My watch list


How the immune system paves the way for SARS-CoV-2

SARS-CoV-2 uses an immune system defense mechanism as a port of entry

© Sigal Lab, Charité/MDC

Intestinal organoids: After treatment with IFN-ƴ, the intestinal cells differentiate. The cell nuclei (blue) of the epithelial cells (green) localize at the basal (outer) edge of the organoids. This is accompanied by an increased production of the ACE2 receptor, which SARS-CoV-2 uses as a port of entry into the cells

22-Feb-2021: The immune system actually wants to fight SARS-CoV-2 with antiviral signaling molecules. But a research team from Charité and MDC has now shown how such a signaling molecule can promote the replication of the virus.

Most people infected with SARS-CoV-2 are able to recover from the disease at home – even if they might experience very stressful disease progressions. Some have no symptoms at all. But about ten percent of those affected become so severely ill that they have to be treated in a hospital. The assumption that a weak immune system is behind a severe progression is short-sighted. Especially with critical progressions, the immune system works under intense pressure, but does not manage to control the virus.

A Berlin research group has now observed how SARS-CoV-2 uses an immune system defense mechanism to increasingly hijack the body’s mucous membrane cells and multiply there. Their study has just appeared in the journal EMBO Molecular Medicine. “This may give us part of the explanation as to why the immune system has difficulty regulating or even defeating the infection in some people,” says Dr. Julian Heuberger, scientist at the Division of Hepatology and Gastroenterology in Charité – Universitätsmedizin Berlin’s Medical Department. He is the first author of the study and a member of an Emmy Noether Research Group led by PD Dr. Michael Sigal at Charité and the Berlin Institute for Medical Systems Biology (BIMSB), part of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). For the study, the research group cooperated with researchers from the Max Planck Institute for Infection Biology (MPIIB), Freie Universität Berlin and Hong Kong University.

SARS-CoV-2 uses defense mechanism as a port of entry

Actually, the human body has a very effective defense mechanism against invaders, based on the interaction of various immune cells. T cells play an important role in this: When they encounter viruses in the organism, they destroy the affected cells. They also secrete the signaling molecule interferon-gamma (IFN-ƴ). On the one hand, IFN-ƴ fights infectious agents. On the other hand, it calls other immune cells to the scene.

Heuberger and his colleagues have now shown how SARS-CoV-2 can turn this protective mechanism mediated by IFN-ƴ into its opposite. For in addition to immune cells, the body’s mucous membrane cells also respond to IFN-ƴ by forming more ACE2 receptors. SARS-CoV-2 needs these ACE2 receptors as a port of entry into the cells. Infected cells, in turn, make more ACE2. In this way, both the IFN-ƴ response of epithelial cells and the virus itself intensify the SARS-CoV-2 infection.

Cell differentiation observed in colon organoids

Patients infected with SARS-CoV-2 sometimes show gastrointestinal symptoms. In order to observe the immune cascade in the intestinal cells, Heuberger cultivated organoids of the human colon. An organoid is a kind of mini-organ in a petri dish, barely the size of a pinhead. The colon organoids are based on cells that come from intestinal biopsies. They grow in three-dimensionally arranged units and replicate the physiology of mucous membrane cells in the human intestinal tract. “These colon organoids are a very helpful tool,” Heuberger emphasizes. “We can use them to explore the complex interplay of different signaling pathways that control cell differentiation from stem cells to specialized epithelial cells.”

The scientists first treated the cultured intestinal cells with IFN-ƴ to simulate the body’s immune response. Then they infected the organoids with SARS-CoV-2. Using gene expression analysis and a laser scanning microscope – a special optical microscope that scans a sample point by point – they were able to measure increased ACE2 expression in the organoids. In addition, quantitative polymerase chain reaction (PCR) detected increased virus production.

In other words, more IFN-ƴ means more ACE2. More ACE2 means more viruses can enter the cells. The more viruses that enter the cells, the more viruses produced. Thus, the immune response and the surface cell response to infection pave the way for SARS-CoV-2.

Balancing an excessive IFN-ƴ response with medication

“We hypothesize that a strong immune response may increase the susceptibility of mucous membrane cells to SARS-CoV-2,” says the head of the study, Dr. Michael Sigal. He directs the Gastrointestinal Barrier, Regeneration and Carcinogenesis Lab at Charité and the MDC and is a gastroenterologist at Charité. “If the IFN-ƴ concentration is higher from the outset or the infection triggers a very excessive production of IFN-y, the viruses probably have an easier time entering the cells.” However, the conditions under which this actually happens must still be investigated in clinical trials.

The results of the study carry the idea of a treatment approach for severe COVID-19 courses, Heuberger feels: “One possible strategy could be to balance the IFN-ƴ response with drugs.” However, this would first require a very detailed analysis of the mechanisms underlying the IFN-ƴ response.

Original publication:
Julian Heuberger et al.; "Epithelial response to IFN-γ promotes SARS-CoV-2 infection"; EMBO Molecular Medicine; 2021

Facts, background information, dossiers

  • SARS-CoV-2
  • immune system
  • coronaviruses
  • T cells
  • immune cells
  • organoids

More about MDC

  • News

    How cells move and don’t get stuck

    Theoretical physicists from Berlin teamed up with experimental physicists from Munich to determine the precise mechanics involved in cell motility. Cell velocity, or how fast a cell moves, is known to depend on how sticky the surface is beneath it, but the precise mechanisms of this relatio ... more

    A potent weapon against lymphomas

    MDC researchers have developed a new approach to CAR T-cell therapy. The team has shown in Nature Communications that the procedure is very effective, especially when it comes to fighting follicular lymphomas and chronic lymphocytic leukemia, the most common type of blood cancer in adults. ... more

    Getting to the heart of an enzyme

    A team led by Oliver Daumke at the MDC has determined the three-dimensional structure of the NatC acetyltransferase in an article published in Nature Communications. This enzyme modifies cell proteins to enable them to perform their functions correctly. In cancer cells, however, NatC is oft ... more

More about Charité

  • News

    How SARS-CoV-2 reaches the brain

    Using post-mortem tissue samples, a team of researchers from Charité – Universitätsmedizin Berlin have studied the mechanisms by which the novel coronavirus can reach the brains of patients with COVID-19, and how the immune system responds to the virus once it does. The results, which show ... more

    Highly effective antibodies against the coronavirus were identified

    Researchers at the German Center for Neurodegenerative Diseases (DZNE) and Charité - Universitätsmedizin Berlin have identified highly effective antibodies against the coronavirus SARS-CoV-2 and are now pursuing the development of a passive vaccination. In this process, they have also disco ... more

    Could the blood of COVID-19 patients be used to predict disease progression?

    Researchers from Charité – Universitätsmedizin Berlin and the Francis Crick Institute have identified 27 proteins which are present at different levels in the blood of COVID-19 patients, depending on the severity of their symptoms. These biomarker profiles could be used to predict disease p ... more

q&more – the networking platform for quality excellence in lab and process

The q&more concept is to increase the visibility of recent research and innovative solutions, and support the exchange of knowledge. In the broad spectrum of subjects covered, the focus is on achieving maximum quality in highly innovative sectors. As a modern knowledge platform, q&more offers market participants one-of-a-kind networking opportunities. Cutting-edge research is presented by authors of international repute. Attractively presented in a high-quality context, and published in German and English, the original articles introduce new concepts and highlight unconventional solution strategies.

> more about q&more

q&more is supported by:


Your browser is not current. Microsoft Internet Explorer 6.0 does not support some functions on Chemie.DE