The novel coronavirus antibody produced after infection has become an accomplice to severe illness and death?
After the novel coronavirus infection, the symptoms of patients vary widely, from asymptomatic to severe pneumonia and even death. The severity of the disease is closely related to inflammation in the body. Severe inflammation is the culprit that causes patients to suffer from respiratory distress and systemic multiple organ failure.
Although the severe disease rate has dropped significantly compared to previous strains during the Omicron epidemic, we still do not understand why some people become severely ill after contracting the novel coronavirus, and how the novel coronavirus ignites inflammation in their bodies stormy?
Recently, a research team from Boston Children’s Hospital unraveled the answer to this question for the first time. Surprisingly, the novel coronavirus actually infects immune cells, causing inflammatory necrosis of monocytes and lung macrophages. One process is relying on the covid antibody to play the role of “matchmaking”. The study was launched on Nature’s official website on April 6 as an Accelerated Article Preview.
The researchers analyzed and compared fresh blood samples from patients with covids and blood samples from healthy people. The results showed that in the blood of patients with covids, about 6% of monocytes are experiencing pyroptosis (Pyroptosis), also known as inflammation. During sexual necrosis, the pyroptotic cells continue to expand until the cell membrane ruptures, releasing cytokines and chemokines.
Not only that, but nearly 1/4 of lung macrophages were observed to have pyroptosis in lung autopsy specimens of COVID-19 deaths. Macrophages and monocytes have similar functions. react when.
In the early stage of infection, the substances released by these pyroptotic cells act as “alarms”, which can recruit other immune cells to the site of infection and clear pathogens in time. However, when more and more pyroptotic cells are released, inflammatory molecules are released in large quantities, and the inflammatory response is out of control. , resulting in respiratory distress and systemic multi-organ failure.
In addition, the researchers also found that the more pyroptotic cells, the more severe the patient’s symptoms. Compared with patients with mild and moderate symptoms of the covid, the blood of critically ill patients has markers of pyroptosis, including GSDMD, LDH, and IL. The levels of -1RA and IL-18 were significantly increased.
So what causes the pyroptosis of monocytes/macrophages in patients with covids?
Then, the surprising thing happened, the researchers found signs of novel coronavirus infection in these pyroptotic monocytes and macrophages – about 10% of monocytes and 8% of lung macrophages. The nucleoprotein capsid and double-stranded RNA of the novel coronavirus are present in cells.
This shows that the novel coronavirus not only entered the cell, but also tried to replicate, and these infected monocytes and macrophages all had inflammasome activation and went to pyroptosis, indicating that the direct infection of the novel coronavirus is a monocyte / The direct cause of macrophage pyroptosis!
We know that the novel coronavirus infects cells by combining the spike protein on the surface of the virus with the ACE2 receptor of the cell, like a key unlocking the door, opening the door to enter the cell. The question is, monocytes do not express ACE2, how does the virus infect it?
One point is very crucial. The researchers found in the experiment that the virus is more inclined to infect those monocytes that carry CD16 (Fc γ RIIIa). About half of the CD16+ monocytes are infected with the novel coronavirus, while the CD16- monocytes are infected with the novel coronavirus. Nuclear cells are hardly infected.
Since CD16 can bind to the Fc segment of the antibody, and then engulf those pathogens linked to the antibody, the researchers speculate that after the novel coronavirus binds to the novel coronavirus antibody produced in the body, the Fc segment at the end of the antibody is in turn absorbed by CD16 on the surface of monocytes. Capture, the cell membrane of monocytes invaginates, and the antibody and virus are engulfed into the cell, causing infection.
In order to prove that SARS-CoV-2 indeed entered monocytes through the “matching” of SARS-CoV-2 antibodies and CD16, the researchers co-cultured monocytes with an infectious engineered virus strain (icSARS-CoV-2-mNG) under in vitro conditions .
It was found that under normal circumstances, the novel coronavirus does not enter monocytes, and only when endotoxin LPS stimulation, new coronary antibodies or plasma of new coronary patients are added, monocytes will be infected by the novel coronavirus.
On the contrary, if the antibody component in the plasma of the covid patient is removed and added to the co-culture system, the number of monocytes infected with the covid virus will drop significantly. Not only that, adding a CD16 antagonist to the culture system to block the binding of the antibody to CD16 can also achieve a similar effect. It shows that the covid antibody and CD16 are indispensable in the process of the covid virus infecting monocytes.
That is to say, the covid antibody not only does not play a protective role, but instead promotes the novel coronavirus to infect monocytes and lung macrophages, causing these cells to undergo pyroptosis and an inflammatory storm, which is reminiscent of the antibody-dependent infection-enhancing effect. (Antibody-dependent enhancement, referred to as ADE effect).
The ADE effect refers to the phenomenon that after the body produces antibodies to a certain pathogen through infection, immunization or passive infusion, these antibodies assist the virus to enter the target cells, increase the infection rate, and cause aggravation of the disease.
The question is, does the covid antibody produced after vaccination also have an ADE effect?
The researchers added the plasma of healthy people who had been vaccinated with mRNA vaccine and produced covid antibodies into the co-culture system of monocytes and virus. The concentration of antibodies in the plasma of vaccinated healthy people was about twice that of patients with covid infection (6.5 ± 1.1 μg/ml vs. 3.6 ± 0.5 μg/ml), even in this case, the infectivity of the virus was not enhanced, indicating that the covid antibodies produced by the mRNA vaccine did not have an ADE effect.
So why do the antibodies in the body protect most people after being infected with the covid, while some people develop severe disease?
Previous studies have shown that the non-fucose-modified (afucosylated) of the Fc region of the antibody can promote the binding of the antibody to CD16. In the co-culture system, high concentrations (~30%) of non-fucose-modified SARS-CoV-2 antibody plasma were added to the co-culture system. Compared with the concentration of non-fucose-modified antibody plasma (~8%), the ability of the virus to infect cells was significantly enhanced, suggesting that the non-fucose modification of the Fc segment of the covid antibody is likely to be the cause of the ADE effect. Further research is needed.
This study is the first to find that the covid antibody has an ADE effect in humans, and it is likely to be the main cause of severe illness and death in patients. These antibodies promote the infection of immune cells by the novel coronavirus, promote cell pyroptosis, trigger strong inflammation, and aggravate the disease.
From this point of view, the use of pyroptosis markers in the blood of patients with covids may be able to predict disease progression, or prevent the progression of the disease from becoming severe by inhibiting the pyroptotic pathway. At present, two GSDMD inhibitors, Antabuse and Tecfidera, have entered the clinical evaluation stage for the treatment of covids ( NCT04485130, NCT04594343, NCT04381936 ), and they are expected to bring good results.