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

The immune system actually wants to fight SARS-CoV-2 with antiviral messengers. A research team from Charité – Universitätsmedizin Berlin and the Max Delbrück Centre for Molecular Medicine in the Helmholtz Association (MDC) has now shown how such a messenger can promote the replication of the virus. The results have been published in the journal EMBO Molecular Medicine*.

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Most people infected with SARS-CoV-2 are able to cure the disease at home – even though they experience very stressful courses of the disease. Some have no symptoms at all. But about ten percent of those affected are so severely ill that they have to be treated in hospital. The assumption that a weak immune system is behind a severe course of the disease is inadequate. Especially in critical courses, the immune system works under high pressure but does not manage to control the virus.

A Berlin research group has now been able to observe how SARS-CoV-2 uses a defence mechanism of the immune system to increasingly hijack mucosal cells of the body and multiply there. „This may give us part of the explanation for why, in some people, the immune system has difficulty regulating or even defeating the infection,“ says Julian Heuberger, M.D., a scientist at Charité’s Department of Medicine with a focus on hepatology and gastroenterology. He is first author of the study and a member of the Emmy Noether research group led by Dr. Michael Sigal at Charité and the Berlin Institute for Medical Systems Biology (BIMSB), which is part of the MDC. For the study, the research group cooperated with researchers from the Max Planck Institute for Infection Biology, Free University Berlin and the University of Hong Kong.

Actually, a very effective defence programme against invaders runs in the human body, based on the interaction of various immune cells. The T cells play an important role in this: When they encounter viruses in the organism, they destroy the affected cells. They also secrete the messenger substance interferon-gamma (IFN-γ). On the one hand, IFN-γ fights infective germs. On the other hand, it calls other immune cells to the scene.

Dr. Heuberger and his colleagues have now shown how SARS-CoV-2 can turn this IFN-γ-mediated protective mechanism into its opposite. This is because, in addition to immune cells, the body’s mucosal cells (epithelial cells) also respond to IFN-γ by forming more ACE2 receptors. SARS-CoV-2 requires these ACE2 receptors as an entry port into the cells. Infected cells, in turn, make more ACE2. Thus, both the IFN-γ response of epithelial cells and the virus itself cause increased SARS-CoV-2 infection.

SARS-CoV-2-infected patients sometimes show gastrointestinal symptoms. In order to be able to observe the immune cascade in the intestinal cells, Dr. Heuberger has 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 derived from intestinal biopsies. They grow in three-dimensionally arranged units and replicate the physiology of the mucosal cells of the human intestinal tract. „These colon organoids are a very helpful tool,“ Dr. Heuberger emphasizes, „we can use them to explore the complex interplay of different signalling 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 a laser scanning microscope – a special light microscope that scans a sample point by point – and gene expression analyses, they were able to measure increased ACE2 expression in the organoids. In addition, quantitative 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 are produced. Thus, the immune response and the mucosal cell response to infection pave the way for SARS-CoV-2.

„We hypothesize that a strong immune response may increase the susceptibility of mucosal cells to SARS-CoV-2,“ says the study’s principal investigator, Dr. Sigal, PhD. He leads a research group at Charité and MDC and is a gastroenterologist at Charité. „If the IFN-γ concentration is higher in the first place or the infection triggers a very excessive production of IFN-γ, the viruses probably have an easier time entering the cells.“ The conditions under which this actually happens, however, remain to be investigated in clinical trials. The results of the study carry the idea of a treatment approach for severe COVID-19 courses, says Dr. Heuberger: „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.

*Heuberger J et al., Epithelial response to IFN-γ promotes SARS-CoV-2 infection. EMBO Mol Med 2021 Feb 5. doi: 10.15252/emmm.202013191

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