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 Centre for Neurodegenerative Diseases (DZNE), the Helmholtz Centre for Infection Research (HZI) and the German Centre for Infection Research (DZIF), along with colleagues from a nationwide research network, presented these findings.
Most patients infected with the coronavirus SARS-CoV-2 show mild or even no symptoms. However, 10% to 20% of those affected develop pneumonia during the course of COVID-19 disease, some of them with life-threatening effects. "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 tend to indicate an ineffective immune response. This is a contradiction," says Joachim Schultze, professor at the University of Bonn and research group leader at the DZNE.
"We therefore assume that although immune cells are produced in large quantities, their function is defective. That is why we examined the blood of patients with varying degrees of COVID-19 severity," explains Leif Erik Sander, professor of infection immunology and senior physician 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) – resulting in the analysis and interpretation of the data being spread across various teams and sites. Joachim Schultze was significantly involved in coordinating the project. The blood samples came 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 Organisation classification. Blood samples from patients with other viral respiratory tract infections as well as from healthy individuals served as important controls.
The investigations involved the use of single-cell OMICs technologies, a collective term for modern laboratory methods that can be used to determine, for example, the gene activity and the amount of proteins on the level of single, individual cells – thus with very high resolution. Using this data, the scientists characterised the properties of immune cells circulating in the blood – so-called white blood cells.
"By applying bioinformatics methods on this extremely comprehensive data collection of the gene activity of each individual cell, we could gain a comprehensive insight of the ongoing processes in the white blood cells," explains Yang Li, professor at the Centre for Individualised Infection Medicine (CiiM) and Helmholtz Centre for Infection Research (HZI) in Hannover. "In combination with the observation of important proteins on the surface of immune cells, we were able to decipher the changes in the immune system of patients with COVID-19," adds Birgit Sawitzki, professor at the Institute of Medical Immunology on Campus Virchow-Klinikum.
The human immune system comprises a broad arsenal of cells and other defence mechanisms that interact with each other. In the current study, the focus was on so-called myeloid cells, which include neutrophils and monocytes. These are immune cells that are at the very front of the immune response chain – they are mobilised at a very early stage to defend against infections. They also influence the later formation of antibodies and other cells that contribute to immunity. This gives the myeloid cells a key position.
"With the so-called neutrophils and the monocytes we have found that these immune cells are activated – 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 Antoine-Emmanuel Saliba, head of a research group at the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg.
But the situation is different in severe cases of COVID-19, explains 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." Sander adds: "The phenomenon can also be observed in other severe infections, although the reason for this is unclear. Many indications suggest that the immune system stands in its own way during severe courses of COVID-19. This could possibly lead to an insufficient immune response against the corona virus, with a simultaneous severe inflammation in the lung tissue."
The current findings could point to new therapeutic options, says Anna Aschenbrenner from 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 actually want to suppress the immune system. "If, however, there are too many dysfunctional immune cells, as our study shows, then one would very much like to suppress or reprogram such cells."
Jacob Nattermann, professor at the Medical Clinic I of the University Hospital Bonn and head of a research group at the DZIF, further explains: "Drugs that act on the immune system might be able to help. But this is a delicate balancing act. After all, it's 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. Possibly we can learn from cancer research. There is experience with therapies that target these cells."
In view of the many people involved, Schultze emphasises 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 data. The parallel analysis of two independent patient cohorts is one of the strengths of our study.
We analysed 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 openly shared and cooperation is based on trust. This is extremely important, especially in the current crisis situation."
Coronavirus Disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, 64 however, a subset of patients progresses to severe disease and respiratory failure. The 65 mechanism of protective immunity in mild forms and the pathogenesis of severe COVID-19, 66 associated with increased neutrophil counts and dysregulated immune responses, remains 67 unclear. In a dual-center, two-cohort study, we combined single-cell RNA-sequencing and 68 single-cell proteomics of whole blood and peripheral blood mononuclear cells to determine 69 changes in immune cell composition and activation in mild vs. severe COVID-19 (242 samples from 109 individuals) over time. HLA-DRhiCD11chi 70 inflammatory monocytes with an 71 interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 72 was marked by occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, dysfunctional mature neutrophils, and HLA-DRlo 73 monocytes. Our study 74 provides detailed insights into the systemic immune response to SARS-CoV-2 infection and 75 it reveals profound alterations in the myeloid cell compartment associated with severe 76 COVID-19.
Jonas Schulte-Schrepping, Nico Reusch, Daniela Paclik, Kevin Baßler, Stephan Schlickeiser, Bowen Zhang, Benjamin Krämer, Tobias Krammer, Sophia Brumhard, Lorenzo Bonaguro, Elena De Domenico, Daniel Wendisch, Martin Grasshoff, Theodore S Kapellos, Michael Beckstette, Tal Pecht, Adem Saglam, Oliver Dietrich, Henrik E Mei, Axel R Schulz, Claudia Conrad, Désirée Kunkel, Ehsan Vafadarnejad, Cheng-Jian Xu, Arik Horne, Miriam Herbert, Anna Drews, Charlotte Thibeault, Moritz Pfeiffer, Stefan Hippenstiel, Andreas Hocke, Holger Müller-Redetzky, Katrin-Moira Heim, Felix Machleidt, Alexander Uhrig, Laure Bosquillon de Jarcy, Linda Jürgens, Miriam Stegemann, Christoph R. Glösenkamp, Hans-Dieter Volk, Christine Goffinet, Markus Landthaler, Emanuel Wyler, Philipp Georg, Maria Schneider, Chantip Dang-Heine, Nick Neuwinger, Kai Kappert, Rudolf Tauber, Victor Corman, Jan Raabe, Kim Melanie Kaiser, Michael To Vinh, Gereon Rieke, Christian Meisel, Thomas Ulas, Matthias Becker, Robert Geffers, Martin Witzenrath, Christian Drosten, Norbert Suttorp, Christof von Kalle, Florian Kurth, Kristian Händler, Joachim L Schultze, Anna C. Aschenbrenner, Yang Li, Jacob Nattermann, Birgit Sawitzki, Antoine-Emmanuel Saliba, Leif Erik Sander
[link url="https://www.dzne.de/en/news/press-releases/press/covid-19-immune-system-derails"]DZNE – German Center for Neurodegenerative Diseases material[/link]
[link url="https://www.cell.com/cell/pdf/S0092-8674(20)30992-2.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867420309922%3Fshowall%3Dtrue"]Cell abstract (preproo)[/link]