Press releases

The research team led by Dr Valentina Puntmann and Professor Eike Nagel from University Hospital Frankfurt and Goethe University Frankfurt followed up around 350 study participants without previously known heart problems who had recovered from a SARS-CoV-2 infection. They found that over half of them still reported heart symptoms almost a year later, such as exercise intolerance, tachycardia and chest pain. According to the study, these symptoms can be attributed to mild but persistent cardiac inflammation. Pronounced structural heart disease is not a characteristic of the syndrome. (Nature Medicine, DOI 10.1038/s41591-022-02000-0).

FRANKFURT. After recovering from a SARS-CoV-2 infection, many people complain of persistent heart complaints, such as poor exercise tolerance, palpitations or chest pain, even if the infection was mild and there were no known heart problems in the past. Earlier studies, predominantly among young, physically fit individuals, were already able to show that mild cardiac inflammation can occur after COVID-19. However, the underlying cause of persistent symptoms, and whether this changes over time, was unknown. 

A team of medical scientists led by Dr Valentina Puntmann and Professor Eike Nagel from the Institute for Experimental and Translational Cardiovascular Imaging at University Hospital Frankfurt followed up 346 people – half of them women – between the age of 18 and 77 years, in each case around four and eleven months after the documented SARS-CoV-2 infection. For this purpose, the team analysed the study participants' blood, conducted heart MRIs, and recorded and graded their symptoms using standardised questionnaires. 

The result: 73 percent reported heart problems at the beginning of the study and in 57 percent these symptoms persisted 11 months after the SARS-CoV-2 infection. The research team measured mild but persistent heart inflammation that was not accompanied by structural changes in the heart. Blood levels of troponin – a protein that enters the blood when the heart muscle is damaged – were also unremarkable. 

Dr Puntmann, who led the Impression COVID&Heart Study, explains: “The patients' symptoms match our medical findings. It is important to note that although triggered by the SARS-CoV-2 virus, the post-COVID cardiac inflammatory involvement differs considerably from classic viral myocarditis. Extensive damage of the heart muscle leading to structural heart changes or impaired function are not characteristic at this stage of disease evolution." The clinical picture is more reminiscent, she says, of the findings in chronic diffuse inflammatory syndromes such as autoimmune conditions. “Although most likely driven by a virus-triggered autoimmune process, a lot more research is needed in order to understand the underlying pathophysiology. Similarly, the long-term effects of cardiac inflammation following a mild COVID infection need to be clarified in future studies." 

Because the study is restricted to a selected group of individuals who took part because they had symptoms, the prevalence of findings cannot be extrapolated to the population as a whole. Bayer AG, the German Heart Foundation and the German Centre for Cardiovascular Research supported the study. 

Publication: Valentina O. Puntmann, Simon Martin, Anastasia Shchendrygina, Jedrzej Hoffmann, Mame Madjiguène Ka, Eleni Giokoglu, Byambasuren Vanchin, Niels Holm, Argyro Karyou, Gerald S. Laux, Christophe Arendt, Philipp De Leuw, Kai Zacharowski, Yascha Khodamoradi, Maria J. G. T. Vehreschild, Gernot Rohde, Andreas M. Zeiher, Thomas J. Vogl, Carsten Schwenke, Eike Nagel Long-term cardiac pathology in individuals with mild initial COVID-19 illness. Nature Medicine (2022) https://www.nature.com/articles/s41591-022-02000-0 

Background: The heart after COVID-19 – Long-term damage from COVID-19 does not always heal without treatment (Forschung Frankfurt 1.2021) https://www.forschung-frankfurt.uni-frankfurt.de/108536066.pdf

Picture download: https://www.uni-frankfurt.de/124064044 

Caption: Visualisation of heart inflammation by means of MRI: cardiologist Dr Valentina Puntmann monitors a study participant at the Institute for Experimental and Translational Cardiovascular Imaging at University Hospital Frankfurt. 

Further information: 

Dr Valentina Puntmann
University Hospital Frankfurt / Goethe University Frankfurt
Institute for Experimental and Translational Cardiovascular Imaging
Email: cvi-info@kgu.de
https://www.cardiac-imaging.org/covid19-faq.html

Goethe University Frankfurt is currently hosting the first “EXPLORE" summer school, giving international students the opportunity to work on real astrophysical data.

FRANKFURT. They had to wait several months until their first “real" meeting could take place. Now they finally get to meet in person – 13 students from Frankfurt's partner city Toronto and 22 of their fellow students at Goethe University Frankfurt are joining a summer school on astrophysics. “It is very nice to finally have everyone come together. The students put so much effort in and came up with great results", says Prof. Laura Sagunski from the Institute for Theoretical Physics, who realised the project together with Prof. Jürgen Schaffner-Bielich and their colleagues at York University in Canada. Already during the last semester, the young people teamed up in self-organised groups to work on real physical data and research questions about Dark Matter. The innovative international teaching project called “EXPLORE: EXPeriential Learning Opportunity through Research and Exchange" enables them to learn about physics hands-on while also experiencing modern international research collaborations. Sagunski emphasizes: “By having them work together, we also want to strengthen the students' competences in intercultural communication and their ability to work in heterogeneous teams." 

On Monday, the first EXPLORE summer school was opened at the Frankfurt Institute for Advanced Studies on Campus Riedberg. Frankfurt's mayor Dr. Nargess Eskandari-Grünberg, who recently visited Toronto herself, welcomed the students warmly: “It is of special importance to me that Frankfurt will be further strengthened as a research location. In times where scientific findings are being questioned, it is particularly important that researchers communicate beyond borders. That young people from Toronto and Frankfurt conduct research on such an exciting topic together makes me especially happy." Next, Prof. Luciano Rezzolla gave a keynote on the first images of Black Holes. “It's great to see how motivated the young generation of scientists is," he says. “Therefore, I am delighted to be able to ideologically and financially support this project through the research cluster ELEMENTS." A week full of interesting workshops and talks awaits the students, accompanied by cultural and sportive activities: They will take a stand up paddling tour on the river Main as well as explore Frankfurt on a guided tour.

Further information:

Prof. Dr. Laura Sagunski
Institute for Theoretical Physics
Goethe University Frankfurt
+49 69 798 47888
sagunski@itp.uni-frankfurt.de

https://astro.uni-frankfurt.de/innovative-teaching/

Picture download: https://www.uni-frankfurt.de/123514666

Caption: Frankfurt's mayor Dr. Nargess Eskandari-Grünberg and organiser Prof. Laura Sagunski from Goethe University (front middle) with participants and lecturers of the EXPLORE summer school (Photo: Uwe Dettmar)

T cells are our immune system's customised tools for fighting infectious diseases and tumour cells. On their surface, these special white blood cells carry a receptor that recognises antigens. With the help of cryo-electron microscopy, biochemists and structural biologists from Goethe University Frankfurt, in collaboration the University of Oxford and the Max Planck Institute of Biophysics, were able to visualise the whole T-cell receptor complex with bound antigen at atomic resolution for the first time. Thereby they helped to understand a fundamental process which may pave the way for novel therapeutic approaches targeting severe diseases.

FRANKFURT. The immune system of vertebrates is a powerful weapon against external pathogens and cancerous cells. T cells play a curcial role in this context. They carry a special receptor called the T-cell receptor on their surface that recognises antigens – small protein fragments of bacteria, viruses and infected or cancerous body cells – which are presented by specialised immune complexes. The T-cell receptor is thus largely responsible for distinguishing between “self" and “foreign". After binding of a suitable antigen to the receptor, a signalling pathway is triggered inside the T cell that “arms" the cell for the respective task. However, how this signalling pathway is activated has remained a mystery until now – despite the fact that the T-cell receptor is one of the most extensively studied receptor protein complexes.

Many surface receptors relay signals into the interior of the cell by changing their spatial structure after ligand binding. This mechanism was so far assumed to also pertain to the T-cell receptor. Researchers led by Lukas Sušac, Christoph Thomas, and Robert Tampé from the Institute of Biochemistry at Goethe University Frankfurt, in collaboration with Simon Davis from the University of Oxford and Gerhard Hummer from the Max Planck Institute of Biophysics, have now succeeded for the first time in visualizing the structure of a membrane-bound T-cell receptor complex with bound antigen. A comparison of the antigen-bound structure captured using cryo-electron microscopy with that of a receptor without antigen provides the first clues to the activation mechanism.

For the structural analysis, the researchers chose a T-cell receptor used in immunotherapy to treat melanoma and which had been optimised for this purpose in several steps in such a way that it binds its antigen as tightly as possible. A particular challenge on the way to structure determination was to isolate the whole antigen receptor assembly consisting of eleven different subunits from the cell membrane. “Until recently, nobody believed that it would be possible at all to extract such a large membrane protein complex in a stable form from the membrane," says Tampé.

Once they had successfully achieved this, the researchers used a trick to fish those receptors out of the preparation that had survived the process and were still functional: due to the strong interaction between the receptor complex and the antigen, they were able to “fish" one of the most medically important immune receptor complexes. The subsequent images collected at the cryo-electron microscope delivered groundbreaking insights into how the T-cell receptor works, as Tampé summarises: “On the basis of our structural analysis, we were able to show how the T-cell receptor assembles and recognises antigens and hypothesise how signal transduction is triggered after antigen binding." According to their results, the big surprise is that there is evidently no significant change in the receptor's spatial structure after antigen binding, as this was practically the same both with and without an antigen.

The remaining question is how antigen binding could instead lead to T-cell activation. The co-receptor CD8 is known to approach the T-cell receptor after antigen binding and to stimulate the transfer of phosphate groups to its intracellular part. The researchers assume that this leads to the formation of structures which exclude enzymes that cleave off phosphate groups (phosphatases). If these phosphatases are missing, the phosphate groups remain stable at the T-cell receptor and can trigger the next step of the signalling cascade. “Our structure is a blueprint for future studies on T-cell activation," Tampé is convinced. “In addition, it's an important stimulus for employing the T-cell receptor in a therapeutic context for treating infections, cancer, and autoimmune diseases."

Publication: Lukas Sušac, Mai T. Vuong, Christoph Thomas, Sören von Bülow, Caitlin O'Brien-Ball, Ana Mafalda Santos, Ricardo A. Fernandes, Gerhard Hummer, Robert Tampé, Simon J. Davis: Structure of a fully assembled tumor-specific T-cell receptor ligated by pMHC. Cell (2022) 185, Aug 18 https://doi.org/10.1016/j.cell.2022.07.010

Picture download: https://www.uni-frankfurt.de/123390758

Caption: The cryo-EM structure of the fully assembled T-cell receptor (TCR) complex with a tumor-associated peptide/MHC ligand provides important insights into the biology of TCR signaling. These insights into the nature of TCR assembly and the unusual cell membrane architecture reveal the basis of antigen recognition and receptor signaling.

Further information:
Professor Robert Tampé
Collaborative Research Centre CRC 1507 – Protein Assemblies and Machineries in Cell Membranes
Institute of Biochemistry, Biocenter
Goethe University Frankfurt
Tel.: +49 69 798-29475
tampe@em.uni-frankfurt.de
Website: https://www.biochem.uni-frankfurt.de/

How do killer T cells recognise cells in the body that have been infected by viruses? Matter foreign to the body is presented on the surface of these cells as antigens that act as a kind of road sign. A network of accessory proteins – the chaperones – ensure that this sign retains its stability over time. Researchers at Goethe University have now reached a comprehensive understanding of this essential cellular quality control process. Their account of the structural and mechanistic basis of chaperone networks has just appeared in the prestigious science journal Nature Communications. These new findings could be harbingers of progress in areas such as vaccine development.

FRANKFURT. Organisms are constantly invaded by pathogens such as viruses. Our immune system swings into action to combat these pathogens immediately. The innate non-specific immune response is triggered first, and the adaptive or acquired immune response follows. In this second defence reaction, specialised cytotoxic T lymphocytes known as killer T cells destroy cells in the body that have been infected and thus prevent damage from spreading. Humans possess a repertoire of some 20 million T cell clones with varying specificity to counter the multitude of infectious agents that exist. But how do the killer T cells know where danger is coming from? How do they recognise that something is wrong inside a cell in which viruses are lurking? They can't just have a quick peek inside.

At this point, antigen processing comes into play. The process can be compared to making a road sign. The molecular barcode is “processed" or assembled in the cell – in the endoplasmic reticulum, to be exact. Special molecules are used in its making, the MHC class I molecules. They are loaded with information about the virus invader in a molecular machine, the peptide loading complex (PLC). This information consists of peptides, fragments of the protein foreign to the body. These fragments also contain epitopes, the molecular segments that elicit a specific immune response. During the loading process, an MHC I-peptide epitope complex thus forms, and this is the road sign that is then transported to the surface of the cell and presented in a readily accessible form to the killer T cells – we could almost say that it is handed to them on a silver platter. The chaperones, special accessory proteins that assist the correct folding of proteins with complex structures in cells, also play a significant role.

The chaperones that support antigen processing are calreticulin, ERp57, and tapasin. But how do they work together? And how important are they for antigen processing? An answer has now been supplied by a study carried out by Goethe University Frankfurt and the University of Oxford and published in Nature Communications. “With this study, we have achieved a breakthrough in our understanding of cellular quality control," says Professor Robert Tampé, Director of the Institute of Biochemistry at Goethe University Frankfurt. He explains the logic underlying this quality control process as follows: “The MHC I-peptide epitope complex, the road sign, needs to be exceptionally stable, and for quite a long time, because the adaptive immune response does not start instantly. It needs 3 to 5 days to get going." So, the sign must not collapse after one day; that would be disastrous, as the immune defence cells would then fail to detect cells infected by a virus. This would mean that they would not destroy these cells and the virus would be able to continue its spread unhindered. A similar problem would arise if a cell in the body had mutated into a tumour cell: the threat would remain undetected. It is imperative, therefore, that a quality control system is in place.

As the study shows, the chaperones are central process components: they give the road sign the long-term stability it must have by making a strict selection. By rejecting the short-lived virus fragments in the mass of available material, they ensure that only MHC I molecules loaded with the best and most stable peptide epitopes in complex with MHC I are released from the peptide loading complex. The chaperones have different tasks in this selection process that is so important for the adaptive immune response, Tampé says: “Tapasin acts as a catalyst that accelerates the exchange of suboptimal peptide epitopes for optimal epitopes. Calreticulin and ERp57, in contrast, are deployed universally." This concerted approach ensures that only stable MHC I complexes with optimal peptide epitopes reach the cell surface and perform their role of guiding the killer T cells to the infected or mutated cell.

In what directions does the study point? “We now better understand which peptides are loaded and how this occurs now. We can also more reliably predict the dominant peptide epitopes, in other words the stable peptide epitopes that will be selected by the chaperone network." Tampé hopes that the new findings will prove useful for developing future vaccines against virus variants. They could also facilitate progress on future tumour therapies. “Both topics are directly linked. But the applications in tumour therapy are certainly more complex and more for the long term."

Publication: Alexander Domnick, Christian Winter, Lukas Sušac, Leon Hennecke, Mario Hensen, Nicole Zitzmann, Simon Trowitzsch, Christoph Thomas, Robert Tampé: “Molecular basis of MHC I quality control in the peptide loading complex" Nature Communications 2022, 13:4701 https://doi.org/10.1038/s41467-022-32384-z

An image to download (copyrights Christoph Thomas & Robert Tampé): https://www.uni-frankfurt.de/123213123

Caption: The mechanism of MHC I assembly, epitope editing and quality control within the peptide loading complex (PLC). The fully assembled PLC machinery of antigen processing is formed by the antigen transport complex TAP1/2, the chaperones calreticulin, ERp57, and tapasin, and the heterodimeric MHC I (heavy and light chain in teal and green, respectively).

Further information
Institute of Biochemistry
Goethe University Frankfurt
Prof. Dr Robert Tampé
Tel: +49 (0)69 79829475
tampe@em.uni-frankfurt.de

Neuroscientists at Goethe University, Frankfurt have discovered a feedback loop that modulates the receptivity of the auditory cortex to incoming acoustic signals when bats emit echolocation calls. In a study published in the journal “Nature Communications", the researchers show that information transfer in the neural circuits involved switched direction in the course of call production. It seems likely that this feedback prepares the auditory cortex for the expected echoes of the emitted calls. The researchers interpret their findings as indicating that the importance of feedback loops in the brain is currently still underestimated.

FRANKFURT. Bats famously have an ultrasonic navigation system: they use their extremely sensitive hearing to orient themselves by emitting ultrasonic sounds and using the echoes that result to build up a picture of their environment. For example, Seba's short-tailed bat (Carollia perspicillata) finds the fruits that are its preferred food using this echolocation system. At the same time, bats also use their vocalisations to communicate with other bats. They use a somewhat lower range of frequencies for this purpose.

Neuroscientist Julio C. Hechavarría from the Institute of Cell Biology and Neuroscience at Goethe University and his team are investigating the brain activities associated with vocalisations in Seba's short-tailed bat. Their most recent study investigates how the auditory cortex and the frontal lobe work together in echolocation. The auditory cortex processes auditory information and the frontal lobe is a region in the forebrain that is associated, in humans, with tasks that include planning actions. To discover more about this, the researchers inserted tiny electrodes into the bats' brains to record neural activity in the frontal lobe and the auditory cortex.

The researchers succeeded in identifying a feedback loop that had previously been entirely unknown in the frontal lobe-auditory cortex network of bats emitting echolocation calls. Information normally flows from the frontal lobe, where call production is planned, to the auditory cortex to ready it to expect an acoustic signal. But it was observed that the flow of information from the frontal lobe to the auditory cortex diminished after the emission of an echolocation pulse until the direction of information transfer switched completely and information flowed from the auditory cortex back to the frontal lobe. Hechavarría hypothesises that this feedback loop readies the auditory cortex to better receive the sounds reflected back from the echolocation call.

The neurobiologists simulated signals originating from the auditory cortex by electrically stimulating the frontal lobe. The activity this generated in the frontal lobe had the expected effect of prompting the auditory cortex to respond more strongly to acoustic reflections. “This shows that the feedback loop we found is functional", neurobiologist Hechavarría sums up. He takes up the metaphor of a highway to illustrate the significance of these findings: “Up to now, it was generally believed that the flow of data on this information superhighway mainly runs in one direction and that feedback loops are exceptions. Our data show that this view is most likely incorrect and that feedback loops in the brain are probably considerably more significant than has previously been hypothesised."

Surprisingly, no pronounced reversal of information flow was observed for bat vocalisations used for communication purposes. “This may be because the bats were alone in a sound-proofed and electrically isolated chamber and therefore did not expect a response to their calls", Hechavarría speculates before going on to note: “One of the aspects that makes our study so interesting is that it opens up new ways to study the social interactions of bats. We want to continue work in this area in the future."

Publication: Francisco García-Rosales, Luciana López-Jury, Eugenia Gonzalez-Palomares, Johannes Wetekam, Yuranny Cabral-Calderín, Ava Kiai, Manfred Kössl, Julio C. Hechavarría: Echolocation-related reversal of information flow in a cortical vocalisation network. Nature Communications 13, 3642 (2022) https://doi.org/10.1038/s41467-022-31230-6

An image to download: https://www.uni-frankfurt.de/122772504

Caption: Bats “see" with their ears. Researchers at Goethe University have discovered how the auditory cortex is readied for incoming acoustic signals. (Photo: Dr. Julio C. Hechavarría)

Further information
Dr. Julio C. Hechavarría (Ph.D.)
Auditory Computations Group (Group Leader)
Institute for Cell Biology and Neuroscience
Tel. +49 (0)69 798-42050
Hechavarria@bio.uni-frankfurt.de
https://www.julio-hechavarria.com/