Research and other activities on COVID-19 and SARS-CoV-2

At the start of the vaccination campaign against SARS-CoV-2, there were no data on how this vaccination works in immunocompromised patients with chronic inflammatory diseases, what adverse effects could occur, and whether the vaccination can possibly lead to new flares of inflammation. A Kiel research team from the Cluster of Excellence "Precision Medicine in Chronic Inflammation" (PMI) has investigated this and published their results now in the scientific journal "Annals of the Rheumatic Diseases". The researchers show for the first time worldwide that the new mRNA vaccines against COVID-19 are effective and well tolerated for people with chronic inflammatory diseases and undergoing immunosuppressive therapy.

Participants and cooperations:

Prof. Bimba Hoyer (senior author) und Dr. Ulf Geisen (first author), Comprehensive Center for Inflammation Medicine at the University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Prof. Stefan Schreiber, Director of the Institute of Clinical Molecular Biology (IKMB), Kiel University and UKSH, Director of the Department of Internal Medicine I of the UKSH, Campus Kiel.

Original publication:

Ulf Geisen, ..., Stefan Schreiber*, Bimba F. Hoyer*: Immunogenicity and Safety of anti-SARS-CoV-2 mRNA Vaccines in Patients with Chronic Inflammatory Conditions and Immunosuppressive Therapy in a Monocentric Cohort. Annals of the Rheumatic diseases (2021). http://dx.doi.org/10.1136/annrheumdis-2021-220272
* These authors contributed equally.

More information:

COVID-19: mRNA vaccination is safe and effective even with chronic inflammatory diseases (press information March 23rd, 2021)

COVID-19 can progress very differently, from symptom-free right through to life-threatening, and severe cases particularly occur in older patients. The reasons for this are unclear. Before the appearance of the novel coronavirus SARS-CoV-2, many people had already been exposed to other coronaviruses, such as those which cause the common cold. Therefore, the hypothesis arose that these prior exposures could possibly afford better immune protection, even against infection with SARS-CoV-2. Members of the Cluster of Excellence "Precision Medicine in Chronic Inflammation" (PMI) in Kiel have investigated this hypothesis. They were able to show that people who have not yet been infected with SARS-CoV-2 do in fact have specific immune cells, so-called memory T cells, which can also recognize SARS-CoV-2 as a foreign body. However, these "pre-existing" memory T cells do not appear to be particularly good at recognizing and fighting a SARS-CoV-2 infection, because they only bind to the virus very weakly. Instead, these memory cells could in fact contribute to a more severe disease progression.

Participants and cooperations:

Several cluster members from the Institute of Immunology and the Institute of Clinical Molecular Biology (IKMB) at Kiel University (CAU) and University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, are involved in the work, around Prof. Petra Bacher (first author), SH-Chair Junior Research Group Leader "Intestinal Immune Regulation", and Prof. Alexander Scheffold (senior author), Director of the Institute of Immunology, CAU & UKSH. The work was developed in cooperation with the research groups of Oliver Cornely and Philipp Köhler at University Hospital Cologne and Maria Vehreschild at University Hospital Frankfurt, as well as the research groups of Andre Franke and Philipp Rosenstiel at the Institute of Clinical Molecular Biology, CAU & UKSH.

Original publication:

Bacher et al.: Low avidity CD4+ T cell responses to SARS-CoV-2 in unexposed individuals and humans with severe COVID-19. Immunity (2020).  DOI: 10.1016/j.immuni.2020.11.016 

More information:

• COVID-19: contact with cold viruses apparently offers no protection (press information Nov. 30th, 2020)
• Protection against COVID-19: experience is not always an advantage for the immune response (press information Aug 12th, 2022)

In severe cases of COVID-19 disease, not only classic immune cells play a role. In particular, the release of immature precursor cells from the bone marrow into the blood indicates a particularly severe course of the disease and could contribute to complications. This has been shown by an international research team involving the DFG Cluster of Excellence "Precision Medicine in Chronic Inflammation" (PMI).

Participants and cooperations:

Several cluster members from the Institute for Clinical Molecular Biology (IKMB), the Christian-Albrechts-University of Kiel (CAU) and the University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, around Prof. Phililp Rosenstiel, are involved in the work. The work was developed in cooperation with the Universities of Bonn, Cologne, Lübeck, Tübingen and Nijmegen as well as the Research Center Borstel - Leibniz Lung Center and the German Center for Neurodegenerative Diseases (DZNE). The study was made possible by the nationwide consortium, the "German COVID-19 OMICS Initiative" (DeCOI), and was developed in cooperation with partners from the "Human Cell Atlas", an international consortium for single cell analysis.

Original publication:

J.P. Bernardes*, N. Mishra*, F. Tran* et al: Longitudinal multi-omics analyses identify responses of megakaryocytes, erythroid cells and plasmablasts as hallmarks of severe COVID-19 trajectories. Immunity (2020). doi.org/10.1016/j.immuni.2020.11.017   *These authors contributed equally.

More information:

COVID-19: Release of immature blood cells from bone marrow as a signature of severe disease (press information Nov. 27th, 2020)

Severe courses of COVID-19 are characterized by a massive inflammatory reaction in the body, which can ultimately lead to multi-organ failure. In epithelial cells of the respiratory tract of symptomatic COVID-19 patients, researchers from the Department of Internal Medicine IV, UKSH, Campus Kiel, have identified a possible trigger of this excessive immune response. They were able to show that a specific protein, the receptor-interacting serine/threonine protein kinase 1 (RIPK1), which leads to regulated cell death, is activated in COVID-19 patients. In the further course of the study, the participants were able to demonstrate in a clinically relevant animal model that the drug primidone significantly inhibits this activation of RIPK1 and thus the excessive immune response. Since primidone is a drug that has been approved and safe for decades, clinical trials can now be conducted directly to test its therapeutic efficacy in the setting of severe SARS-CoV-2 infection.

Participants and cooperations:

Cluster members Prof. Ulrich Kunzendorf, Director of the Department of Internal Medicine IV, and Prof. Stefan Krautwald, Head of the Research Laboratory of the Department of Internal Medicine IV, UKSH, Kiel Campus, were involved in the study. The work was made possible in part by funding from the German Research Foundation (DFG). It was also carried out in cooperation with the universities of Göttingen, Munich and Essen as well as the research group of Prof. Pascal Meier (Institute of Cancer Research, London, UK).

Original publication:

Riebeling et al.: Primidone blocks RIPK1-driven cell death and inflammation. Cell Death Differ. (2020). DOI: 10.1038/s41418-020-00690-y

The SARS-CoV-2 virus can also penetrate and damage the so-called beta cells in the pancreas, as a research team involving the Cluster of Excellence "Precision Medicine in Chronic Inflammation" has now observed for the first time. These cells are responsible for producing the insulin necessary for a healthy metabolism. Professor Matthias Laudes, Schleswig-Holstein Excellence-Chair for Endocrinology, Diabetology and Clinical Nutrition at the Kiel University (CAU), and his research team from the Clinic for Internal Medicine I of the University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, together with researchers from Munich and Dresden, published the first case report of insulin deficiency diabetes after COVID-19 disease in Nature Metabolism.

Participants and cooperations:

First authors: Dr. Tim Hollstein, Clinic for Internal Medicine I, UKSH, Campus Kiel, and Prof. Dominik M. Schulte, SH-Chair Junior Research Group Leader, CAU. Senior Author: Prof. Matthias Laudes, SH-Chair for Endocrinology, Diabetology and Clinical Nutrition, CAU. The work was done in cooperation with Prof. Stefan Bornstein from the University Hospital Dresden and Prof. Anette-Gabriele Ziegler from HelmholtzZentrum München.

Original publication and more information:

• Tim Hollstein* Dominik M. Schulte*, Juliane Schulz, Andreas Glück, Anette G. Ziegler, Ezio Bonifacio, Mareike Wendorff, Andre Franke, Stefan Schreiber, Stefan R. Bornstein und Matthias Laudes: Autoantibody-negative Insulin-dependent Diabetes Mellitus after SARS-CoV-2 infection: a case report. Nat Metab (2020). DOI: 10.1038/s42255-020-00281-8  *these authours contributed equally.
• press release: Diabetes as a consequence of COVID-19

Although COVID-19 mostly affects the respiratory tract or the lungs, during the acute stage it already also affects many other organ systems. In light of the severity of the attack on the organs in some cases, it can be expected that there might also be long-term damage to these organs. A clinical research team at Kiel University (CAU), the University of Lübeck (UzL) and the University Medical Center Schleswig-Holstein (UKSH), under the leadership of cluster spokesperson Prof. Stefan Schreiber, would like to investigate these consequences in a new study on patients infected with SARS-CoV-2 in Schleswig-Holstein.

Participants and cooperations:

COVIDOM is being carried out at the University Medical Center Schleswig-Holstein (UKSH) as well as at Kiel University and the University of Lübeck. The UKSH plays a leading role. Prof. Stefan Schreiber is heading the study. He is the Director of the Department of Internal Medicine I at the UKSH, Campus Kiel, and the Director of the Institute of Clinical Molecular Biology (IKMB), CAU and UKSH.

More information:

• Study website covidom.de
• Initial findings from the COVIDOM study on the long-term effects of COVID-19 (press information July 18th, 2022)

The large-scale study "ELISA" provides information about the actual spread of the novel coronavirus. In particular, it should investigate to what extent the measures for curbing the virus and their relaxation affect the further spread of SARS-CoV-2. Key activities include the generation of health data as well as testing for current and past SARS-CoV-2 infections in selected groups.

Participants and cooperations:

• Prof. Dr. Christine Klein (PMI), Prof. Dr. Katalinic, Prof. Dr. Jan Rupp (PMI) (scientific director of the study)
• The study is a collaboration between the University of Lübeck, the University Medical Center Schleswig-Holstein in the framework of the COVID-19 Research Initiative Schleswig-Holstein, and the local health authorities in Lübeck.
• The study includes scientists from the University of Lübeck and Kiel University, the University Medical Center Schleswig-Holstein and the Research Center Borstel - Leibniz Lung Center (FZB, Borstel).

The University Hospital Schleswig-Holstein (UKSH), Campus Kiel, is conducting a study on the efficacy of a molecular nutritional intervention in SARS-CoV-2 positive patients with symptoms. The aim is to stabilize mild disease, accelerate recovery and reduce the number of severe courses. To this end, the nutritional status of patients is specifically optimized with regard to nicotinamide (vitamin B3). Participation in the study is possible nationwide from home.

Participants and cooperations:

The COVit trial is headed by Prof. Dr. Stefan Schreiber and Prof. Dr. Matthias Laudes and conducted by the Department of Internal Medicine I of the UKSH (Campus Kiel) together with the Competence Network Intestinal Diseases.

Why do some people become seriously ill with COVID-19 while others hardly show any symptoms? In the world's first large-scale genetic study, scientists at the University Medical Center Schleswig-Holstein (UKSH) and Kiel University (CAU), in cooperation with a working group from Norway, have found gene variants which significantly impact the progression of the disease – one of them affects the gene for the blood group attribute. The work was published in the New England Journal of Medicine and has gained significant media attention world-wide.

Participants and cooperations:

Prof. Andre Franke (senior author), Director at the Institute of Clinical Molecular Biology (IKMB) at the CAU and the UKSH, Dr. Frauke Degenhardt (first author) and Prof. David Ellinghaus (first author), also from the IKMB, were all involved. Prof. Andre Franke led the research work together with the Norwegian specialist in internal medicine Prof. Tom Karlsen.

Original publication and more detailed information:

• David Ellinghaus & Frauke Degenhardt et al.: Genomewide Association Study of Severe Covid-19 with Respiratory Failure. NEJM (2020). DOI: 10.1056/NEJMoa2020283
• COVID-19: First large-scale genome-wide study on risk genes (press release on the study)

A group of international researchers in the fields of genetics and archaeology from Kiel and Cambridge, with the participation of the PMI member Dr. Michael Forster, has succeeded in tracing the origin and spread of the novel coronavirus (SARS-CoV-2), through the application of phylogenetic network analysis. The results published in the renowned scientific journal PNAS show that in the first phase of the outbreak in Europe and America, mainly other SARS-CoV-2 types (A, C) spread, instead of the type B predominant in Wuhan at that time. After independent validation by the working group led by Andrew Rambaut (Edinburgh), the classification of the virus types A and B is now also used in the official database GISAID.

Participants and cooperations:

Scientists Dr. Michael Forster, Institute of Clinical Molecular Biology (IKMB) at Kiel University (CAU) and the University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, and the team led by Dr. Peter Forster from the McDonald Institute for Archaeological Research at the University of Cambridge.

Original publication:

Peter Forster, Lucy Forster, Colin Renfrew, Michael Forster (2020): Phylogenetic network analysis of SARS-CoV-2 genomes. Proceedings of the National Academy of Sciences First published 08.04.2020. DOI: 10.1073/pnas.2004999117

Pharmacovigilance data are primarily used to identify adverse drug reactions. However, scanning for associations of drugs and adverse events that occur less frequently than expected provides hypotheses for drug-repurposing, i.e. a known drug could be therapeutically beneficial for a new indication like the coronavirus disease (COVID-19). Drugs associated with viral respiratory tract infections and/or influenza were extracted from the U.S. FAERS pharmacovigilance data using the pharmacovigilance tool OpenVigil2.1-MedDRA17, filtered for significant inverse associations, checked for plausibility, and grouped by their anatomical-therapeutic-chemical (ATC) classification.

Participants and cooperation:

• Böhm R, Bulin C, Waetzig V, Herdegen T, Cascorbi I, Institute of experimental und clinical pharmacology, Kiel University
• Klein HJ, Institute for informatics, Kiel University

The researchers have the goal of blocking the multiplication of coronaviruses through intervention in the biochemical processes of the host cells. They have been able to prove that inhibitors of the enzyme phospholipase A2α significantly reduce the reproduction of coronaviruses by disrupting the formation of the replicative cell organelles.

Participants and cooperation:

PD Dominik Schwudke, Bioanalytical Chemistry, Research Center Borstel (FZB)
Cooperation with Prof. John Ziebuhr, Medical Virology, Giessen University (JLU), and Dr. Christin Müller (DZIF - Cooperation)

Original publication:

Müller C, Hardt M, Schwudke D, Neuman BW, Pleschka S, Ziebuhr J.: Inhibition of Cytosolic Phospholipase A2α Impairs an Early Step of Coronavirus Replication in Cell Culture. J. of Virol. 2018 Jan 30;92(4):e01463-17. DOI: 10.1128/JVI.01463-17.

In this project, metabolic computer models are created of virus-infected cells, to determine which cellular changes related to aging determine the relationship between age and the severity of COVID-19. Using the sequencing data of individual cells, the researchers were able to show that the cells of older patients are less able to produce viruses. Based on this, they developed the hypothesis that SARS-CoV-2 counteracts this limitation of the viral replication ability in old age by recruiting specific immune cells, which activate cellular programs that promote viral replication, but thereby cause major damage to the lung tissue. Building on this, the research team wants to use computer models of infected cells in this project to identify specific enzymes which are highly important for viral replication, and inhibiting which offers a starting point for new treatment approaches, especially for severe progression of COVID-19.

Participants and cooperations:

Prof. Christoph Kaleta, Institute of Experimental Medicine/Medical Systems Biology, CAU In cooperation with Dr. Andreas Dräger & Alina Renz (University of Tübingen), Prof. Nathan Lewis & Dr. Chintan Joshi (University of California, San Diego).