Genetic Diversity of Coronaviruses: From SARSCoV to SARS-CoV-2 – (Part 2)

Middle East respiratory syndrome coronavirus (MERS-CoV), a novel coronavirus linked to severe respiratory tract illness, was initially identified in 2012. Since then, 1401 individuals have been infected with this virus in 26 countries, with 543 people (39%) dying. Severe respiratory infection, sometimes accompanying shock, acute renal damage, and coagulopathy are all symptoms of these disorders. This pandemic has sparked worldwide worry because of its human-to-human transmission via intimate contact. The Eastern Province, Riyadh, and Makkah were severely hit. In 2014, the pandemic progressed fastest in Makkah, Riyadh, and Eastern Province in 2013. Effective therapeutic and immunological solutions based on solid molecular research were critical, with the threat of an epidemic looming. The MERS-CoV intrinsic genetic heterogeneity across different clades may have set the way for crossspecies transmission and alterations in inter-species and intra-species tropism. Host protease blockers include transmembrane serine protease 2 (TMPRSS2), cathepsin L, and furin. According to sequence comparison and modeling research, the viral spike features a putative receptor-binding domain (RBD) that enables this interaction.2.

The dipeptidyl-peptidase 4 (DPP4)-propeller engages with the receptor-binding subdomain but not the intrinsic hydrolase domain. The receptor binding subdomain of MERS CoV and severe acute respiratory syndrome coronavirus (SARS CoV) is drastically different. This chapter aims to explain the genetic architecture of host proteins involved in MERS-CoV and compare it with other coronaviruses.

The current outbreak of SARS-CoV-2 has raised various clinical and scientific questions, including the effect of host genetic factors on pathogenesis and disease susceptibility. MERS-CoV is a highly pathogenic virus in humans, causing high mortality (30-40%) and morbidity. CoVs are found to be widespread in man, poultry, and mammals. MERS-CoV enters the host cells by attachment with DPP4 receptors; it hijacks the host cell cycle, which helps in its survival and proliferation. Understanding the innate immune response against MERS-CoV is essential in the treatment development and precautionary measures. Nonstructural protein 1 (nsp1) has attracted greater attention as a potential virulence factor and a possible target for vaccine development. Downregulation of Th2, inadequate Th1 immune response, and overexpression of inflammatory cytokines IL-1α IL-1β, and IL-8 occur in the lower respiratory tract of patients infected with MERS-CoV. Research has shown that high viral load, high expression of inflammatory cytokines, and the downregulation of Th1 and Th2 response result in severe infection, contribute to lung inflammation, develop acute respiratory distress syndrome (ARDS) and pneumonia, and cause high fatality.

Human CoVs (hCoVs) were discovered in people suffering from the common cold during the early 1960s. This family is comprised of four well-known genera, viz. α-CoV, β-CoV, γ-CoV, and ∆-CoV. Mammals, including humans, pigs, cats, and bats, may be infected by α-CoV and or β-CoV. γ-CoV mainly affects avifauna, whereas ∆-CoVs affect both birds and mammals. The coronavirus (CoV) outbreak has caused great devastation globally. CoVs are positive-sense, nonsegmented single-stranded RNA viruses of the order nidovirales and the family Coronaviridae. Deep sequencing examination of lower respiratory tract pathological studies on affected people revealed the presence of a new coronavirus strain, which was termed SARS-CoV-2. Four structural proteins, viz. envelope protein (E), membrane protein (M), nucleocapsid protein (N), and spike protein (S) have also been determined. Following the very initial reports of the novel severe acute respiratory syndrome (SARS) coronavirus back in late 2019 from Wuhan, China, a plethora of research attempts arose on how SARS-CoV-2 made its entry into humans. There is still a difference in ideology for its laboratory escape or the zoonotic spread, but the exact phenomenon is not known yet. Completing a thorough review, the studies suggest that the virus's origin is more complicated than previously known. 

The coronavirus disease-19 (COVID-19) spread worldwide in no time. Finally, the World Health Organization declared it a pandemic in March 2020. The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) can mutate, and many mutations have been observed worldwide. The severity of symptoms varies from mild to critical cases, and the incubation period ranges from 5-14 days. Various studies have shown that the diversity of SARS-CoV-2 within the hosts is prevalent, and some genomes are more susceptible to the alterations due to mutation. Some of the tissues that exhibited the highest ACE2 expression in different host tissues (humans) were kidneys, thyroid, heart, adipose tissue, small intestine, and testicles. Endothelial cells have also been the site for SARS-CoV-2. Chinese people were the first to be reported with the polymorphism detection for the ACE2 gene. Different variants of the ACE2 gene that are closely linked with hypertension were rs464155, rs4240157, and rs4830542. There has been a close association between ACE2 and TMRSS2 and SARS-COV-2, SARS-CoV-1, and influenza virus. The inducibility of heme oxygenase-1 (HO-1) enzyme to reactive oxygen species is regulated by the GT dinucleotide repeat mutation and polymorphism of the HO-1 gene.

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) virus appeared at the end of 2019 and was subsequently named coronavirus disease-19 (COVID-19). Its worldwide emergence resulted in a large number of infections. Many studies depicted that the information about genomic variations in viruses has important effects on the prognosis and treatment of transmissible diseases. In this chapter, we collected various genomic variants, performed a phylogenetic analysis of recently registered genomes at various databases, and characterized the SARS-CoV-2 operating on silicon tools. Many complete sets of SARS-COV-2 are available in different databases such as GenBank and verified by National Genomics Data Center (NGDC) and National Microbiology Data Center (NMDC) databases. We found various variants, and the most common variants were 3037C>T (ORF1ab), 14408C>T (ORF1ab), 23403A>G (S), 25563G>T (ORF3a), 1059C>T (ORF1ab) and 241C>T (5' UTR) in online data samples. In addition, the complete genome sequence identity of the SARS-COV-2 results was 96.2% similar to that of a bat. These identified variations have increased the frequency of the spread of SARS-CoV-2. This information assists a comprehensive collection that combines genomic characterization, epidemiological and graphical records

Proteins are the functional units of the cell that allow viruses to reproduce inside host cells. Proteins are essential for a cell's proper operation. Gene variations can reveal potential new therapeutic targets. Examining the innate immune system, coagulation, and other host proteins about the severity or mortality of COVID-19 reveals potentially changeable maladaptive host responses. Proteins are considered to be the high prevalent biological group of pharmacological factors, and high-throughput proteomics methods are quickly being employed to find prospective target molecules for innovative development of new drugs and repurposing studies. Researching the naturally occurring variations in the human gene sequence that code for therapeutic targets can also show how treatments work and ensure that people are safe. Researchers can create novel or repurposed therapeutics by examining the host protein’s genetic makeup that interacts with SARS-CoV-2 or supports host responses to COVID-19.

The researchers revealed a novel coronavirus in the Chinese population on 7th January 2020, named severe acute respiratory syndrome coronavirus-2 (SARSCoV-2). The previous coronaviruses proved merely the tip of the iceberg after the emergence of the recently identified SARS-CoV-2. The potential of pandemic status significantly revealed the concealed capabilities of virulence and contagiousness of the betacoronaviruses group. This book chapter discusses the landscape of host genetic factors correlating with SARS-CoV-2. All SARS-CoV-2 genes code for the structural and non-structural proteins that have distinct interactions with host proteins. NSP13 is associated with centrosome and insulin signals in humans, NSP5 is associated with the ATPases of host cells, and NSP9 is associated with the nuclear pore's host proteins. The ORF8ab and ORF8b avoid the host immune responses and inhibit the signaling cascade of INF-β. Cytokine storm is associated with TLR2, FOXO1, and MYC genes of SARS-CoV-2 that further cause host cell death during infection. STAT1, IFIH1, IRF9, OAS1-3, and PML are associated with the immune response to SARS-CoV-2 infection, particularly the production of type I interferon. The SARS-CoV-2 entry is affected by the TMEM106B gene, and this gene can prevent virus-induced cell death. Replication of SARS-CoV-2 reduces due to deletions in TMEM106B and VAC14 genes. Genetic variants also influence the host susceptibility in the major histocompatibility complex antigen loci (HLA). The susceptibility of COVID-19 is considerably associated with the genetic variation in HLA and plays a significant role in identifying populations at higher risk.

All genetic variations are the outcome of mutations in the genetic material. The greater the mutation ratio, the greater will be the genomic diversity. Currently, epigenomics enables us to locate, read, and translate the epigenetic mechanism that monitors and reins the whole genome of coronaviruses at different stages. Many researchers reported the role of epigenetic mutations in the development and progression of several common viral infections, especially age-related diseases. Many families of viruses can counter the immune response by utilizing a cascade of epigenetic events and taking over the regulatory capacity for their benefit. Coronaviruses possess the same mechanism to affect epigenetic machinery, i.e., by improving mutations in the epigenetic code, DNA methylation, post-translational alterations of histone proteins and other proteins linked with epigenome, or direct dysregulation of enzymes.

This chapter comprises the neurological pathogenesis of Coronaviridae in the central nervous system (CNS). These viruses manifest their virulence factors involving multiple organs of the body, initiating from febrile conditions, respiratory distress, and hypoproteinemia leading to edematous fluid accumulation. They pave their path to CNS by directly affecting the cranial plus vagus nerve fibers and synapses or through systematic circulation. The viruses can have an affinity with various receptor sites present on organs that help in hematogenous and retrograde mobility towards CNS. Comorbidities occur excessively due to these viruses in the living system involving vital organs such as the liver, heart, and lungs. Neurological dissemination of these viruses is characterized by a permanent loss of nerves or part of the CNS, either entirely or partially. Prevention is suggested, accompanied by adequate treatment and care management to avoid extensive spreading of the virus throughout CNS.

For the third time in the last few decades, novel coronavirus-19 (2019-nCoV or COVID-19) has been described as the most fatal coronavirus ever, capable of infecting not just animals but even humans all over the world. Healthcare policy makes use of advanced technologies such as artificial intelligence (AI), big data, the internet of things (IoT), and deep machine learning to tackle and forecast emerging diseases. AI is increasingly being used to help in disease identification, prevention, reaction, rehabilitation, and clinical analysis. Since these developments are currently in their initial phases of development, slow improvement in their application for significant deliberation at local and foreign strategy levels is being made. Nevertheless, a current case shows that AI-driven technologies are improving in reliability. Companies like BlueDot and Metabiota used AI technology to predict the coronavirus disease-19 (COVID-19) in China before it surprised the world in late 2019 by spying on its effects and propagation. One approach is to use computational techniques to discover new target drugs and vaccines in silico. Machine learning-based algorithms trained on particular biomolecules have provided affordable and quick-to-implement tools for the development of successful viral treatments during the last decade. Drug repurposing is a technique for finding new uses for accepted or experimental drugs. For novel diseases like COVID-19, a drug repurposing approach is a viable approach. Future directions of AI are drug discovery and vaccination, biological research, remote video diagnosis, tracking patient contacts, COVID-19 recognition and therapy via smart robots, and identification of non-contact infection. This chapter aims to explore AI-based technology for diagnosis, management, drug repurposing medications, novel drug discovery, and vaccines for coronaviruses (SARS-CoV and MERS), including during the COVID19 pandemic.