Zhong Nanshan's team: the origin, intermediate host and sensitization characteristics and hypotheses of SARS-CoV-2｜MDPI Healthcare

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About the author, Academician Zhong Nanshan, Chinese Academy of Engineering, slide down to see more academician Zhong Nanshan, Han nationality, member of the Communist Party of China, born in October 1936, from Xiamen, Fujian, director of the National Respiratory Disease Clinical Research Center of the First Affiliated Hospital of Guangzhou Medical University, academician of the Chinese Academy of Engineering, " Recipient of the Medal of the Republic
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Representative of the 11th and 12th National People's Congress, member of the 8th, 9th and 10th National Committee of the Chinese People's Political Consultative Conference
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Long-term commitment to the research, prevention and treatment of major respiratory infectious diseases and chronic respiratory diseases, with fruitful results and outstanding achievements
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Won the first prize of the National Science and Technology Progress Award and the titles of "National Advanced Worker" and "Reform Pioneer"
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In 2003, during the SARS epidemic in China, the etiology of Guangdong was clarified, the SARS prevention and control research in Guangdong was organized, and the method of “reasonable use of corticosteroids, reasonable use of non-invasive ventilation, and reasonable treatment of complications” was established to treat critically ill SARS patients.
The highest survival rate (96.
2%)
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Organized and compiled domestic guidelines for the diagnosis and treatment of bronchial asthma, chronic obstructive pulmonary disease, cough, SARS, and human highly pathogenic avian influenza
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In 2013, he served as the leader of the H7N9 prevention and control expert team in Guangdong Province, and published the H7N9 series of studies in New England Journal Medicine (IF51.
658), making important contributions to H7N9 prevention and control
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After the outbreak of the new crown pneumonia in January 2020, he served as the leader of the high-level expert group of the Health Commission.
He dared to speak up and proposed the phenomenon of “person-to-person transmission”, thus setting off a new starting point for the nation’s anti-epidemic, emphasizing strict prevention and control, leading Wrote the new coronary pneumonia diagnosis and treatment plan, and made outstanding contributions in epidemic prevention and control, critical illness treatment, and scientific research
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Professor Tao Ailin, the Second Affiliated Hospital of Guangzhou Medical University, scroll down to see more Tao Ailin, Ph.
D.
, professor, doctoral supervisor, currently director of Guangdong Key Laboratory of Allergy and Immunity and National Key Clinical Specialty of Allergy, The Second Affiliated Hospital of Guangzhou Medical University Deputy Director, State Key Laboratory of Respiratory Diseases PI and Deputy Group Leader of Allergic Pulmonary Diseases, Member of the National Genetically Modified Safety Evaluation Committee, Member of the Protein Allergenicity-Toxicity-Bioinformatics Committee of the International Society of Health and Environment, Guangdong Preventive Medicine Vice President of the Association, Vice Chairman of the Allergy Branch of the Guangdong Medical Association, Vice Chairman of the Clinical Immunology Branch of the Guangdong Immunological Society, Vice Chairman of the Professional Committee of Hospital Research Laboratory Construction and Management of the Guangdong Hospital Association, China Research Hospital Association Member of the Standing Committee of the Allergy Medicine Specialty Committee, member and secretary-general of the Child Allergy and Rheumatism Branch of the Asia-Pacific Society of Medical Bioimmunology, and deputy leader of the Basic and Transfer Chemistry Group (preparatory) of the Allergy Branch of the Chinese Medical Association
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Leading the development of the allergen family characteristic peptide AFFP algorithm to analyze allergens.
The allergen sequence identification software SORTALLER established on this basis has the highest accuracy.
It has been used by researchers in more than 30 developed countries in the United States, Britain, Germany, Japan, Canada, and Russia.
Continuous application; put forward the concepts of major representative allergens, antigenic weakening, multi-targeting of allergens and antigen balance stimulation hypothesis, in-depth allergic disease prevention theory and practice, editor-in-chief Allergy Bioinformatics English monograph, related chapters have been downloaded more than 13,000 Times
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Perennial reviewers of more than 10 SCI magazines
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Published more than 40 SCI papers
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The leading achievement won the second prize of Guangdong Science and Technology Award and the first prize of Guangzhou Science and Technology Award each
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In 2015, he was selected as a key medical talent for high-level health professionals in Guangzhou, and in 2019, he was selected as an outstanding expert in Guangzhou (A certificate)
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Professor Yan Jie Second Affiliated Hospital of Guangzhou Medical University, sliding down to see more Professor Yan Jie, 2006--2009 studied at the Beijing Cancer Hospital, Peking Union Medical College, Cancer Institute, PhD
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In September 2009, he went to the Ben May Department for Cancer Research at the University of Chicago to work as a postdoctoral fellow and research assistant
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In early 2017, he was introduced to China through a high-level university construction project and worked in the Allergy Department of the Second Affiliated Hospital of Guangzhou Medical University.
He is a member of the Allergy, Inflammation and Immunity Innovation Team (C3I) of Guangzhou Medical University
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The research direction is the molecular regulation mechanism of inflammation in programmed cell death and allergic inflammation
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He has long been engaged in the research on the pathogenesis of inflammation-related diseases such as allergies, enteritis, and asthma and the molecular mechanisms of cell signal transduction networks, especially the molecular mechanisms of programmed cell death regulation.
He first proposed the molecular pathways for cytotoxic TNFα to regulate cell apoptosis, and The application of inhibitors of related regulatory molecules in the clinical treatment of sepsis has been preliminary explored
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Related research results have been published in high-impact journals such as Cell and Cell Research
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Dr.
Huang Yuyi Huang Yuyi, Doctor of Medicine, The Second Affiliated Hospital of Guangzhou Medical University, is a staff member of the Allergy Laboratory, Department of Allergy, The Second Affiliated Hospital of Guangzhou Medical University
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The main research directions are: bioinformatics and research on the mechanism of allergic diseases
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As the main developer, he constructed allergen database ALLERGENIA/ALLERGENIA 2.
0, allergen online discrimination software SORTALLER/SORTALLER 2.
0, disease pathway analysis software LESSGEN and other bioinformatics tools
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The above online software has been put into operation on the Internet, and is continuously used by researchers in more than 30 developed countries and regions
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Participated in data processing and analysis in this research
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Article Introduction Acute Respiratory Disease (COVID-19) was first reported in Wuhan, China in December 2019, and then reported throughout China and the world.
As of September 18, 2021, there were more than 227 million confirmed cases of COVID-19 worldwide.
, There were more than 4.
68 million deaths
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Although the main source of the virus (SARS-CoV-2) is reported to be snakes, bats, minks, even pangolins and cats, the intermediate host of the virus to humans has not been determined
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Recently, the team of Academician Zhong Nanshan published a study on the origin, intermediate host, and sensitization characteristics and hypotheses of SARS-CoV-2 in the Healthcare journal.
This study attempts to decipher the intermediate host source and allergenicity of SARS-CoV-2.
And how this virus appeared, how and when it will disappear
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The new coronavirus infection initiates the inflammatory waterfall, which belongs to the category of hypersensitivity.
The inflammatory waterfall further promotes the necrosis, pyrolysis, apoptosis and even iron death of immune cells, and the pyrolysis of immune cells such as macrophages can form an inflammatory storm, making Inflammation is further amplified, on the other hand, the body is severely immune to insufficiency, resulting in a situation of malignant amplification of inflammation, especially the coexistence of non-hormone-responsive inflammation, so that hormone intervention often has little effect and the disease can easily progress to severe illness
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From this perspective, if the initial inflammation of the virus is controlled first, the body's responsiveness to the virus can be greatly reduced or even eliminated
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Research process and methods This research conducted a comprehensive amino acid sequence analysis of the sliding sequence fragments of the spike protein of the new virus, and confirmed that bats are the natural hosts of the new coronavirus SARS-CoV-2, which are then transmitted to humans through rodents
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At the same time, through a comparative analysis of allergenicity, it was found that the new coronavirus SARS-CoV-2 and the SARS virus that broke out in Guangdong in 2002-2003, namely SARS-CoV, exhibit similar sensitization, but they have different HLAs.
The allele-polypeptide binding capacity suggests that the two viruses specifically infected people are different, with similar but different symptoms
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Based on the proportion of the population of 5 HLA class I sites and 9 class II sites that have high binding capacity to polypeptides, we can get: without any intervention, about 7.
36% of Chinese people have symptoms after being infected with the new coronavirus Obviously, and 92% of people do not show symptoms or symptoms are not obvious even if they are infected
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The frequency of different genotypes in different countries is different, and the infection rate and the rate of severe illness are also different.
If there is no intervention after the new crown, about 4.
68% of Americans will show severe symptoms, and about 95% of the people who are infected without showing symptoms— -Such asymptomatic individuals are the objective conditions for the long-term existence and spread of the virus.
Moreover, even if such individuals are infected with the virus, they will not initiate subsequent inflammatory reactions and have no obvious symptoms.
Therefore, the effect of vaccination is not obvious, but After vaccination, it is often easy to count this part of the population as the population who has been successfully vaccinated
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Through the analysis of meteorological parameters, it is found that the meteorological characteristics of Guangdong in 2002-2003 and Wuhan in 2019 are highly similar, with extremely high average temperatures and extremely low precipitation.
This may provide important conditions for the survival or development of the virus and is worth continuing.
Monitoring
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Based on the laboratory's group survey data on SARS virus antibodies from 2011 to 2012, it is believed that the coronavirus exists in the population and will not disappear in the population until the entire population is successfully immunized
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If the conclusion of the study is correct, it is true that the mouse acts as an intermediate host, and animals such as cats and mice in close contact with humans carry the coronavirus and spread it, then the coronavirus will be difficult to extinct in the population
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Comprehensive analysis and put forward the "hypothesis of the self-limiting of the virus infection population", that is: when a new coronavirus is mutated, a certain type or several types of individuals with a specific MHC genotype become susceptible individuals, and when the susceptible individuals die or acquire After immune self-healing, those who account for the vast majority of asymptomatic individuals and recovered individuals after infection still carry the mutant virus.
This new virus circulates within the population without causing disease epidemics; when conditions are right, the virus accumulates mutations To a certain extent, individuals with another type of MHC genotype will be infected and enter the next epidemic season, thus starting a new cycle within the population
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When the virus acquires a mutation that spreads across species, it begins to evolve into a gradual balance of infection-epidemic-asymptomatic carrier within the new species
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This rule is true in mammals and other animals, including humans
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When the virus acquires a mutation that spreads across species and accumulates to have strong binding to all MHC sites, it becomes a super virus.
This super virus has the power to extinct the population, but the super virus will also follow the population.
Extinction and disappeared
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Early immunization with weak viruses with weakened allergenicity can resist strong viruses.
Examples of smallpox and vaccinia are important evidence of this measure
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Vaccines that have allergenicity attenuated on the whole genome antigens will be safe and effective vaccines, which will be the new target of the new coronavirus vaccine in the future
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Therefore, joint monitoring of changes in special meteorological factors and virus mutations, and early inoculation of hypoallergenicity (Hypoallergenicity) virus will be an ideal preventive method against the virus
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Research results 01 Evolutionary analysis confirms that the natural host of human SARS-CoV-2 is likely to come from bats.
In order to track the source of SARS-CoV-2 and its evolutionary route, the study analyzed human SARS-CoV-2, SARS-CoV and reported The evolutionary relationship of the spike glycoproteins of coronaviruses such as bats and civet cats
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The study found that the natural host of human SARS-CoV-2 is likely to come from these bats, and that there should be other intermediate hosts for the spread of human SARS-CoV-2 (as shown in the figure below)
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02 Rodents may be the intermediate host for the spread of SARS-CoV and SARS-CoV-2 to humans.
In order to determine the intermediate host of human SARS-CoV-2, the sliding peptide of human SARS-CoV-2 spike glycoprotein is used as the scanning window.
The entire biological database was scanned and compared
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The results showed that there were 17 murine peptide fragments that matched the human SARS-CoV-2 stimulatory glycoprotein completely
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The author further verified these fragments in the NCBI BLAST reference protein library and non-redundant protein sequence library.
The results showed that 7 fragments are rat-specific peptides, which only exist in the mouse database (Mus or Rattus), but not in others.
Mammal database
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Through the overall proteomics scan of the protein library, it was found that the characteristic fragment HAIHVSGT was specifically present in Rattus norvegicus and mice
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Therefore, rodents may be the intermediate hosts for the spread of SARS-CoV and SARS-CoV-2 to humans (as shown in the figure below)
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03SARS-CoV-2 and SARS-CoV have similar HLA molecular binding affinity and similar allergenicity.
Through the affinity analysis of human SARS-CoV-2, SARS-CoV and HLA class Ⅰ and Ⅱ molecules, it is found that it is similar to SARS-CoV- 2 The HLA alleles that strongly bind to the SARS-CoV spike protein are very similar, indicating that human SARS-CoV-2 and SARS-CoV can also induce similar strong immune responses in people with the same genetic background
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However, it is worth noting that the number and location of human SARS-CoV-2 and SARS-CoV strong binding alleles are not exactly the same, which indicates that they may induce different actual immune responses
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HLA alleles with high binding affinity to SARS-CoV-2, including DRB3*03:01, DRB1*10:01 and DRB1*09:01, etc.
, people who carry these genes produce severe immune responses
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Among them, DRB3*03:01 is the most common allele, and 79.
59% of the S protein fragment of SARS-CoV-2 can bind tightly to it
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Among 103,259 Chinese, the ratio of HLA allele DRB1*09:01 is as high as 24.
28%
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Integrating 12 high-binding HLA alleles and estimating 4188607 American populations and 103259 Chinese populations containing these specific gene loci, it is concluded that there are 4.
78% and 7.
36% of the two national populations in the United States and China, respectively.
People will show obvious symptoms after infection
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On the other hand, most other HLA alleles show low or zero affinity for SARS-CoV-2 and SARS-CoV.
People who carry these genes may become at high risk of recessive infection after being infected with SARS-CoV-2.
, That is, these infected people may have no obvious symptoms, but they are still contagious
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For example, the proportion of DQB1*03:02 in the Chinese population is about 10.
54%, and the proportion in the American population is about 25.
85%
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These complex situations will make the prevention of COVID-19 more difficult (as shown in the figure below and Table 1)
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Table 1.
Specific HLA alleles and high affinity peptides of SARS-CoV-2 spike protein
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04Extreme climate may be one of the factors leading to the spread of the virus.
The analysis of meteorological factors found that the Fuqiu continuous drought that occurred in 2019 was the most severe year of summer and autumn droughts in Hubei Province in the past 69 years.
Its main feature is abnormally low precipitation.
And accompanied by long-term high temperature weather
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The temperature-precipitation relationship in Guangdong from 2002 to 2003 was in a similar state
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Such extreme weather factors may make it easier for the coronavirus to spread widely
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Therefore, continuous climatic factors and virus monitoring should be included in the daily work of disease prevention and control (as shown in the figure below)
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Identify the QR code to read the original English text.
; Zhong, N.
SARS-CoV-2: Origin, Intermediate Host and Allergenicity Features and Hypotheses.
Healthcare 2021, 9, 1132.
DOI: 10.
3390/healthcare9091132 Healthcare Journal Introduction Editor: Dr.
Rahman Shiri, Finnish Institute of Occupational Health, Finland Healthcare The original theoretical and experimental research results published in the journal involve various topics and aspects related to medical and health care
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