Mutations in Coronavirus; this has been the biggest topic of discussion in the last few months. The news of new strains in brazil, UK, and South Africa created a fearful atmosphere over the world. millions of people been affected and many of them failed to survive. Recently some new variants of coronaviruses are doing their job silently but pretty effectively, especially in India.
If we look back to the history of mankind, several pandemics had knocked again and again and caused many deaths and losses. From the end of 2019, COVID-19 has started to spread and become a pandemic that spread all over the world. Mankind survived in past, and fight in the present scenario. How!
It will sound a little bit shocking that about 8% of the human genome consists of viral genomic fragments! These fragments are also called ‘genetic fossils’ which have come from past viral epidemics that our vertebrate ancestors survived. The genetic fossils have assimilated into the human genome by the endogenization process and carry forward by germline cells.
Though a virus is a very tiny creature, it has the ability to destroy human civilization. Yes, vaccines are already discovered; but never forget, the mutations in Coronavirus will continue, then why vaccine?
Undoubtfully, it’s a big question, and I personally received several requests for a proper explanation on this topic. I tried to introduce the facts of viral mutation related to coronavirus in a brief and simplest way. Hope, this will help you to realize the answers that you are looking for.
VIRUS: ACELLULAR PARTICLE
Viruses are acellular particles that lack a cellular structure, which means cellular organelles and plasma membrane are absent. They become live only within the host or host cells. Outside a host, it has no ability to do any work and acts as a non-living particle, which is then called a virion.
Within host cells, viruses complete their life-cycle by repeating the following steps:
- attachment to host cell surface
- gene expression
- release of new viruses which again infect healthy host cells.
During the replication (the process of reproduction of multiple genomes from the mother genome) of the viral genome, they often do mistakes; as a result, gene mutations (permanent change in the sequence of genetic material) take place.
Not all gene mutations are harmful or lethal, some mutations lead viruses to become less infective. Even some mutations are not phenotypically expressed and are called silent mutations. In reverse, if a mutation makes a virus extremely deadly to its host, the viral strain will become eventually extinct along with the death of the host species.
So, those gene mutations are in our concerns which make a virus more infective. The same explanations are applicable for any virus, including the gene mutations in coronavirus.
HOW DO VIRUSES MUTATE
After the entrance of the viral genome into the host cell, it replicates using host cell organelles and cellular reservoirs and unfortunately often make copying mistakes. Sometimes different viral strains recombine within the cell, as a result, gene mutation occurs.
Some mutations cause minor changes in the expressing antigens and are called antigenic drift. Antigenic drift doesn’t make a radical change in a viral strain. So this type of mutation generally is not harmful to the host. Antigenic drift usually occurs naturally during the viral replications over time.
Not all viral genetic mutations result in antigenic changes. For example, if a mutation happens in the non-coding region or if the result of mutation causes alteration in such region that does not interfere with the host immune system, these mutations don’t cause antigenic changes.
One example of antigenic drift has been seen in SARS-CoV-2. In this case, the alteration of a single nucleotide in the RNA sequence results in the replacement of amino acid aspartate(D) present at the 614th position of the spike protein by glycine (G). Virologists call it the D614G mutation. This replacement results in the loosening of the triplet peptide structure of the spike protein, which helps the virus to fuse with the host cell more easily. At the end of June 2020, this variant has been found in almost all samples around the world.
Influenza viruses frequently undergo antigenic drift over time. Sometimes host’s immune system may not recognize the newer virus and the existing antibodies fail to neutralize it. That is why people get flu more than once.
On the other hand, the antigenic shift represents a drastic change in the viruses, which can occur through genetic reassortment when two or more different strains of viruses infect the same cell. As a result of antigenic shift, a novel virus forms, which is very different from the previous subtype, and the host cell completely fails to recognize the new virus.
If the newly formed virus is infectious, then a pandemic may occur. For example, Influenza A viruses undergo both antigenic drift and antigenic shift, whereas in Influenza B viruses antigenic shift never occurs. Such an antigenic shift occurred in 2009, the pandemic was called Swine flu. The causative organism was the H1N1 virus with recombined genes from North American swine, Eurasian swine, humans, and birds.
Another example of a reassorted virus is the novel coronavirus, SARS-CoV-2. Its genome seems to be 96% identical to the virus BatCoV-RaTG13, which infects the horseshoe bat Rhinolophus affinis. This evidence strongly suggests that the SARS-CoV-2 was originated from the bats and later appeared in its present form via antigenic shift. Besides bats, another wild mammal pangolin has found to be living with a coronavirus similar to SARS-CoV-2.[1-3]
So far, many other mammals were found to be infected by SARS-CoV-2, both in the lab and outside the lab (such as cats, fruit bats (Rousettus aegyptiacus), ferrets, rhesus macaques, hamsters, and dogs, tigers and lions at zoos, and farmed mink) probably from the human.
Types of Gene Mutations in Coronavirus
Gene mutations in coronavirus (SARS-CoV-2) usually occur at a slower rate. Scientists have observed three major mutations of the COVID-19 virus so far:
- D614G (an antigenic drift, previously explained)
- VUI 2020-12/01 (Variant Under Investigation, year2020, month12, variant01)
All of these mutations allow the virus to become more transmissible from human to human. Investigations are going on to find if the new variants are associated with any changes in symptoms, human antibody responses, or vaccine efficacy.
Influencing Factors for the Rate of Viral Mutation
There are several known and unknown factors that influence the gene mutation in viruses. I’m highlighting here some of the most important ones. These factors explain the reasons behind a slower rate of gene mutations in coronavirus.
1. Genetic Material: RNA/DNA
RNA viruses mutate faster than DNA viruses. The best probable cause is the replication of RNA in RNA viruses is catalyzed by the enzyme RNA-dependent RNA polymerases (RdRp) which don’t have a proofreading activity. This enzyme is also called RNA replicase that catalyzes the synthesis of the RNA strand complementary to a given RNA template.
On the other hand, DNA viruses use DNA polymerases for replication. DNA polymerase has proofreading activity for the correction of mistakes during replication.
However, there are some exceptions. Members of the order Nidovirales, including coronaviruses, roniviruses, and toroviruses have an RNA polymerase-independent proofreading activity, but its function is not much efficient as the DNA polymerase. However, this proofreading lowers the rate of mutation in those viruses.
2. Size of the Genome
Viruses with a short genome tend to mutate faster than that of a larger genome. Coronaviruses have the largest genomes (30-33kb) among all RNA viruses and thus have a slower mutation rate. The evolution of proofreading capacity is one of the reasons that explain why they possess larger genomes.
3. Single or Double-stranded Genome
Single-stranded RNA or DNA viruses mutate faster than double-stranded viruses. Though the exact reason for this is still unclear, one possible explanation for this is the single-stranded nucleic acids are more accessible to oxidative deamination and other chemical damages. That is why the mutation rates of some double-stranded RNA (dsRNA) viruses are similar to that of some single-stranded DNA viruses (ssDNA).
4. Other Factors
Apart from the above-mentioned factors, viral mutations are controlled by different factors, which include polymerase fidelity (the ability of a polymerase to accurately replicate a template), cellular microenvironment, proofreading activity, and access to post-replicative repair.
RECOGNITION OF SARS-CoV-2 BY HOST CELL RECEPTOR
Antigens are foreign particles recognized by the specific antibodies of the immune system. In viruses, specific proteins of the outer cover work as antigens and recognized by the antibodies. Each antibody contains a paratope that recognizes a specific epitope of an antigen; this acts like a lock and key mechanism, which means the binding is structurally determined.
In the case of SARS-CoV-2, an envelop-anchored spike protein binds to a host cell receptor called ACE2 (angiotensin-converting enzyme 2) and enters into the host cell. ACE2 is a protein attached to the cell membranes of the cells present in almost all vital organs of the human body, such as lungs, heart, kidneys, arteries, and intestines (for similar information: visit HERE and see MIS-A).
ACE2 receptor is present in more than 215 vertebrates. All of them may be susceptible to SARS-CoV-2.
After the entry of coronavirus into the host, innate immune responses call the adaptive immune responses into play. Both innate immunity (inborn primary immunity) and adaptive immunity or acquired immunity (secondary immunity) work together to eliminate the pathogens.
Specific antibodies are produced by adaptive immunity against the spike protein of SARS-CoV-2. Antibodies bind to the spike proteins and hence block the binding with ACE-2 receptor, and prevent viral entry. Antibody production is comparatively lower in older men than in younger, that’s why aged persons are getting affected more easily and severely. Vaccination induces adaptive immune responses and helps to fight against the pathogen.
Mutations in Coronavirus will Continue; Then Why Vaccine?
So, the above information clearly indicates, mutations in coronavirus will not stop because it’s a natural process.
Coronaviruses have an RNA polymerase-independent proofreading activity and thus they mutate at a slower rate than most other RNA viruses. Sequencing the genetic material of SARS-CoV-2 in different samples has shown that a virus accumulates only two single-letter mutations per month. If we compare it with other RNA viruses like influenza, which mutates at a double speed, and HIV, which mutates four times faster.
So, the proofreading quality of a coronavirus makes the virus much more stable and that is good news for making a vaccine with a long-term effect.
Individuals may have partial immunity to the existing viral strain from previous viral exposure or vaccination. But due to antigenic drift, some viral antigen changes its shape, and sometimes our immune system doesn’t recognize the virus and we get sick.
Antigenic shift generates novel virus, to which our immune system is not prepared for fighting; consequently pandemic occurs. So, if genetic recombination occurs between human virus and closely related animal virus, the vaccine doesn’t work for newer lineages.
Vaccines produce protection by developing an immune response to the coronavirus and provide a safety guard that restricts the severity of COVID-19. So far, the vaccines for COVID-19 are derived based on past strains. Until and unless the critical antigenic shift mutations of coronavirus happen, it is expected that the developed vaccines will keep working. But, the world has been changed; so, every type of precaution is essential up to the next 2-3 years. These include,
- Social distancing
- Washing hands frequently.
- Wearing mask