Text/Photo by Zhang Jinjian /Professor Zhang Jinjian
This article is excerpted from "Changchun Monthly" Issue 449
According to the UN World Health Organization and the United States John Hopkins University statistics, the Coronavirus confirmed cases as of July 27 with 16,230,427 people diagnosed and 649,538 deaths. North America, Latin America and Europe each accounted for about 25%, Asia and the Middle East each accounted for 11% and 9% respectively. In particular, Europe, due to economic pressure, eased pandemic prevention restrictions and implemented unblocking measures before the pandemic subsided. Rebound in many countries, the pandemic has no signs of slowing down, plus Beijing, China June 11 suddenly appeared a second wave of new coronavirus spread of the disease, the China National Center for Disease Control and Prevention on June 18 announced the viral genome sequence data day and found 3 groups, 6 dated, 11 collected daily samples with D614G mutants.
According to two scientific teams in the United States, this strain is more infectious than the original virus, and it is easier to invade human cells. We can't help but think of such an RNA virus. It is really treacherous, insidious and cunning. It always finds its way to survive. It mutates at regular intervals and is more likely to infect humans. How exactly does this virus mutate? Increase or decrease in infectious power? Will it last forever on the earth? How to respond to the immune mechanism in the human body is an important topic to be discussed and understood in this article.
The rise and mutation of the Corona virus
Experience Jan 9, 2020, China Center for Disease Control and Prevention released and solve the full-length genome sequences, related scholars and institutions around the world have invested in research, there is an organization called "Global Sharing of Influenza Data Initiative ( GISAID)", is the world's largest virus The gene database actively collects virus strains sent by research institutions from various countries and provides a sharing platform for experts and scholars from all over the world. It is well known that RNA viruses are extremely unstable and have a higher mutation rate than DNA viruses. On March 31, 2020, Chinese Academy of Sciences journal "State Scientific Review" published by the Center for Biological Information Research Fellow in the School of Life Sciences, Peking University Lu Jian 103 Ge COVID-19 genome-wide analysis, found 149 mutations point, the virus has evolved L and S subtypes. Among them, 3 cases are samples from Taiwan, 2 cases are new L -type, and 1 case is older S -type (similar to bat-derived coronavirus). Domestic experts and scholars believe that RNAVirus mutation in line with the normal laws of epidemiology, for a new type of world's longest single-stranded RNA viruses (3 million base pairs) over a period of time to accumulate 149 mutation point is not unexpected. For the new coronavirus, it replicates rapidly in the host. During its transmission, random mutations will accumulate in the genome. This random mutation can help track the spread of the pathogen and understand its transmission route and dynamics.
In China, Liao Junzhi, the dean of the Academia Sinica, took from the "GISAID database" and actively analyzed the gene sequences of more than 2,000 strains of viruses around the world. In late April, he divided the viruses into 6 large-scale viruses and discovered that this observational study showed a virus. The amount of mutation is positively correlated with the lethality rate, and there is an increasing trend over time. Dean Liao pointed out that the six major types include Asia One, Asia Two, Europe One, Europe Two, America and Oceania/Asia. Diverse types can be distinguished by 13 major mutation signatures. The rise and fall of these 13 mutation signatures may be related to the growth and decline of various virus strains are closely related to the infectivity and fatal rate, and the real reasons need to be further studied. In particular, the variability of the virus in Taiwan is not low. It is said that the severity of the disease is high, but the fatality rate in Taiwan is low. This may be because the number of samples is too low, making the results more difficult to interpret.
More noteworthy that the above-mentioned Beijing recently epidemic is D614G mutant virus, this mutated virus is by the American Research Center (Scripps Research Institute) virus experts Hyeryun Choe found D614G mutation makes the virus spike protein (pike protein) increases and makes the protein more stable and easier to invade human cells. In addition, the New York Genome Research Center, Neville E. Sanjan's team found that if there is a D614G mutation, the ability of the virus to infect human host cells is increased by 2.4 to 7.7 times. This research still needs more clinical data to support.
In short, there will be more and more mutations of the Coronavirus, which is inevitable. Because more than 10 million people (about half the population of New York) have been infected so far, and it has spread to all corners of the world and all races, just imagine how many human cells the virus has invaded. The more infected cells, the more it replicates in the cell, and its mutation rate is higher the higher, even for the infected individual, different mutations may occur at the same time. So far, according to the analysis by Dr. Ching-Yung Lin, CEO of Graphen, a startup company of GISAID and AI, a total of 56,214 virus strains have been collected from patients so far, and they are evolving at a rate of one to two mutations per week. Viruses can be divided into eight categories according to their occurrence time and distribution area. The ancestor is the starting point of all viruses, A, and A is divided into A1 and A2, and then gradually evolved into B, C, D, E, F, G, and H (Figure 1, Table I). A and B as early as last year, 12 appeared in May, H until 2 February 19 It was only discovered in Japan that the original A type has now been reduced to about 400 strains, and most of the mutant strains, such as GH, appeared at the latest (Figure 2). In summary, it is well known that the new coronavirus RNA virus is less stable than DNA virus, so it is easy to mutate continuously. At present, scientists cannot know at what time the virus will mutate. As for the Academia Sinica team, the more mutated, the stronger the transmission. The higher the severity of the disease, it is not always true, but it can be confirmed that the Coronavirus will continue to evolve, and it is generally believed that the president exists on the earth and it is difficult to disappear. Studying the evolution process of viruses and tracing the source to explore its infectiousness and viruses are still the focus of everyone's attention.
Why is COVID-19 more terrible than SARS?
The new coronavirus is named because the spike protein (S protein) on its surface looks like a raised decoration around the crown under an electron microscope. The S protein can be divided into two parts, S1 and S2. S1 is responsible for binding to the ACE2 (type 2 angiotensin converting enzyme) receptor of human cells, S2 is responsible for fusion with human cell membranes, and there is a cleavage site between S1 and S2 that can be the human cell surface protease called the furin (Flynn) cut, Sl and S2 after the separation, S2 immediately fused with human cells, and the virus into human cells.
In the S1 and S2 cleavage site between, the only Corona virus will be more particularly unique PRRA sequence (numbered 681-684) plus number 685 of R & lt, there are three R & lt, R & lt spermine positively charged Acid, the three positive charges of arginine contained in just five amino acids can carry out high-efficiency protein shearing, resulting in the ability to infect humans even in asymptomatic or incubation periods. These new coronaviruses are sheared the special structure of the bit is not available in the other six human coronaviruses. It can quickly make the new coronavirus tightly fuse with human cells, easily enter the cell, and perform replication work (Figure 3), so it is extremely infectious. More terrifying than SARS. How does the new coronavirus attack the body to activate the immune mechanism?
(1) Human innate immunity against viruses
When the new coronavirus invades the human body, the innate immune response (Innate Immunity) is immediately activated, which is the body's first line of defense against virus invasion. The main reason is that when the virus infects the lung epithelial cells, the lung epithelial cells will release type I and Type III interferon also triggers a series of cytokines, such as pro-inflammatory tumor necrosis factor (TNF- α), interleukin -1 (IL-1), IL6 and IL-18 are also released. So far, type I and type III interferons are recognized as the most important cytokine against viruses, and then TNF- α, etc. will increase the acquired immune response (Adaptive Immunity) to strengthen the antiviral function. When the defense mechanism is applied properly, the virus will be wiped out, the patient will not have symptoms, and of course no severe pneumonia will be caused (Figure 4). (2) Human beings are naturally immune to fight the virus
In addition, when a virus invades the human body's immune response, the body's natural killer cells (NK cells) will kill the virus-infected cells to stop the virus from spreading and produce the interferons to prevent virus replication. Macrophages will then the special antigen of the virus is presented to T cells and B cells to activate the killer T cells to attack and kill the cells infected by the virus and make the cells produce antibodies to bind to the virus, neutralize the virus, and make the virus lose the ability to infect other cells. ability. Some of these T cells and B cells activated by the virus may become memory cells. If the human body encounters the same virus invasion again, the body's immune system can use these memory immune cells to quickly produce a certain amount of antibodies. And viruses, also produce a large number of killer T cells that can kill viruses and virus-infected cells. If the virus cannot replicate, the virus is completely eliminated and health is restored (Figure 5). (3) Why do serious symptoms occur?
The human body has innate and acquired immune systems, why can't it stop the virus infection, but cause severe pneumonia or other serious symptoms? It is generally believed that because the new coronavirus is a brand-new virus, the human body is still unable to recognize it. Of course, it cannot quickly produce a large amount of interferon to inhibit virus replication, it cannot produce neutralizing antibodies, and it cannot immediately derive virus-killing T cells. During the incubation period or asymptomatic, there is a considerable amount of the virus, which will be transmitted to other people by droplets. According to the literature, some people think that asymptomatic patients are as high as 40% to 45%. These people are often negligent and will become the root of infection among the population (Table 2). In addition, according to this review paper from the Annals of Internal Medicine by Dr. Topol of the Scripps Translational Medical Research Center in Florida, it is pointed out that these asymptomatic confirmed patients are infectious for a period of more than 14 days. And it is recommended that this ethnic group be expanded for virus testing; unfortunately, there is no statistical data in Taiwan, and it is impossible to show the percentage of asymptomatic confirmed cases in Taiwan. The most worrying thing is that this virus will produce Cytokine Storm ; the so-called Cytokine Storm is that when viruses continue to invade and replicate in human cells (such as lung epithelial cells), these viruses Proteins such as ORF3, etc., will enhance the activation of the host's inflammatory pathway, and continuously produce and induce the secretion of large amounts of cytokines by pneumonia epithelial cells, such as interleukin 1- β (IL-1- β) and IL-6 (interleukin 1) IL-6 , IL-18 (interleukin IL-18), tumor necrosis factor (TNF) And many kinds of pro-inflammatory factors and various inflammatory factors, and these factors or hormones will attract more inflammatory cells (including macrophages and neutrophils) to gather in the infected lung epithelial cells, and produce a larger amount of Inflammation-promoting hormones and inflammatory factors, such a vicious cycle makes the lungs suffer from cell infiltration, edema, injury, and even fibrosis, sometimes causing permanent damage to the lung function. In addition, some inflammatory factors can cause damage to the microvascular endothelial cells in the lung tissue, increase penetration, and cause leakage. Large amounts of fluid are stored in the alveoli, resulting in poor ventilation and insufficient oxygen uptake, causing acute respiratory distress syndrome (ARD), you must be admitted to the ICU and use a respirator. In addition, there is literature that points out that it will cause tiny blood clots in the pulmonary blood vessels, resulting in insufficient blood supply, or even fatal (Figure 6). Will the new coronavirus disappear? Or will it last forever on the earth?
According to recent reports and predictions by experts and scholars from various countries, most believe that although the epidemic has slowed down in some countries, the fever has continued to spread in the United States, India's new confirmed cases have reached a new high, and Australia has eased the epidemic, but the number of confirmed cases increased sharply in early July. Forced to block the borders of Victoria and New South Wales again. Tokyo, Japan's cases have been added to more than 100 confirmed cases every day for many consecutive days. It seems that the global pandemic has not yet eased, although the death rate has been slightly reduced. The ratio of the number of recovered people to all confirmed people has also risen, but it is still not to be taken care of.
Especially recently, 239 well-known scientists jointly issued an open letter, stating that the new coronavirus is not only a droplet infection, but the possibility of airborne infection is not ruled out. The Taiwan epidemic has indeed been successfully controlled, but everyone agrees that the Corona virus cannot disappear from the earth.
According to the statistics and forecasts of Harvard University School of Public Health:
(1) The new coronavirus will coexist with humans at least until 2025, or longer.
(2) The effect and efficacy of the vaccine may not be as expected.
(3) The human body produces antibodies against the virus, and its existence time determines the future epidemic and outbreak of COVID-19. For example, if the validity period of the antibody is 40 weeks, an epidemic will break out once a year; if the validity period of the antibody is 2 years, every There will be a pandemic in 2 to 3 years.
Therefore, we must think about the way to coexist with the virus. At present, many countries have plans to unblock and return to the workplace. The World Health Organization, the United States and the European Union have different regulations and recommendations. I personally think that the EU's recommendations are more in line with domestic conditions. Especially the list of its regulations (such as Table 3) for readers' reference. Concluding remarks
Including SARS and MER =, together with the COVID-19, humans have a deep understanding of the stubbornness and high infectivity of the virus. In particular, the spread and invasion of the new coronavirus has caused an unprecedented catastrophe, which makes us rethink humans and viruses. We must humbly recognize the importance of interactions and symbiosis of human beings. Viruses have existed on the earth longer than human beings, and the number is far greater than human beings. Our ability to adapt to the environment is stronger. Our strategy should be based on harmony and respect for viruses. Peaceful coexistence.
Of course, to stop the spread of the virus, the vaccine is needed, but still needs time to develop, and whether enough vaccine to supply 70 everyone who has not been infected with multi-billion people, or else there will be a new crown pneumonia second, third wave Wait for seasonal transmission, or become a regional epidemic, so we still expect the high efficiency of the vaccine and natural immunity to protect more people. Although the new coronavirus continues to exist, we deeply hope that it will no longer be a plague that endangers all mankind.
Originally in Chinese