The "rebellion" of the immune system has become the key cause of severe covid-19

Image source @ Visual China

Text | Chen Gen

Since the outbreak of the new crown epidemic, a clear change is that the mutation of the new crown virus has developed in the direction of increasingly strong transmission and weaker harm. As a result, although the number of people infected with the new crown virus remains high globally, the number of critical cases and severe cases is significantly lower than before.

At present, targeted prevention and treatment of critically ill cases and severe cases has become a new way of thinking to combat the new crown epidemic. Among them, the severity of the known disease is closely related to the inflammation in the body, and the severe inflammation is the culprit that leads to respiratory distress and systemic multi-organ failure. However, it is not yet known how the new crown virus ignited the inflammatory storm in the human body.

People still don't know what the epidemic will be tomorrow, whether it will coexist with the virus or whether it will actually eliminate the new crown virus. But before that, it has become an inevitable measure to reduce the severe cases of the new crown virus infection as much as possible and effectively treat the severe cases of the new crown virus infection.

Inflammation causes severe COVID-19?

According to a paper published by Nature on April 6 and a preprint paper published online on April 1, immune cells infected with the new coronavirus can trigger a large-scale inflammatory response, and this inflammatory response is a key cause of severe COVID-19.

In fact, the appearance of inflammation is not an absolutely bad thing, inflammation as a healthy defensive response to inflammatory factors, originally a self-protection mechanism of the body to turn on the protection of the immune system.

But at the same time, the presence of inflammation also harms the human body: the important weapon of the immune system to protect the human body from external damage is reactive oxygen species (free radicals), and these reactive oxygen species can damage normal cells in the body while working, thus triggering cell dysfunction. This can be confirmed by the increase in levels of immune cytokines after infection with the new crown virus, which can cross the blood-brain barrier, which may lead to long-term toxic brain changes that affect the entire nervous system.

Since the beginning of the outbreak, studies have shown that inflammation can lead to severe respiratory distress and other organ damage, which are all signs of severe COVID-19. But scientists have struggled to determine what causes these inflammations. Now, for the first time, a team of researchers from Boston Children's Hospital has unveiled the answer to this question. Researchers have found that the new crown virus can infect immune cells, causing inflammatory necrosis of monocytes and lung macrophages, leading to the occurrence of severe covid-19.

In past studies on the new crown virus, the S protein of the new crown virus is considered to be an important part of the new crown virus that infects the human body. The S protein exists in the form of a trimer, shaped like a flower, where the S2 trimer forms the stalk structure in the form of a spiral, while the three S1s cover the top of the S2 trimer. At the same time, the S protein is composed of S1 and S2, of which S1, which is composed of N-terminal domain (NTD) and receptor binding domain (RBD), is responsible for binding to ACE2, while S2 is mainly responsible for fusion with human cell membranes to complete the release of genetic material.

Among them, ACE2 is the key to the invasion of the new crown virus into the human body - the new crown virus, like the SARS virus, also enters human cells by recognizing the ACE2 receptor protein. This makes the highly expressed ACE2 the main invading target of the novel coronavirus due to direct contact with the outside lung tissue.

This time, the research team found that the new crown virus can actually enter the cell through the Fcγ receptor with the "help" of the antibody, and infect monocytes and macrophages. The large number of cytokines released by infected monocytes and macrophages may be the trigger trigger for the large-scale inflammatory response in severe patients with new coronary pneumonia.

By giving mice drugs that block inflammation bodies, the researchers validated the effect of inflammation caused by the new coronavirus on aggravating the condition. The researchers found that giving mice drugs that blocked the inflammasome prevented severe respiratory distress. The researchers say the drugs "saved the lives of the mice so they didn't get too sick." In other words, infected monocytes and macrophages play a role in pneumonia in severe COVID-19 patients.

Study co-author Richard Flavell, an immunologist at Yale University and the Howard Hughes Medical Institute, believes that the inflammatory response of these macrophages may be the method they use to stop the replication of the new coronavirus.

After the inflammasome is activated, the new coronavirus stops replicating within the cell. But if the researchers block the inflammasome, macrophages begin to produce infectious viral particles. Immune cells eventually become accomplices in aggravating viral infections.

Coronavirus infects immune cells?

Further, the study is based on "inflammation caused by the new crown".

First, the researchers found that about 6 percent of the plasma of patients with COVID-19 had monocytes in a scorched state, a type of cell death associated with inflammation. Nearly 1/4 of lung macrophages in COVID-19 deaths have also been observed in lung autopsy specimens, and macrophages and monocytes function similarly, acting as "sentinel cells" that respond to pathogen invasion.

Among them, scorch death is also called inflammatory necrosis, and the scorched cells continue to expand until the cell membrane ruptures, releasing cytokines and chemokines. In the early stage of infection, these scorched cells release substances as an "alarm", can recruit other immune cells to the site of infection, timely removal of pathogens, but when more and more scorched cells, a large number of inflammatory molecules are released, the inflammatory response is out of control, which will lead to respiratory distress and systemic multi-organ failure.

The researchers found that the levels of all biomarkers associated with scorch death in the plasma of covid-19 patients were significantly higher than in the plasma of healthy people, and in patients, it was particularly prominent in patients with severe disease. That is to say, the more cells that are scorched, the more severe the symptoms of the patient, and compared with the mild and moderate symptoms of the new crown patients, the blood coke death markers in the severe patients, including GSDMD, LDH, IL-1RA, IL-18 levels increase significantly.

Usually, pathogen infection is a major trigger for inflammation, and there have been a few studies that have said that monocytes and macrophages can be infected by the new crown virus, which has led researchers to put forward the hypothesis that monocytes and macrophages may be infected by the new crown virus.

Facts confirmed the researchers' suspicions, and the researchers found signs of coronavirus infection in these scorched monocytes and macrophages — about 10 percent of monocytes and 8 percent of lung macrophages had the new coronavirus's nuclear protein shell and double-stranded RNA.

This shows that the new crown virus not only enters the inside of the cell, but also tries to replicate, and these infected monocytes and macrophages without exception all activate the inflammasome and go to scorch. That is to say, the direct infection of the new crown virus is the direct cause of the scorch death of monocytes and macrophages.

Based on this understanding, in the study of Shunto, the researchers further found that the virus is more inclined to infect those monocytes that carry CD16, about half of the CD16+ monocytes are infected with the new crown virus, and the CD16- monocytes are almost uninfected.

Since CD16 can bind to the Fc segment of the antibody and then engulf those pathogens connected to the antibody, the researchers speculate that after the new coronavirus combines with the new crown antibody produced in the body, the Fc segment at the end of the antibody is captured by CD16 on the surface of the monocyte, and the cell membrane of the monocyte is inverted, and the antibody and the virus are swallowed into the cell together, causing infection.

What is the possibility of ADE?

In fact, through antibodies to promote the infection of monocytes and lung macrophages by antibodies, causing these cells to scorch, rise up an inflammatory storm, and further aggravate the disease, which is the so-called antibody-dependent enhancement effect (ADE).

In principle, specific antibodies against proteins on the surface of the virus can often "neutralize" the virus, causing it to lose the ability to infect cells. But in some cases, antibodies play the opposite role in the process of viral infection: they assist the virus to enter the target cell and increase the rate of infection, which is the enhancement of antibody dependence.

The mechanism of action of ADE is mainly two: one is that the virus-antibody complex binds to cells with FcR on the surface of the membrane through the Fc segment of the antibody, which mediates the virus to enter these cells, thereby enhancing the infectious process of the virus; the other is that the virus-antibody complex binds to complement and then enters the cell through complement receptors.

In fact, the ADE effect has been observed in dengue virus, in sars-CoV, cat coronavirus (cat-borne) and other viruses, as well as HIV, measles virus, yellow fever virus, respiratory syncytial virus, West Nile virus, Coxsackievirus and other viruses, the existence of ADE is one of the main obstacles to HIV vaccine development.

Fortunately, not all antibodies can help the virus invade, and the research team found that the antibodies produced by Pfizer and BioNTech's mRNA vaccinators could not help mononuclear cells engulf the new crown virus.

The researchers added healthy human plasma that had been vaccinated with mRNA vaccine and produced new crown antibodies to the co-culture system of monocytes and viruses, and the antibody concentration in the plasma of healthy people who were vaccinated was about 2 times that of patients infected with new crown infection, even in this case, the infective ability of the virus was not enhanced, which showed that the new crown antibodies produced by the mRNA vaccine did not have an ADE effect.

At present, the scientific community's understanding of ADE is still not perfect, and there are no experimental methods and markers that can identify and diagnose ADE. Due to species differences, animal models also cannot accurately predict the ADE response of vaccines and antibodies in humans. Therefore, we still cannot predict whether ADE will occur, but it also suggests that we need to find ways to prevent ADE from occurring and treat ADE before proceeding with experimental antibody therapy.

Finally, from the perspective of preventing severe disease, the severe disease rate has been a key issue that has attracted people's attention since the outbreak of the new crown epidemic. Successful treatment of critically ill patients is the key to reducing the mortality rate of new crown pneumonia, and also requires the redundancy of medical treatment. Although numerous studies on the effectiveness of COVID-19 vaccines have shown that existing vaccines are deficient in their protective effects against infections. However, the role of vaccines in preventing severe diseases and preventing deaths can still not be ignored.

Recently, a data provided by the Hong Kong Department of Health has given strong evidence, which is also a more detailed data on the reduction of the mortality rate of COVID-19 infection by vaccination. According to an analysis by the Hong Kong Hospital Authority, as of 13 April, the median age of the deceased was 86 years old, with more than 95% aged 60 and above. And 73 percent of them are not vaccinated.

Further analysis showed a mortality rate of 2.97 per cent for those who had not been vaccinated and 0.04 per cent for those with three doses of vaccine. In other words, three doses of the vaccine can reduce mortality by 98.7%. Even a single injection can reduce the mortality rate by 67.3%. The report calls for "a significant reduction in the risk of death from any three doses of the vaccine, especially in the older age groups." ”

In fact, experts have been emphasizing the important role of vaccination for the elderly. Therefore, as long as the physical health is stable and there are no contraindications to vaccination, it is still necessary to receive the new crown virus vaccine as soon as possible, and if the second dose has been vaccinated for half a year, it is also necessary to receive the reinforcing injection as soon as possible. So far, COVID-19 vaccination remains the most effective and safest measure to prevent and control COVID-19, and is a direct way to build immune barriers at the social level.