How viruses evolve and what will become of the SARS-CoV-2 virus?

The internal and external structure of the coronavirus.
How viruses evolve.

How viruses evolve and what will become of the SARS-CoV-2 virus?

Mankind can handle a new coronavirus, but it's still unclear at what cost. The equation called "COVID-19 pandemic" still has too many unknowns, and much depends on what happens to the SARS-CoV-2 virus itself. 

The SARS-CoV-2 virus mutates and it is unclear whether it will become more dangerous or become a harmless virus with which we will coexist peacefully.

How viruses evolve?


In the spring of 1997, a three-year-old boy in Hong Kong contracted a disease that resembled a common cold for all symptoms. Coughing and fever did not go away for six days, so the little patient was taken to Queen Elizabeth Hospital.

Despite intensive therapy, the boy's condition was only worsening, and it was never possible to save him. For about a month virologists analyzed the boy's sputum samples, trying to find out what caused the sudden death, but all in vain. As a result, Chinese experts decided to send the biological material to their American colleagues, who were able to determine that the culprit is the H5N1 influenza virus, or avian influenza.

During that year, avian influenza was diagnosed in 18 other people, six of whom died. The death rate from H5N1 was higher than that of the Spanish flu, which caused more than 50 million deaths in the early twentieth century.

At that time, humanity was very lucky because the avian influenza virus did not acquire the ability to transmit from person to person. But things could have been different if the H5N1 virus had encountered seasonal influenza, for example, in a pig's body. In such cases, when several viruses penetrate the cell at once, reassortment occurs - the exchange of their genetic material, resulting in the emergence of new versions of viruses.

Sources of new viruses


The influenza virus genome consists of 8 separate segments of RNA. If a cell is simultaneously infected with two influenza viruses, these are already 16 segments that produce different combinations. In theory, 2 influenza viruses can give 256 different combinations.
Reassortment is one of the main mechanisms for the emergence of pandemic viruses. A striking example is the (H1N1)pdm09 virus, which caused a pandemic in 2009. The (H1N1)pdm09 virus is the product of reassortment of human, swine and poultry viruses in swine organisms.

The H5N1 virus has not yet 'co-operated' with other viruses, so disposing of birds at outbreak sites can quickly localize the disease, preventing it from spreading to millions of people, which is not the case with the new SARS-CoV-2 coronavirus.

This is not the first coronavirus that mankind has encountered. The coronavirus became known back in the mid 1960s. In 2002, the SARS-CoV coronavirus caused an epidemic of severe acute respiratory syndrome (SARS). A total of 8437 cases were reported, of which 813 resulted in deaths. Ten years later, another coronavirus, MERS-CoV, started raging, causing Middle East Respiratory Syndrome (MERS) with a 35 per cent mortality rate.

Both of these viruses, as well as the new coronavirus SARS-CoV-2, came to man from bats. But unlike the avian influenza virus, the SARS-CoV and SARS-CoV-2 coronaviruses are easily transmitted from person to person.

The MERS-CoV virus is mainly transmitted from animal to human, and human to human transmission is only possible through very close contact, for example within the family or between an infected patient and a doctor.

The SARS-CoV and SARS-CoV-2 viruses have been able to spread to humans due to the fact that the S-protein of the virus crown mimics the angiotensin converting enzyme 2 (ACE2). Thanks to this, they successfully bind to the receptors of ACE2 (there are many of them on the surface of lung cells - alveolocytes), and then inject their RNA inside the cell.

Comparison of SARS-CoV and SARS-CoV-2 viruses shows that the latter has a higher binding force with ACE2 receptor. A study by Chinese scientists shows that the major differences between SARS-CoV and SARS-CoV-2 viruses are concentrated between 435 and 510 amino acid residues of the receptor-binding domain (RBD). This is the region of the receptor-binding motif (RBM) within the RBD.

Analysis of the RBM amino acid sequences of two types of bat coronaviruses (RaTG13-CoV, Bat-CoV), Pangolin Coronavirus (GD Pangolin-CoV) and SARS-CoV-2 showed five key differences in the amino acid sequence that are common only to GD Pangolin-CoV and SARS-CoV-2.

This allows researchers to assume that the Pangolin Coronavirus can be considered as a potential intermediate host, in which recombination could occur.

According to Chinese researchers, GD Pangolin-CoV transmitted to the RaTG13 virus genes responsible for the synthesis of RBD, so that the new virus has the ability to overcome the interspecific barrier. But this is still a hypothesis, because the similarity between the two viruses may be the result of convergent evolution, where two species independently acquire the same set of features due to similar living conditions.

Both SARS-CoV and MERS-CoV have managed to be restrained relatively quickly given their high mortality incidence and rapid symptom development. Oddly enough, the more lethal the virus is, the easier it is to localize it. SARS-CoV-2 is different in this regard. In most cases, the infection is mild, allowing the virus to gain time and spread further.

Overcoming interspecies barriers: the origin of SARS-CoV-2 virus


There are several ways in which the virus can overcome the interspecies barrier. These are mutations and recombinations .

The gene reassortment mentioned above is a type of recombination and is characteristic of segmented viruses (in particular influenza viruses). Coronaviruses have nonsegmented RNA, so other recombination options are possible for them when one virus brings a fragment of the genome into the other.

The second mechanism of virus variability is mutation. Since RNA replication, unlike DNA, occurs without the possibility of error correction, the probability of errors in RNA synthesis is 10 thousand times higher than in DNA replication.

At each replication cycle, about 10 percent of RNA viruses have mutations. This may be a deposition or insertion of one or more nucleotides. Mutations in RNA are one of the main sources of antigenic drift - changes in antigenic characteristics.

The SARS-CoV virus was present first in the body of bats, whose immune system coped well with it. It spread to the civet (predatory mammals in Asia and Africa), and then spread to people. The MERS-CoV virus was transferred from bats to camels, which became a source of infection for humans.

An intermediate host of the new coronavirus SARS-CoV-2 has not yet been identified. Analysis of its S-protein receptor-binding domain indicates that these may be pangolins. But there is another study of phylogenetic analysis, in which scientists assume that there is no intermediate host, and the virus has migrated to humans directly from the bats.

Viruses constantly mutate throughout their journey. They are forced to do so by external conditions.

When a viral infection occurs, the host organism triggers various protection mechanisms. In addition to the production of antibodies, there is the launch of the programmed cell death (PCD), production of interferons, which activate the synthesis of protein kinase and disrupting the synthesis of proteins, including viral.

In order to survive in the host organism, viruses resort to three main strategies: 

  • "secret presence" which allows the virus to avoid immediate recognition by the immune system.
  • "sabotage" which leads to damage of the protective mechanisms of the immune system
  • "exploitation" aims to use the immune system for its own purposes.
    There are different molecular mechanisms through which viruses implement each of these strategies.

    Mutations of epitopes (parts of antigens recognized by the immune system) are examples of "secret presence", where a virus hides from the immune system of the host. Herpes viruses resort to the "sabotage" tactic; herpes viruses bind to Fc fragments of immunoglobulins, block the complement system and neutralizes antibodies. The tactic of "exploitation" is successfully used by HIV, infecting the circulating cells of the immune system.

    How the immune system prevails?


    Most respiratory viruses, passing from person to person, eventually lose their positions under the pressure of the immune system. This phenomenon is known as viral attenuation. The closest relative of the new coronavirus, SARS-CoV, weakened already in the middle stages of the epidemic.

    Studies have shown that SARS-CoVs isolated from civets and humans in the early stages of the epidemic differed from viruses isolated in the late stages. The most striking difference was the absence of a sequence of 29 nucleotides in an open reading frame (ORF) (a sequence of nucleotides capable of encoding a protein) of ORF8 in later-stage viruses.

    Further studies on cell cultures showed that the 29 nucleotide deletion in SARS-CoV in ORF8 reduced its replicative activity. In infected cells, the concentration of viral particles in an area affected by deletion was 23 times lower.

    The evolution of SARS-CoV-2 is closely monitored by more than one dozen research institutions. An international group of scientists shares information in real time about new mutations of the SARS-CoV-2 virus on nextstrain.org, a real-time tracking of pathogen evolution.

    The obtained information allowed the head of the association, computational biologist Trevor Bedford, to assume that the transition of the SARS-CoV-2 virus from a bat to an intermediate host was 20-70 years ago. 

    All changes occurring with the virus, fit into the logic of natural evolution, usual for viruses. In so doing, the scientist refuted theories about genetically engineered virus creation.

    In the beginning of March, a study by Chinese scientists about identification of two forms of the SARS-CoV-2 virus was published. The two forms differ from each other only by two single-nucleotide polymorphisms (SNPs). However, the earlier form (S) of the virus is less aggressive than the later (L) form.

    More than 96 percent of those infected in Wuhan have contracted the L-form, while in other countries SARS-CoV-2 L-type accounts for just over 60 percent of cases. A group of scientists at the University of Glasgow's Centre for Virus Research think these conclusions are incorrect.

    First, the researchers maintain that two single-nucleotide polymorphisms are insufficient to separate the virus into two types. By the time the article was published, 111 mutations had been identified that did not have a significant impact on the functional context.

    Second, Scottish experts emphasize that the prevalence of the L-type virus does not necessarily indicate that it is easier to transmit. To assert this, a zero hypothesis study is needed that assumes equal transmission rates, which was not done by researchers from China.

    The first encouraging changes in the SARS-CoV-2 virus were observed on March 11 in Singapore. It is a deletion of a huge segment all in the same OFR8 (as in SARS-CoV and MERS-CoV), 382 whole nucleotides.

    So far, scientists have not made clear conclusions about the replicative properties of the modified virus. Given the fact that the deletions of SARS-CoV in ORF8 virus led to a change in the N-protein of the virus responsible for replication, the researchers assume that in this case we are talking about attenuation of the virus.

    Will SARS-CoV-2 return?


    There is a legitimate question - is this the first and last meeting with SARS-CoV-2 or will we have to deal with it again after the current pandemic? Let us remind you that the pandemic of the Spanish flu quieted down in July-August 1918, and in autumn came the second, more deadly wave.

    It's hard to answer the question about a possible re-introduction of the SARS-CoV-2 virus now. If everything goes down the path of significant weakening of the virus, it will eventually turn into one of the non-hazardous circulating viruses that causes colds.

    If you look at the SARS-CoV (causing SARS), there have been no repeated outbreaks of this virus. The epidemic started in November 2002 and ended in June 2003.

    In 2004, there was an outbreak of SARS in China, but this was due to contact between a Chinese laboratory employee and a sample of SARS-CoV. No transmission from person to person or from animal to person has been recorded since June 2003. However, the virus still lives in bats and civets, and no one knows whether or not the virus will infect humans again.

    As for the coronavirus MERS-CoV, it still makes itself known. After 2013, an outbreak of MERS was recorded in South Korea. The diagnosis was confirmed in 182 patients, 33 of whom died of SARS. In 2019, 212 cases of infection and 57 deaths were reported in Saudi Arabia and Oman. According to WHO, two cases of MERS-CoV infection in the United Arab Emirates were laboratory confirmed on 9 and 13 January 2020.

    Types of possible SARS-CoV-2 vaccines


    In the fight against the new coronavirus, high hopes are placed on vaccines, its development is carried out by many laboratories. However, the rapidly changing genome of the SARS-CoV-2 virus does not yet allow scientists to guarantee complete success. To date, current mutations have not made it any harder to find a vaccine, but what happens in a month or two is difficult to predict.

    Scientists also benefit from the existing developments in vaccines against the SARS-CoV virus. About 23 percent of T-cells and 16 percent of B-cells are conservative for both viruses. This suggests that further mutations are not likely to affect these epitopes.

    The simplest way is to create a vaccine based on attenuated or inactivated viruses, but such vaccines have more side effects and are also more sensitive to storage conditions. The second type is the recombinant vaccine, which is a S-protein subunit of the SARS-CoV-2 virus, synthesized by yeast or bacteria. This vaccine does not contain any viral material, so its range of side effects is extremely low.

    The third type is RNA or DNA vaccines, which are a genetically engineered structure that begins to synthesize SARS-CoV-2 virus proteins when it enters the body. The advantages of RNA and DNA vaccines are that they provide not only humoral immunity (production of antibodies), but also specific cellular immunity - activation of macrophages and cytotoxic T cells. Testing of the new vaccine on volunteers has already started in the USA.

    References:

    1. Wong, Matthew C., Sara J. Javornik Cregeen, Nadim J. Ajami, and Joseph F. Petrosino. "Evidence of recombination in coronaviruses implicating pangolin origins of nCoV-2019." bioRxiv (2020).
    2. Li, Xingguang, Junjie Zai, Qiang Zhao, Qing Nie, Yi Li, Brian T. Foley, and Antoine Chaillon. "Evolutionary history, potential intermediate animal host, and cross‐species analyses of SARS‐CoV‐2." Journal of Medical Virology (2020).
    3. Oostra, Monique, Cornelis AM de Haan, and Peter JM Rottier. "The 29-nucleotide deletion present in human but not in animal severe acute respiratory syndrome coronaviruses disrupts the functional expression of open reading frame 8." Journal of virology 81, no. 24 (2007): 13876-13888.
    4. Muth, D., Corman, V.M., Roth, H. et al. Attenuation of replication by a 29 nucleotide deletion in SARS-coronavirus acquired during the early stages of human-to-human transmission. Sci Rep 8, 15177 (2018).
    5. Tang, Xiaolu, Changcheng Wu, Xiang Li, Yuhe Song, Xinmin Yao, Xinkai Wu, Yuange Duan et al. "On the origin and continuing evolution of SARS-CoV-2." National Science Review (2020).
    6. Oscar A. MacLean, Richard Orton, Joshua B. Singer, David L. Robertson.
    7. MRC-University of Glasgow Centre for Virus Research (CVR). Response to “On the origin and continuing evolution of SARS-CoV-2”
    8. Su, Yvonne, Danielle Anderson, Barnaby Young, Feng Zhu, Martin Linster, Shirin Kalimuddin, Jenny Low et al. "Discovery of a 382-nt deletion during the early evolution of SARS-CoV-2." bioRxiv (2020).

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