The cytokine Transforming Growth Factor β (TGFβ) has potent immune-modulatory effects, playing a role in downregulating the body’s immune response once a pathogen has been successfully controlled. For this reason, its production is normally timed to coincide with the end of an infection. Now, a new study finds a different situation with a SARS-CoV-2 infection. A Berlin-based team of researchers has revealed that patients with severe disease show an increase in the production of TGFβ as early as the first week of infection.

This work is published in Nature in the paper, “Untimely TGFβ responses in severe COVID-19 limit antiviral function of NK cells.

“We observed no such increase in other types of pneumonia, which came as a big surprise,” said Mario Witkowski, PhD, a postdoc in the Diefenbach Lab at Charité’s Institute of Microbiology, Infectious Diseases, and Immunology. The team discovered that this untimely release of immune-dampening TGFβ has an effect on the body’s innate immune response.

For the first time, the researchers were able to show that NK cells play a role in the early control of SARS-CoV-2. However, their ability to eliminate SARS-CoV-2-infected cells was impaired by the early release of TGFβ.

“In short, NK cells help the body fight SARS-CoV-2,” explained Witkowski. “According to our laboratory tests, however, cells isolated from patients with severe disease were far less effective against the virus than cells taken from individuals with mild symptoms.”

The researchers identified the early release of TGFβ as the underlying cause through a study that analyzed more than 80,000 single NK cells from a total of 68 samples taken from COVID-19 patients with varying degrees of disease severity. By establishing which genes were activated in each of the cells, the researchers created an “atlas of gene expression” which provided extremely detailed data on immune cell responses.

Their analysis pointed to a profound effect being exerted by the immune-dampening cytokine TGFβ. “Our data show that, while NK cells are activated early in patients with COVID-19, they are then promptly blocked by TGFβ,” said Mir-Farzin Mashreghi, PhD, head of the DRFZ research group which conducted the gene expression analyses. “NK cells find it harder to bind to virus-infected cells and are therefore unable to eliminate them.” This effect is primarily observed in COVID-19 patients with severe disease. Here, high levels of TGFβ are seen in the initial days of infection. In contrast, individuals with mild symptoms only produce this chemical messenger after more than three weeks. In patients with other severe pneumonias, NK cells were not found to be affected by TGFβ.

“It is therefore clear that, in addition to other factors, the clinical course of COVID-19 is determined by the timing of the TGFβ release,” explained Andreas Diefenbach, PhD, director of Charité’s Institute of Microbiology, Infectious Diseases, and Immunology.

Diefenbach described his working hypothesis as follows: “It is likely that in most people with COVID-19, the innate immune system is able to push back against the virus shortly after infection. In some patients, however, the immune response to the pathogen is so profound that the body acts to correct this and produces TGFβ, the biochemical messenger which, among other things, impairs NK cell function. This of course happens at a point in time when SARS-CoV-2 is yet to be eliminated, meaning the blocking signal is sent too early. The end result of this faulty immune response is an inability to fight the virus in an effective manner, which in turn causes the damage typically associated with severe disease. We did not observe this combination of robust activation and simultaneous blocking of NK cells in patients with other infections like influenza; it appears to be a hallmark of COVID-19.”

Based on their findings, the researchers anticipate that the timely inhibition of TGFβ could prevent progression to severe COVID-19. Candidates capable of blocking the chemical messenger are currently undergoing testing as part of clinical trials. They include a range of substances originally developed for use in the treatment of cancer and rheumatoid arthritis, disorders in which TGFβ also plays a role. “The use of anti-TGFβ treatments to correct the timing of the body’s immune response would make for an interesting strategy. Before anything else, however, it will be necessary to test the experimental TGFβ-inhibitors in animal models,” emphasized Diefenbach. “We believe there is a further potential treatment target. It may be possible to target NK cells directly and, through their activation, restore their ability to eliminate SARS-CoV-2-infected cells. We will therefore study the precise mechanisms by which immune cells recognize and eliminate their target cells.”

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