Transmission power is better than SARS, need to worry about the new crown virus mutation?

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Where does the new coronavirus come from? Why is it so difficult to prevent and control? Will it cross-spread among infected people and mutate into a more powerful virus? This article gives an answer from the perspective of virus evolution and virulence changes.

The outbreak of novel coronavirus pneumonia (NCP) at the end of 2019 is the most serious new viral infectious disease in China since SARS in 2003. It not only seriously threatens the life safety of the people, but also has a great impact on China's economic and social development, which has attracted great attention from all walks of life. We can't help but ask, the new coronavirus (Novel Coronavirus,2019-nCoV, the International Commission on Classification of Viruses (ICTV) named the new coronavirus SARS-CoV-2, there is still controversy in the academic community, Chinese experts call for the name HCoV-19, we temporarily use the familiar new coronavirus name) How did it come about, how will the epidemic develop next, and what should we do to avoid new epidemics? To answer these questions, we need to understand where the new virus comes from, how it will evolve and develop after infecting the human body, and what challenges the evolution of the virus brings to the prevention and control of the virus. Next, let's look at viruses from an evolutionary perspective.

Before discussing virus evolution, let's make a clarification. "Evolution" is generally translated as "evolution", but more accurately, it should be translated as "evolution". There is no doubt that the word "evolution" has a subjective positive color. It implies thinking or judging from simple to complex, from low to high, etc., that evolution must advance along a certain "bright future. In fact, evolution is a neutral process without subjective will, no value judgment, no intelligent design, and its concept is"Changes in genetic characteristics of successive generations of biological populationsThis change undergoes natural selection, which manifests itself in a particular outcome: survival of the fittest. Adaptability (adaptation) can theoretically be measured by fitness (fitness),Fitness is the relative ability of a genotype within a population to survive and pass its genes on to the next generation.(comparative advantage compared to other genotypes). The greater the fitness, the higher the chances of survival and reproduction. And what is the "fittest" depends on the specific conditions of natural selection. Usually, people are accustomed to using the word "evolution" is no problem.

  Study on the origin and evolution of virus

Virus evolution is an important field of virus research.

Since viruses themselves are a class of intracellular obligate parasites, the discussion of the evolutionary origin of viruses has focused on the relationship between viruses and the origin of cellular organisms, with three main hypotheses.[1](See Figure 1):

  1)priority hypothesis: Viruses are independent and precede cellular organisms.

  2)degradation hypothesis: Viruses originate from cellular organisms and are the result of the degradation of certain cellular organisms.

  3)escape hypothesisViruses are part of certain cellular organisms that detach from the cell to form independent replicative elements.

More recent ideas include the co-evolution hypothesis and the chimeric origin hypothesis, both of which are modifications or combinations of the above three hypotheses.[1]. Given that viruses have a variety of different genomic types and particle structures, different viruses may have different evolutionary origins. For example, RNA viruses may evolve independently, while DNA viruses may originate from cellular organisms.

  virus evolution researchMainly through the analysis of the genome sequence of the virus, the genome structure is similar or the sequence has homology, the virus has a genetic relationship, the closer the sequence, the closer the phylogenetic relationship, the replication cycle, host range, pathogenicity, immunogenicity is often more similar. On a large time scale, due to the extensive exchange of genetic information between viruses and cellular organisms, viruses play a huge role in the evolution of cellular organisms.[3]The study of virus evolution can help us understand the "virosphere" of the virus circle, the highly diverse genetic information base in the life circle.[2]It is helpful to study the evolution and development of important viruses, especially pathogenic viruses. From a short time scale, virus sequence difference and its evolution is an important aspect of influenza (influenza virus), AIDS (AIDS) and hepatitis (such as HBV, HCV) and other viral diseases epidemiological research, but also the theoretical basis of vaccine design and virus resistance research.

  virus mutation

Differences in genetic characteristics during virus evolution are provided by virus mutation.

In the study of virus variation, the most important thing is the antigenic change of pathogenic virus. "Viral antigenic variation" has two proprietary concepts, namely, antigenic drift (antigenic drift) and antigenic drift (antigenic shift). The former refers to more subtle changes, while the latter refers to large changes in antigenicity.

Viral variation can occur anywhere in the viral genome, and the phenotype it affects is not limited to antigenicity. From the whole genome of the virus, the virus variation can be divided into 1)base mutation(mutation), including insertions or deletions of single bases or small fragments; 2)Reorganization(recombination), I .e., the exchange of large fragments of genomic molecules between different strains of the same virus; 3)Rearrangement(reassortment), that is, the gene molecular recombination of segmented genome viruses. The mechanisms by which these three viruses mutate are completely different. Base mutations are caused by incorrect replication of viral genome replicase, recombination is caused by intermolecular recombination exchange or template transfer, and rearrangement is caused by segmental genome selection and allocation during viral packaging. The virus genome is compared to a book, the replicase is equivalent to a scribe, and the base mutation is similar to that in the process of copying, the scribe is distracted and copies the wrong characters; the reorganization is equivalent to the scribe changing half of the book in the process of copying, the first half of the book is Journey to the West, and the second half is A Dream of Red Mansions. The rearrangement is similar to putting 1-4 volumes of Harry Potter and 5-7 of the Chronicles of Narnia together. From this analogy, it is not difficult to see that base mutation is a form of variation that can occur in the replication of all viral genomes. Its frequency mainly depends on the fidelity of the replicase of the genome of the scribe virus. For RNA viruses, their RNA replicase does not have proofreading activity, so the mutation rate of RNA viruses is the highest, and the replicase of DNA viruses has proofreading activity, so the mutation rate is low. On the other hand, recombination and rearrangement can only occur under specific conditions, just as a scribe faces more than two kinds of books, and only when two or more viruses with similar relatives are infected in the same cell can recombination and rearrangement occur.

It should be pointed out that for the base mutation, since it is caused by the wrong replication of the viral genome replicase, this error occurs randomly, so the virus mutation can occur at any site. So when we examine the sequence of the virus, can we see that the mutations are randomly distributed throughout the genome?

Viral mutations do not affect the coding of proteins and RNA or DNA element sequences necessary for viral replication, so that a large number of mutations are often harmful, and these viruses containing harmful mutations are unable to replicate themselves and are eliminated. In addition to harmful mutations, a considerable part of the remaining mutations belong to "synonymous mutations", that is, there is no effect on the virus before and after the mutation.Ultimately, only a few mutations have a positive effect on viral fitness, are enriched and fixed.. Because the viral genome is generally short, information redundancy is very low, limited by the virus's own survival and replication needs, host innate immunity and adaptive immune pressure screening, most of the mutation sites of the viral genome are concentrated in some regions of the viral genome, so we can detect the distribution of viral mutations in the genome is uneven.

Specifically for coronavirus, more mutations can be detected in some hypervariable regions of the virus spike peplomers (S) gene. These mutations often affect the affinity of the virus to the host receptor and the immunogenicity of the virus (the ability to trigger the body's immune protection response), which may lead to the virus acquiring new abilities such as the ability to infect new hosts and the ability to escape adaptive immune protection. The S protein of the new coronavirus in this outbreak has four key amino acid point mutations that are different from other bat coronaviruses, and has similar receptor binding ability with SARS-CoV, resulting in its ability to infect humans.[11].

  The "accelerator" of virus evolution ":Human and wildlife encounters and host transitions

New viruses generally come from wild animals. When the survival boundary between humans and wild animals is broken, there will be contact between the two that should not have happened, creating opportunities for viruses to infect humans.

Animal viruses and the original host have undergone a long-term co-evolution process, generally will not cause serious disease or death, and most animal viruses can not infect people, but a small number of animal viruses can cause serious diseases and high mortality. At present, serious infections caused by coronaviruses are: severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (Middle East Respiratory Syndrome,MERS) and 2019 novel coronavirus pneumonia. New viral diseases, including HIV, Ebola virus and three coronaviruses, can infect humans and animals.zoonosis(zoonosis). ThereforeWildlife is an important source of emerging viruses.

Whether theoretical analysis or molecular epidemiological testing, there are indications that bats are a repository of viruses.[5, 6]. One study showed that the coronavirus carrier rate in bats is 8.6 percent, much higher than the 0.12 percent in non-human primates and 0.32 percent in rodents, and there are as many as 91 species of coronavirus in bats.[7]. The reason why bats become an ideal "virus reservoir" is that they have a long life span, a large range of activities, social habits, and a special immune system, which enable them to be exposed to a wide range of virus sources and can carry the virus for a long time. The coronavirus can be passed through civet, dromedary camel, pangolin (whether pangolin is an intermediate host is currently controversial, pangolin-carried coronavirus and 2019-nCoV is quite different.[14]) and other intermediate hosts are transmitted to humans. At present, the closest known genetic relationship to 2019-nCoV is RaTG13 virus found in chrysanthemum-headed bat, which is more than 96% similar to 2019-nCoV and has only a difference of nearly 1100 nucleotides. According to the estimation of nucleotide differences between viruses and the assumed mutation rate of other coronaviruses, the two viruses had a common ancestor 25 to 65 years ago. Therefore, it may take decades for RaTG13 virus to mutate into 2019-nCoV, but due to the existence of different protease cleavage sites between the two, it is speculated that RaTG13 is not the direct ancestor of 2019-nCoV either.[15]. In addition, it is currently believed that 2019-nCoV is not a new virus produced by recombination.[16]. Therefore,The direct origin of 2019-nCoV needs further study.

The host range of some viruses is not particularly specific, and they can infect humans opportunistically; and viruses carried by wild animals may also spread across species in the process of continuous evolution, and gain the ability to infect humans-although this The probability is extremely low, but it cannot be ignored. On the other hand, although the mechanism of recombination mutation of coronavirus is not clear, sequence analysis found that recombination did occur between coronaviruses. Therefore, it is possible for coronaviruses in wild animals to acquire new genetic characteristics through recombination. We assume that these viruses exist in wild animals deep in the mountains and forests, far away from human society, and would not have caused human infection. After the destruction of the environment, in the process of hunting, selling or slaughtering and eating wild animals,The living boundary between human and wild animals has been broken, resulting in contact between the two that should not have occurred, creating conditions for the virus to transition from the host to the spread of people.Therefore, the two coronavirus infections in China occurred in the game market and its consumption chain, while avian influenza and swine herpes virus infections are prone to occur in high-risk places such as live poultry markets and farms or in high-risk groups such as veterinarians.

Animal hosts play a key role in the evolution of viruses, and the most famous example is the evolution of influenza viruses: different influenza viruses can infect different animals, and some animals can be infected by multiple influenza viruses.

Influenza viruses contain a segmented genome of eight RNA fragments, and if a cell is infected with two different influenza viruses, the RNA of both viruses will replicate in the nucleus. When the new virus particles are assembled on the plasma membrane, 8 of the original two sets of genomes are randomly selected and combined to produce a new viral genome. The new virus produced from two parental genetic RNAs is called a reassortant, and this process is known as rearrangement. Rearrangement exchange of RNA segments between mammalian influenza and avian influenza viruses can cause influenza pandemics. For example, the 2009 H1N1 pandemic strain is a reassortant of three influenza viruses: avian, human and swine. In this process, the key role is that pigs-chickens and ducks can be infected with avian influenza from wild birds and transmitted to pigs. Pigs can also be infected with human influenza viruses. Pigs can be infected with two or more influenza viruses at the same time, and gene rearrangements occur in the body, which will produce virulent influenza viruses that can infect humans. Therefore,Pigs become mixers of influenza viruses, accelerating the process of virus evolution.


Virulence and Evolution Direction of Viruses

After the virus enters the new host, it will optimize the virulence and enhance the adaptability.

We can look at the harmfulness of the virus from two dimensions: first, the transmission rate (Transmission rate); Second, virulence (virulence) or mortality (Mortality). In the long-term evolution process,There is a trade-off between virulence and the ability of the virus to spread.. Virulent virus causes great damage to its host, and produces a large number of virus offspring, and has a strong ability to spread. However, if the host's disease restricts the host's mobility so that it cannot contact the new host, the virus cannot effectively infect the new host, but has a relatively low evolutionary fitness. Conversely, a less virulent virus may infect more hosts because these hosts are well enough to make contact with many other potential hosts, but its virulence must be able to produce enough progeny virus and spread to new hosts.

Virulence (virulence) is a relatively general concept, which refers to the ability of microorganisms to infect the host and cause damage to the host. It is a complex feature determined by pathogens, hosts and environmental factors. Considering the virus alone,Virulence of a virus can be broadly defined as its morbidity or mortality. Natural selection occurs in the host of the virus and in the process of transmission of the virus,The measure of virus evolution is the fitness of the virus.Not the poison. A direct explanation for virulence evolution is that natural selection "optimizes" virulence levels to maximize pathogen fitness.

  Fitness can be expressed in general terms as the basic number of infections (R0). In epidemiology, the basic infection number R0(Basic reproduction number) refers to the average number of people infected with a certain infectious disease who will transmit the disease to other people without external force intervention and all people have no immunity (R0<1, the virus gradually dies out; R0 = 1, local epidemic of virus; R0>1, epidemic spread of virus).

  The direction of virus survival and evolution should be to "pursue" higher adaptability by "optimizing" virulence., that is, the maximization of R0, and the so-called "optimization" of virulence may be increased virulence or decreased virulence. Whether natural selection increases or decreases the virulence of a virus depends on the particular combination of host, virus, and environment. Therefore,The evolution of the virus does not necessarily lead to an increase in the virulence of the virus.But there is no doubt that the evolution of viruses with increased virulence is more likely to attract people's attention.[10]:

Oral polio vaccine (OPV):OPV is an attenuated form of the poliovirus that occasionally reverts to a virulent form and causes polio outbreaks.

2. West Nile virus: In 1999, the mutation of NS3 protein T239P of West Nile virus produced a high lethal strain to corvids.

3. Chicken Marek's disease virus: The first generation of chicken Marek's disease vaccine in the 1960 s can only provide partial protection against wild virus infection and reduce disease symptoms. About ten years after the vaccine was used, a more virulent wild strain appeared, and people had to develop a second-generation vaccine. After switching to a new vaccine, a new virulent wild strain appeared again in a shorter time.

4. Zika virus: Before 2007, only minor cases of infection were found in Asia and Africa. However, in 2013, a neurotoxic Zika virus broke out in South America. The study found that it evolved from Asian Zika virus, and the mutation of S139N site may be related to its enhanced virulence.

Ebola virus: The Ebola virus A82V mutation may increase human infectivity by increasing the binding to the human NPC1 receptor, and is strongly associated with an increase in the number of cases and an increase in mortality. However, current animal studies have not confirmed this.

6, rabbit myxoma virus: virulent myxoma virus has been used to inhibit the proliferation of European and Australian rabbits, the virus in the early cause of a large number of hare death, the survival of the hare virus has a certain resistance to the virus, the virus showed weak virulence, but in the process of virus evolution repeatedly strong virus strains, the average virulence showed a slow upward trend.

 The Variation and Evolution of Coronavirus

Coronaviruses have a medium-high mutation rate of RNA viruses and the possibility of recombination, but they are not the focus of our attention in the short term.

This is because the genome of the coronavirus is a single-stranded positive strand RNA, and there is no possibility of rearrangement. In terms of base mutation, it has been reported that the RNA replicase of coronavirus has exonuclease activity, which plays a certain error correction function for viral genome replication and subgenome synthesis.[13]However, studies have shown that the base replacement rate of the coronavirus is at a medium to high level, about 10 compared to other single-stranded RNA viruses.-4Replacement/year/site[8]That is to say, within one year, the probability of mutation at a certain site in the process of virus replication is one in ten thousand. In addition, sequence analysis found that there is a recombination phenomenon between different coronavirus genomes, and this recombination occurs both between human-infecting coronaviruses and animal coronaviruses.[8].

The latest study reported an R0 of 3.77 for 2019-nCoV, higher than estimates from earlier 2.2.[12]This shows that, compared with SARS-CoV, the outbreak of the new coronavirus transmission capacity is stronger, the incubation period is long, the carrier symptoms are not typical, mainly through droplets transmission, and recently found that it may also be transmitted through the mouth-dung route, to the epidemic prevention brings great difficulties. The mode of transmission of the virus is related to the distribution of its cellular receptors in the human body, the route of virus release, the environmental resistance of the virus in vitro and the minimum load required for virus transmission. Recently, there have been reports discussing the possibility of new coronavirus aerosol transmission or "remote air transmission". The author believes that the aerosol produced by coughing or sneezing is small in volume, the virus load itself is very small, and the aerosol is very easy to dry, and drying will greatly reduce the infection power of coronavirus. Therefore, the probability of coronavirus remote transmission through aerosol is extremely small, so it is safe to open windows in wilderness activities or homes for ventilation. It should be noted that from the Hong Kong "Kang Mei Building" case[17], The virus may spread across floors through defecation pipes, so pay attention to the tightness of the sewer system.

Due to limited medical resources, the country has built a number of shelter hospitals to treat infected patients. Many readers are concerned about whether this environment will promote the evolution of the virus and may lead to an increase in the epidemic?

First of all, I think it is not necessary to question the safety of the shelter hospital from the perspective of coronavirus evolution, because the base mutation of the virus is a naturally occurring process, and its evolution rate will not change without the presence of mutagens. In addition, patients infected in the short term may be carrying the same virus strain, and there is little possibility of recombination between the new coronavirus to produce a new strain. The author believes that,Attention should be paid to the prevention and treatment of infectious diseases other than COVID-19 in the square cabin hospital to avoid multiple infections and aggravate the condition of the patient, and attention should be paid to the accumulation of psychological pressure of the patient in this highly intensive and special environment.


COVID-19 itself is a new virus disease. Because 2019-nCoV has the characteristics of strong transmission ability and hidden symptoms of virus carriers, it has caused great difficulties in prevention and control. If 2019-nCoV is to disappear like SARS-CoV, I am afraid it will take greater efforts. The author believes that compared with influenza virus, the new coronavirus may not develop into a seasonal epidemic due to the lack of natural virus hosts closely related to humans. In the long run, if 2019-nCoV cannot be completely eliminated, as people's understanding of 2019-nCoV continues to deepen, treatment experience accumulates, and the mortality rate is greatly reduced, we can treat it as a general influenza, and develop drugs or vaccines to prevent it. If COVID-19 drugs or vaccines need to be developed in the future, virus mutation must be considered becauseVirus mutation will lead to changes in drug sensitivity and antigenicity, which will affect the effect of drug treatment and vaccine protection. Even if 2019-nCoV is defeated, it does not rule out the possibility that another new coronavirus will cause another new viral disease outbreak. Wild animals are the main source of new viral diseases, and their migration is uncertain and cannot be managed. At present, environmental damage, deforestation, urbanization, increased long-distance air travel, and frequent international exchanges between animals (including livestock) and people have led to frequent contact and encounters between people and wild animals ...... These factors have brought great troubles to the prevention and control of infectious diseases. It is normal for wild animals to carry various pathogenic microorganisms. Whether it is to protect wild animals or to protect human health, wild animals should not be killed and eaten. After experiencing SARS and this new coronavirus pneumonia epidemic, we should learn a lesson, resolutely resist the killing of wild animals, and never eat wild animals.Transmission power is better than SARS, need to worry about the new crown virus mutation?