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What went wrong in the body when a SARS-CoV-2 infection brings people to the hospital? A study now shows that in severe COVID-19 courses, a messenger substance is released at the beginning, which normally shuts down the immune system at the end of infections. As a result, the fight against the pathogens is apparently impaired by killer cells of the innate immune system. The researchers say there may be potential in the findings for the development of drugs that prevent the severe course of the disease.
Many people survive a SARS-CoV-2 infection with comparatively no problems – others, however, end up in the intensive care unit. Obviously, the immune system of the severely affected patient is comparatively poorly able to keep the pathogens in check. Research into the background of the different processes is an important topic in corona research. Studies have already shown that various factors can play a role. The focus of the researchers around Mario Witkowski from the Charité – Universitätsmedizin Berlin was now the role of the so-called innate defense. This department of our immune system forms the body’s first line of defense against pathogens. Intruders are attacked unspecifically. The acquired immune system, which is based on the function of specific antibodies, on the other hand, first has to “get to know” a pathogen and therefore does not get going until later.
The role of the early combat troops in sight
When the early protection system against viral pathogens is used, the so-called natural killer cells (NK cells) in particular become active. They recognize virus-infected cells in the body based on their changed surface and then switch them off so that they cannot spread the pathogen any further. The investigation of the role of these units in the fight against SARS-CoV-2 infections formed the basis of the current study. To do this, the researchers isolated NK cells from the blood of patients with COVID-19 courses of varying severity and examined the characteristics of the killer cells in the laboratory. They used NK cells from healthy individuals or patients with other serious diseases that affect the respiratory system as a comparison.
The laboratory tests initially showed that NK cells can recognize and eliminate SARS-CoV-2-infected lung cells. In addition, it became apparent that in people who had many of these immune cells in their blood at the beginning of the SARS-CoV-2 infection, the amount of virus in the throat had rapidly decreased. “So NK cells help fight SARS-CoV-2,” Witkowski sums up this partial result of the study. During the investigations, however, the researchers also came across an important note: “NK cells that we removed from severely affected people were much less effective against the virus in the laboratory than killer cells from people with symptoms,” reports Witkowski.
Premature damping is becoming apparent
To investigate the cause of this difference, the researchers analyzed the genetic activities in thousands of individual NK cells obtained from patients with different degrees of severity and from different stages of COVID-19 disease. In doing so, they encountered patterns of subdued activity in response to a known messenger substance: TGFβ. “Our data show that NK cells in patients with severe COVID-19 were activated early, but are then immediately blocked again by TGFβ,” says co-author Mir-Farzin Mashreghi from the German Rheumatism Research Center Berlin. As the scientists explain, the messenger substance TGFβ has different functions in the body – one of them is the regulation of the immune system: It regulates the reaction after successfully fighting a pathogen and is therefore normally only formed towards the end of an infection.
The analyzes showed that people with mild COVID-19 courses actually only produce the messenger substance after more than three weeks. In the seriously ill, however, TGFβ was already detectable in high quantities in the first days of infection. “As a result, NK cells have a harder time docking with virus-infected cells and therefore cannot render them harmless,” says Mashreghi. The premature formation of the immunocompromising messenger substance does not occur in other types of pneumonia and is therefore apparently a characteristic of COVID-19, the scientists state.
Hope in the fight against difficult courses
“In addition to other factors, the timing of the TGFβ release decides how COVID-19 proceeds,” explains co-author Andreas Diefenbach from the Charité. “The innate immune system of most people with COVID-19 is probably able to push back the virus shortly after infection. In some patients, however, the immune system reacts so strongly to the pathogen that the body counter-regulates and forms the dampening messenger substance TGFβ. Among other things, this blocks the functionality of the NK cells. This misdirected immune reaction ultimately means that the virus cannot be fought efficiently early enough, ”says Diefenbach, explaining the possible background to the effect.
The researchers now see the findings as an important clue for the development of treatment options: early inhibition of TGFβ could perhaps prevent severe courses of COVID-19. It appears that there are already agents that could take on this function that have been developed for the treatment of other diseases in which TGFβ also plays a role. “Anti-TGFβ therapies would be an interesting approach to correct the timing of the immune response. First, however, the TGFβ inhibitors would have to be tested against COVID-19 in an animal model, ”emphasizes Diefenbach. “We also see another starting point for future therapies: Possibly the NK cells in the body could be activated in a targeted manner in order to enable them to render SARS-CoV-2-infected cells harmless. To this end, we will now investigate how exactly the immune cells recognize and eliminate their target cells, ”says the scientist.
Source: Charité – Universitätsmedizin Berlin, specialist article: Nature doi: 10.1038 / s41586-021-04142-6