Novel coronavirus pneumonia: advantages and disadvantages of recognizing antibodies

The infection of novel coronavirus caused more than 60 thousand cases of infectious pneumonia, and thousands of patients lost their lives No matter the government departments, scientific research teams or the general public are looking forward to the emergence of antibody drugs, and the practice of directly collecting the serum of cured patients to treat severe patients during SARS directly reflects the importance of antibody for the treatment of such infectious diseases It is true that antibody is one of the most important weapons to fight against virus infection Once it is produced, it is not only large in quantity but also long-lasting, so as to effectively block the virus from entering the cell If the virus cannot enter the cell, it cannot reproduce and expand, and the virus outside the cell will gradually decompose itself This is the magic of the antibody If the inactivated virus particles are injected directly into the body, the body will produce antibodies against the virus, which is the traditional vaccine, and the effect of vaccination will be produced The current vaccine development of new coronavirus also follows this basic principle Novel coronavirus pneumonia is a kind of illusion, but the reality is far from it Some antibodies can even promote the development of new crown pneumonia So, is this alarmism, or is it scientifically justified? Novel coronavirus pneumonia is what is happening in many new severe pneumonia patients Why can't these antibodies control the virus? This is due to the complexity of the antibody There are 20 kinds of amino acids in the same virus and a variety of antibodies Chemical covalent bond connects one amino acid to form a long chain, which is commonly called protein Antibody is a kind of protein molecule, which has a Y-shaped structure like a tree branch The tree branch part recognizes and binds antigens (usually alien proteins) There are all kinds of alien proteins in nature If antibodies want to recognize them, their branches are correspondingly various (biologically called the branches are variable regions of antibodies), and even form all kinds of antibodies, but the trunk parts of these different antibodies are basically the same (biologically called the constant regions of antibodies) A novel coronavirus nucleic acid substance RNA is located at the core, wrapped by nucleocapsid protein, then coated with a spike protein (amplified after the shape of nails), envelope protein, envelope protein, membrane protein, namely membrane protein In addition to these proteins that maintain the structure of the virus, the nucleic acid genetic material of the virus can also guide the generation of other virus proteins that are not involved in the structure of the virus (these virus proteins exist in the infected cells, not in the virus particles) All these viral proteins are alien proteins For any alien protein, the body may produce antibodies specifically for it Therefore, the novel coronavirus infection population can produce various antibodies against viruses in individuals Most of the antibodies lack antiviral effect since the body has produced a variety of antibodies against the virus, does each antibody play an antiviral protective role? The answer is No Antibody should play the role of antiviral, the precondition is that antibody should recognize and combine with virus particles However, nonstructural viral proteins do not exist in virus particles (in the infected cells) Therefore, antibodies against this large class of viral proteins have no antiviral effect So, does the antibody have antiviral effect on the protein in the virus particles (the so-called target, generally speaking, is a radish and a pit, and this antibody specifically binds to this protein)? The answer is that only antibodies against viral surface proteins can produce antiviral effects The surface of the novel coronavirus is a layer of envelope, which can not be exposed to the viral protein in the envelope Therefore, this antibody does not have the antiviral effect In a word, after the virus particles infect the body, the body can produce a variety of different antibodies against the virus protein, but most of the antibodies actually have no antiviral effect Only the antibodies that recognize the surface protein of the virus particles can have antiviral effect The effective anti-virus way of action recognizes the antibodies of the surface proteins of virus particles, which can produce the anti-virus effect, so what is the way for these antibodies to play the role? The pathogenicity of coronavirus particles is through spike protein on the surface of virus particles and a kind of angiotensin converting enzyme 2 (angiotensin converting enzyme) on the surface of lung epithelial cells 2, ACE2) protein binding, ACE2 subsequently changes the shape and structure, causing the virus to enter the cell, and use the cell's own amino acid molecules, nucleotide molecules and lipid molecules to synthesize new virus particles through chemical reactions These new virus particles are released outside the cell, and use the same way to infect the surrounding normal cells The antibody against spike protein binds to spike protein on the surface of virus particles and blocks the binding of spike protein and ACE2, which also blocks the virus from entering cells This kind of antibody against spike protein is called neutralizing antibody Neutralizing antibodies play a protective role by preventing the virus from invading the cells, which is the main strength of the antiviral effect of antibodies There are also envelope proteins and membrane proteins on the surface of coronavirus, but these two proteins may not mediate the virus into the cell Therefore, the combination of antibody with envelope protein or membrane protein may not affect the virus into the cell However, if this combination affects the conformation (three-dimensional spatial structure) of spike protein, which makes spike protein and ACE2 not well combined, it can hinder The virus is less likely to enter the cell The antibody against the envelope protein or membrane protein, which binds with the corresponding protein on the surface of the virus, can mediate the phagocytosis of the virus particles by the immune cells of the body even though it does not affect the spike protein to mediate the virus into the pulmonary epithelial cells This is due to the specific protein (called Fc receptor) on the surface of phagocyte, which can recognize the trunk part of antibody, namely the constant area In this way, the antibody, through its variable region and virus binding, through its constant region and phagocyte binding, so as to greatly promote phagocyte phagocytosis of virus particles, and the phagocytized virus is decomposed and cleared in phagocyte To sum up, there are two ways for antibody to play a role: the combination of neutralizing surface antibody and virus to prevent the virus from entering the cell (keep the enemy away from the country); the combination of non neutralizing surface antibody and virus to mediate the phagocytosis of immune cells and eliminate the virus (kill the enemy in the country) In the aspect of anti-virus, non neutralizing surface antibody combines with virus and mediates the phagocytosis of immune cells, which are mainly macrophages (specialized phagocytes in human body) After macrophages swallow the virus, the virus particles are wrapped in a kind of vesicle called endocytosis, and then the endocytosis moves away from the cell surface to the center of the cell In this process, it fuses with a kind of vesicle called lysosome, and the lysosome contains a variety of hydrolases, which can hydrolyze the virus, thus eliminating the virus But while the immune system has evolved such an antiviral mechanism, the virus is also evolving, using all means to avoid phagocytosis and killing One mechanism is that the virus escapes the endocytosome before it fuses with the lysosome How to escape? After the virus is encapsulated in the endocytosis, the fluid in the endocytosis capsule is acidified gradually (pH value is reduced) The virus can take off the outermost envelope by acidification, expose the virus nucleic acid, and transport the virus nucleic acid from the endocytosis to the cytoplasma, in which the virus nucleic acid can be copied to form new virus particles and released to the outside of the cell In this way, with the aid of surface antibody, the virus transforms immune cells into intermediates of the virus to escape from immune killing The expansion of virus in macrophage cells may not be the worst thing What's worse, the virus may promote the inflammatory storm through macrophages The damage of novel coronavirus to lung cells usually does not directly lead to death of patients The main reason for the death of patients is the excessive activation of non-specific immune cells, and the release of a large number of proinflammatory factors, such as interleukin -1, interleukin -6 and tumor Necrosis factors, etc., form the so-called cytokine storm, known as the cytokine release syndrome (CRS) The main pathological damage of CRS is capillary The capillary wall is arranged by a single layer of endothelial cells The gap between the endothelial cells is only 1-2nm, and the gap between the endothelial cells is only 5-8nm This is because the endothelial cells and the endothelial cells are adjacent to each other There are many connective proteins on the surface, which are closely connected with each other, resulting in such a small gap But the above-mentioned pro-inflammatory factors act on the capillary endothelial cells of lung tissue, making the endothelial cells no longer express or greatly reduce the number of connective proteins on the surface, so that the gap between the endothelial cells becomes very large all of a sudden, and the blood in the capillary flows out of the increased gap and fills the alveoli, which is the inflammatory storm So, what kind of immune cells release the cytokines that cause the inflammatory storm? Macrophages are the culprit Macrophages are important first-line defense cells in the body When the virus infects macrophages, it can activate macrophages rapidly and induce macrophages to release pro-inflammatory factors However, when the virus proliferates in macrophages, the activation of macrophages is particularly strong, which can release excessive pro-inflammatory factors and trigger cytokine storms The effect of non neutralizing surface antibody depends on the time phase Since the virus propagates in macrophages, there is a risk of great harm to the body, is non neutralizing surface antibody not good at all? The answer is not It depends on the time In the early stage of virus infection, macrophages function well in all aspects The phagocytic antibody mediated virus is more hydrolyzed in lysosome Even if some viruses escape to the cytoplasm, the interferon signal pathway initiated by macrophages can effectively inhibit the replication and expansion of the virus In the middle and late stage of virus infection, macrophages not only feel the signals of virus, but also the signals of various cytokines The function of macrophages changes The virus can take advantage of this opportunity, on the one hand, it escapes to the cytoplasm, on the other hand, it expands in a large amount, and the large number of expanded viruses, in turn, forces macrophages to be strongly activated, and then release excessive pro-inflammatory factors Damage to lung tissue Therefore, for virus surface proteins, neutralizing antibodies always play a protective role by preventing the virus from entering the lung epithelial cells, but non neutralizing antibodies mainly mediate the virus into macrophages, play an antiviral role in the early stage, but may mainly lead to lung immune damage in the middle and late stage The elimination of virus depends on T cell neutralization antibody to keep the virus out of the cell, but it can't do anything for the virus that has entered the cell At the same time, neutralization antibody can only prevent the virus from invading the cell, and a small part or a part of the virus will still enter the cell For the virus hiding in the cell, its final killing depends on the T cells in the human body virus