].
Although both of SARS-CoV-2 and SARS-CoV-1 bind to the same human host receptor, ACE2, there are five important amino acid residues out of six, found in the RBD, are different between them leading to a increase in the binding affinity of SARS-CoV-2 to the receptor than SARS-CoV-1 resulting in changing of their pathogenicity. Only one of those six amino acid residues is similar between RaTG13 and SARS-CoV-2, although it is the most similar one to SARS-CoV-2. Interestingly, GD Pangolin-CoV shows similarity in those six amino acid residues with SARS-CoV-2 indicating the occurrence of several recombination events to the spike protein RBD region [16].
Summary and Conclusion
Coronaviruses outbreaks lead to many cases of death worldwide in the past 20 years. The origin of SARS-CoV-1, MERS-CoV and SARS-CoV-2 need to be known in order to find the best treatment for them. Phylogenetic analysis is conducted on different species with coronaviruses in order to know the origin of the aforementioned three types of coronaviruses that infect humans. Civet or cats like coronaviruses are considered the closest one to SARS-CoV-1. Although bat CoV-HKU25 shows 87% similarity with MERS-CoV, it is unclear till now what is the actual reservoir MERS-CoV. Finally, different phylogenetic analysis showed that RaTG13 and GD Pangolin SARSr-CoV are the closest coronaviruses to SARS-CoV-2.
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