After the new crown virus infection, the symptoms shown by patients vary greatly, from asymptomatic to severe pneumonia and even death, the severity of the disease is closely related to the inflammation in the body, and severe inflammation is the culprit that causes patients to develop respiratory distress and systemic multi-organ failure.
Although the severe illness rate has dropped significantly during the Omiljung epidemic compared to previous strains, we still do not understand why some people develop severe illness after contracting the new crown virus, and how the new crown virus ignites the inflammatory storm in their bodies.
Recently, a team of researchers from Boston Children's Hospital unveiled the answer to this question for the first time, and surprisingly, the new crown virus can infect immune cells, resulting in inflammatory necrosis of monocytes and lung macrophages, and this process relies on new crown antibodies to play a "matchmaking" role. The study went live on The Nature website on April 6 in the form of an Accelerated Article Preview.
The researchers compared fresh blood samples from new crown patients with blood samples from healthy people, and the results showed that in the blood of new crown patients, about 6% of monocytes were experiencing pyroptosis( pyroptosis), also known as inflammatory necrosis, and the scorched cells continued to expand until the cell membrane ruptured, releasing cytokines and chemokines.
Not only that, but nearly 1/4 of the lung macrophages in the lung autopsy specimens of the new crown death cases have also observed scorch death, and macrophages and monocytes function similarly, acting as "sentinel cells" that respond to pathogen invasion.
In the early stage of infection, these scorched cells release substances as an "alarm", which can recruit other immune cells to the site of infection and remove pathogens in time, but when more and more scorched cells are killed, a large number of inflammatory molecules are released, 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 scorched cells, the more severe the symptoms of the patient, compared with mild and moderate symptoms of the new crown patients, the blood of the scorch death markers, including GSDMD, LDH, IL-1RA, IL-18 levels increased significantly.
So what causes the death of monocytes/macrophages in COVID-19 patients?
Then, surprisingly, 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 nucleoprotein shell and double-stranded RNA.
It 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 react to inflammation and die, indicating that the direct infection of the new crown virus is the direct cause of the coke death of mononuclear/macrophages!
We know that the new crown virus infected cells rely on the spike protein on the surface of the virus to bind to the cell's ACE2 receptor, just like the key to unlock, open the door into the cell. The problem is, monocytes do not express ACE2, how do viruses get infected?
Crucially, the researchers found in their experiments that viruses are more susceptible to infecting monocytes that carry CD16 (FcγRIIIa), with about half of CD16+ monocytes infected with the new coronavirus, while 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.
Illustration: Schematic diagram of single-core/macrophage infection with COVID-19
Source: Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies, originally depicting the infection enhancement effects of dengue virus and FIPV antibody dependence.
To prove that the new coronavirus did enter monocytes through the "matchmaking" of COVID-19 antibodies and CD16, the researchers co-cultured monocytes with infectious engineered strains (icSARS-CoV-2-mNG) under in vitro conditions.
It was found that under normal circumstances, the new crown virus does not enter monocytes, and only if endotoxin LPS stimulation, new crown antibodies or the plasma of new crown patients are added, monocytes will be infected with the new crown virus.
Conversely, if the antibody component in the plasma of COVID-19 patients is removed and added to the co-culture system, the number of monocytes infected with the new crown virus will drop significantly. Not only that, adding CD16 antagonists to the culture system to block the binding of antibodies to CD16 can also get a similar effect. This shows that the new crown antibody and CD16 are indispensable in the process of infection of monocytes by the new crown virus.
That is to say, the new crown antibodies not only do not play a protective role, but will promote the new crown virus infection of monocytes and lung macrophages, causing these cells to scorch and cause inflammation storms, which is reminiscent of antibody-dependent enhancement (ADE effect).
ADE effect refers to the phenomenon that the human body produces antibodies to a certain pathogen through infection, immunization or passive input, and these antibodies assist the virus to enter the target cell, increase the infection rate, and cause aggravation of the disease.
The question is, do the new crown antibodies 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 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 the newly infected patients (6.5± 1.1 μg/ml vs. 3.6±0.5 μg/ml), even in this case, the infective capacity of the virus was not enhanced, indicating that the new crown antibodies produced by the mRNA vaccine did not have an ADE effect.
So why do most people have a protective effect on antibodies after being infected with the new crown, while some people develop severe diseases?
Previous studies have shown that non-fucosylated (afucosylated) of the antibody Fc segment will promote the binding of antibodies to CD16, and the addition of high concentrations (~30%) of non-fucose-modified NEO antibody plasma to the co-culture system, compared with low concentrations of non-fucose modified antibody plasma (~8%), significantly enhances the ability of the virus to infect cells, suggesting that the non-fucose modification of the Fc segment of the new crown antibody is likely to be the cause of the ADE effect, and further research is needed on this point.
This study is the first to find the ADE effect of covid-19 antibodies 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 with the new crown virus, promote the death of cells, trigger strong inflammation, and aggravate the disease.
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[3] Liu Y, Soh WT, Kishikawa JI, et al. An infectivity-enhancing site on the SARS-CoV-2 spike protein targeted by antibodies. Cell. 2021;184(13):3452-3466.e18. doi:10.1016/j.cell.2021.05.032
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