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

February 16, 2021

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-γ). On the one hand, IFN-γ 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-γ into its opposite. For in addition to immune cells, the body's mucous membrane cells also respond to IFN-γ 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-γ 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-γ 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-γ 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-γ 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-γ 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-γ response with drugs." However, this would first require a very detailed analysis of the mechanisms underlying the IFN-γ response.
-end-
Contact

Dr. Michael Sigal
Head of the Gastrointestinal Barrier, Regeneration and Carcinogenesis Lab
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Charité - Universitätsmedizin Berlin
michael.sigal@mdc-berlin.de

The Max Delbrück Center for Molecular Medicine (MDC)

The Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) was founded in Berlin in 1992. It is named for the German-American physicist Max Delbrück, who was awarded the 1969 Nobel Prize in Physiology and Medicine. The MDC's mission is to study molecular mechanisms in order to understand the origins of disease and thus be able to diagnose, prevent, and fight it better and more effectively. In these efforts the MDC cooperates with Charité - Universitätsmedizin Berlin and the Berlin Institute of Health (BIH) as well as with national partners such as the German Center for Cardiovascular Research (DZHK) and numerous international research institutions. More than 1,600 staff and guests from nearly 60 countries work at the MDC, just under 1,300 of them in scientific research. The MDC is funded by the German Federal Ministry of Education and Research (90 percent) and the State of Berlin (10 percent), and is a member of the Helmholtz Association of German Research Centers. http://www.mdc-berlin.de

Max Delbrück Center for Molecular Medicine in the Helmholtz Association

Related Stem Cells Articles from Brightsurf:

SUTD researchers create heart cells from stem cells using 3D printing
SUTD researchers 3D printed a micro-scaled physical device to demonstrate a new level of control in the directed differentiation of stem cells, enhancing the production of cardiomyocytes.

More selective elimination of leukemia stem cells and blood stem cells
Hematopoietic stem cells from a healthy donor can help patients suffering from acute leukemia.

Computer simulations visualize how DNA is recognized to convert cells into stem cells
Researchers of the Hubrecht Institute (KNAW - The Netherlands) and the Max Planck Institute in Münster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells.

First events in stem cells becoming specialized cells needed for organ development
Cell biologists at the University of Toronto shed light on the very first step stem cells go through to turn into the specialized cells that make up organs.

Surprising research result: All immature cells can develop into stem cells
New sensational study conducted at the University of Copenhagen disproves traditional knowledge of stem cell development.

The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.

Healthy blood stem cells have as many DNA mutations as leukemic cells
Researchers from the Princess Máxima Center for Pediatric Oncology have shown that the number of mutations in healthy and leukemic blood stem cells does not differ.

New method grows brain cells from stem cells quickly and efficiently
Researchers at Lund University in Sweden have developed a faster method to generate functional brain cells, called astrocytes, from embryonic stem cells.

NUS researchers confine mature cells to turn them into stem cells
Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute at the National University of Singapore and the FIRC Institute of Molecular Oncology in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification -- by confining them to a defined geometric space for an extended period of time.

Researchers develop a new method for turning skin cells into pluripotent stem cells
Researchers at the University of Helsinki, Finland, and Karolinska Institutet, Sweden, have for the first time succeeded in converting human skin cells into pluripotent stem cells by activating the cell's own genes.

Read More: Stem Cells News and Stem Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.