Caught in the loop

How COVID-19 leads the immune system astray

Contrary to what has been generally assumed so far, a severe course of COVID-19 does not solely result in a strong immune reaction – rather, the immune response is caught in a continuous loop of activation and inhibition.

Experts from Charité – Universitätsmedizin Berlin, the University of Bonn, the German Center for Neurodegenerative Diseases (DZNE), the Helmholtz Centre for Infection Research (HZI) and the German Center for Infection Research (DZIF), along with colleagues from a nationwide research network, present these findings in the scientific journal Cell.

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Image source: NIH Image Gallery from Bethesda, Maryland, USA, Novel Coronavirus SARS-CoV-2 (49919836457), marked as public domain, details at Wikimedia Commons

Most patients infected with the novel coronavirus SARS-CoV-2 show mild or even no symptoms. However, 10 to 20 percent of patients develop pneumonia during the course of COVID-19 disease, some of them with life-threatening consequences. "There is still not very much known about the causes of these severe courses of the disease. The high inflammation levels measured in those affected actually indicate a strong immune response. Clinical findings, however, rather indicate an ineffective immune response. This is a contradiction," says Prof. Dr. Joachim Schultze of the University of Bonn and the DZNE. "We therefore assumed that immune cells are produced in large quantities, but that their function is defective. Therefore, we analyzed the blood of patients with varying degrees of COVID-19 severity," explains Leif Erik Sander of Charité’s Medical Department, Division of Infectious Diseases and Respiratory Medicine.

The study was carried out within the framework of a nationwide consortium - the "German COVID-19 OMICS Initiative" (DeCOI) - meaning that the analysis and interpretation of the data was spread across various teams and sites. Prof. Schultze was centrally involved in coordinating the project. The blood samples were derived from a total of 53 men and women with COVID-19 from Berlin and Bonn, whose course of disease was classified as mild or severe according to the World Health Organization classification. Blood samples from patients with other viral respiratory tract infections as well as from healthy individuals served as important controls.

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The investigations involved the use of single-cell OMICs technologies, a collective term for modern laboratory methods used to determine, for example, the gene activity and the amount of proteins on the level of individual cells – thus with very high resolution. Using this data, the scientists characterized the properties of immune cells in the blood – so-called white blood cells. "Applying bioinformatics methods to this very extensive data set of the gene activities of each individual cell, allowed us to gain a comprehensive view of the activities of white blood cells," explains Prof. Dr. Yang Li of the Centre for Individualised Infection Medicine (CiiM) and Helmholtz Centre for Infection Research (HZI) in Hannover. "Combining sequencing with the detection of important proteins on the surface of the immune cells, allowed us to decipher the changes in the immune system of patients with COVID-19," adds Prof. Dr. Birgit Sawitzki of the Institute of Medical Immunology on Campus Virchow-Klinikum.

The human immune system comprises a broad arsenal of cells and other defense mechanisms that closely interact with each other. The current study focused on so-called myeloid cells, which include neutrophils and monocytes. These are immune cells that are at the forefront of the immune response, i.e. they are mobilized at a very early stage to defend against infections. These cells also impact subsequent responses including formation of antibodies and other cells that contribute to immunity, placing the myeloid cells in a key position. "We found that neutrophils and monocytes were activated, i.e. ready to defend the patient against COVID-19 in the case of mild disease courses. They are also programmed to activate the rest of the immune system. This ultimately leads to an effective immune response against the virus," explains Dr. Antoine-Emmanuel Saliba of the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg.

It is not a matter of shutting down the immune system completely, but only those cells that slow down themselves

Jacob Nattermann

In contrast, the situation is different in severe cases of COVID-19, explains Prof. Sawitzki: "Here, neutrophils and monocytes are only partially activated and they do not function properly. We find considerably more immature cells that have a rather inhibitory effect on the immune response." Prof. Sander adds: "This phenomenon can also be observed in other severe infections, although the reason for this is unclear. The findings indicate that the immune system stands in its own way during severe courses of COVID-19. This possibly leads to an insufficient immune response against the coronavirus, while severe inflammation in the lung tissue proceeds.“

The current findings could point to new therapeutic options, says Dr. Anna Aschenbrenner of the LIMES Institute at the University of Bonn: "Our data suggest that in severe cases of COVID-19, strategies should be considered that go beyond the treatment of other viral diseases." The Bonn researcher says that in the case of viral infections one does not normally aim to suppress the immune system. "In the case of excessive dysfunctional immune cells, as our study shows, one would however very much wish to suppress or reprogram such cells." Prof. Dr. Jacob Nattermann of the Medical Clinic I of the University Hospital Bonn and the DZIF, further explains: "Drugs that act on the immune system might be helpful. But this is a delicate balancing act. After all, it is not a matter of shutting down the immune system completely, but only those cells that slow down themselves, so to speak. In this case, these are the immature cells. We can possibly learn from cancer research. There is experience with therapies that target these cells."

 In view of the many people involved, Prof. Schultze emphasizes the cooperation within the research consortium: "As far as we know, this study is one of the most comprehensive studies to date on the immune response in COVID-19 based on single cell analysis. The parallel analysis of two independent patient cohorts is one of the strengths of our study. We analyzed patient cohorts from two different sites using different methods and were thus able to validate our findings directly. This is only possible if research data is shared openly, and cooperation is based on trust. This is extremely important, especially in the current crisis. “


Source: Charité – Universitätsmedizin Berlin

07.08.2020

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