Infection with the Sars-CoV-2 coronavirus is mild in many cases, but can also be life-threatening. According to a study, an antiviral messenger substance of the immune system could contribute to such severe courses: interferon-gamma actually fights pathogens and activates other immune cells, but also ensures more ACE2 receptors on mucous membrane cells. These serve as a gateway for SARS-CoV-2. The results could provide an impetus for research into new treatment approaches.
In order to multiply in the body, the coronavirus has to penetrate the cells. With the spike proteins on its surface, it binds to certain receptors on the cells, so-called ACE2 receptors. These can be found almost everywhere in the body – for example in the lungs, heart, brain and gastrointestinal tract. The symptoms of Covid-19 can also affect any of these organ systems. The more ACE2 receptors a cell has, the easier it is for the virus to dock, penetrate and multiply inside the cell.
Immune system as a pioneer of the virus
A team led by Julian Heuberger from the Charité Universitätsmedizin Berlin has now proven that of all things a messenger substance of the immune system, called interferon gamma, could make it easier for the virus to penetrate cells. “With this we can possibly provide part of the explanation why in some people the immune system has difficulties regulating or even defeating the infection,” says Heuberger.
Interferon-Gamma is part of the body’s own defense system against viruses, bacteria and other germs. It is released by T cells of the immune system and serves on the one hand to bind to the pathogens and to destroy them. On the other hand, it alarms other cells of the immune system and thus strengthens the defense and inflammatory reaction. But mucous membrane cells also react to interferon gamma. As Heuberger and his team have now shown, this could explain why patients with particularly strong immune reactions often suffer from severe courses of Covid-19.
Gut organoids as a model system
In order to be able to observe the immune reactions to Sars-CoV-2 in the laboratory, the researchers cultivated so-called organoids of the human large intestine. These are a kind of mini-organs in the Petri dish, grown from cells obtained from intestinal biopsies. Heuberger and colleagues first treated some intestinal organoids with interferon gamma, thereby simulating a strong immune reaction in the body. They then infected the organoids with Sars-CoV-2. The researchers recorded the reactions of the cells in the intestinal models, which are only a few millimeters in size, with the aid of a microscope, PCR tests and gene expression analyzes.
The result: Treatment with interferon gamma resulted in the mucous membrane cells forming more ACE2 receptors on their surface. If these cells came into contact with Sars-CoV-2, they were more susceptible to infection and, in tests after 24 and 48 hours, their viral load was significantly higher than with untreated organoids. The infection also caused the cells to produce even more ACE2 receptors, which made it easier for the viruses to penetrate. “These data suggest that infection-related inflammation can create a vulnerable condition, which in turn enables massive virus replication and release. This can have consequences for the clinical course of the disease and for virus transmission, ”the researchers conclude.
More research needed
While doctors originally assumed that severe courses of Sars-CoV-2 mainly affect patients with a weakened immune system, it has now been found that particularly severe courses are often accompanied by particularly strong immune responses. “We assume that a strong immune response can increase the susceptibility of mucous membrane cells to SARS-CoV-2,” says Heuberger’s colleague Michael Sigal. “If the interferon-gamma concentration is higher from the start or if the infection triggers a very excessive production of interferon-gamma, it is likely that the viruses will have an easier time penetrating the cells.”
However, the conditions under which this actually happens must first be investigated in clinical studies. A detailed analysis of the mechanisms underlying the interferon gamma response could even lead to new treatment approaches. “One possible strategy could be to balance the interferon gamma response with drugs,” says Heuberger.
Source: Julian Heuberger (Charité – Universitätsmedizin Berlin) et al., EMBO Molecular Medicine, doi: 10.15252 / emmm.202013191