A new study published reveals that the host immune response, mediated by two RNA editors, causes the SARS-CoV-2 to adapt and change strain characteristics. With time, scientists have discovered a mutation in coronavirus. The SARS-CoV-2 is a single-strand betacoronavirus, with a large genome encoding. It also inhibits both structural and non-structural proteins including the spike (S) protein, the nucleocapsid (N) protein, the envelope (E) protein, and the membrane (M) protein.
The complete virus requires all four of these proteins to be present. During the viral infection, the S proteins mediate viral attachment to the host ACE2 receptor and then the fusion of the viral and host cell membranes, with viral cleavage, that allows the virus to gain entry into the cell and initiate active infection. The N protein assures it’s binding to the RNA genome and triggers replication and assembly of the viral proteins, as well as initiating the host cellular response.
Mutagenesis in SARS-CoV-2
The scientists associated with the current research used a tracker to examine the mutational history of the virus. It was found that almost 15,000 mutations have occurred so far, with over a thousand being on the S gene which impacted the infectivity of the virus because different geographic and demographic characteristics and exposure adversely affect the viral genome that drives these mutations. Research shows that the virus is mutating at a slower rate than other common viruses such as the common cold and influenza viruses.
This is attributed to the efficient proofreading apparatus in the coronavirus genome. Mutations in the SARS-CoV-2 arise from three routes: random replication errors, due to genetic drift, and exposure to spontaneous genotoxins. One method to understand this is by genotyping, which allows researchers to trace the course of the mutation. Earlier, the Wuhan strains of the virus showed hypermutations C>T occurring as a result of deamination during RNA editing as a result of APOBEC. The two RNA editing mechanisms known in human cells are deaminases, namely, the RNA-APOBEC and RNA-ADAR (adenosine deaminases acting on RNA) editing mechanisms.
A very high proportion of these mutations because of RNA mechanisms indicate that they are part of the host reaction to the virus. A random mutation rate will result in a ratio of ~8% permutation, but the C>T mutation accounts for ~24% of mutations – hypermutation. This indicates that the host immune system is fighting the virus via its RNA editing mechanisms. However, the virus counter-attacks, using its proofreading and repair mechanisms, accounting for the high reversed mutations
Age and hypermutation
Hypermutations are far more common with age and over 42% of them being found in patients over 90 years of age. This means that their immune responses are aggressive, or due to poor responses as seen in the cytokine storm often seen in severe COVID-19 infection. This phenomenon often causes inflammation thereby causing organ damage. This may account for the higher mortality due to COVID-19 in the elderly.
The study indicates the vital role played by the APOBEC proteins in innate and adaptive antiviral responses early in the course of the infection. A higher frequency of the hypermutation demonstrates strong host immunity. This leads to an efficient viral clearance but it can also turn hyperactive and lead to organ damage and death by triggering a cytokine storm.
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Ref link: https://arxiv.org/abs/2008.07488