CeMM Scientific Director Giulio Superti-Furga with Prof. Orly Goldwasser (©Laura Alvarez / CeMM).
On 27 April 2021, CeMM hosted its 10th S.M.A.R.T. Lecture with Orly Goldwasser, Professor of Egyptology at the Hebrew University of Jerusalem and an Honorary Professor at the University of Göttingen.
The S.M.A.R.T. lecture series is an initiative launched by CeMM dedicated to diverse topics around the fields of science, medicine, art, research, and technology. They address contemporary challenges of science in an interdisciplinary manner and at the interface of science and society, with the aim of establishing an open dialogue with the broader public. Once a year CeMM invites an international speaker renowned for having made extraordinary achievements in their fields.
This year in an online format, Prof. Goldwasser talked about one of the greatest and lasting inventions in history: the alphabet. Interestingly, the alphabet was invented only once: all alphabetic scripts of all languages of the world originated from one single invention.
During her talk, Prof. Goldwasser introduced the history of how the alphabet was invented from hieroglyphs, dating back to C. 1840 BCE in the Sinai Desert. She explained how ancient inscriptions that were discovered in the mines during this period of history were made by the Canaanites, which were the people originally from Israel, Palestine and Lebanon who spoke a Semitic language, the mother language of the modern Hebrew and Arabic used nowadays. The essence of the invention of the alphabet lied in identify the meaning of the picture in the hieroglyph, naming it in Canaanite, extracting only the first sound of the picture and discard then the meaning of the picture entirely. Each sign became then one single sound.
In the past, there was no agreement in the international scientific community about where and when exactly was the alphabet invented. Prof. Goldwasser’s research work has been paramount in the reconstruction of the invention process. She made a breakthrough contribution by suggesting hieroglyphic models in the Sinai repertoire of Egyptian hieroglyphs that could have served as models for the inventors. She also identified through her work that the inventors were indeed illiterate Canaanites working in the mines of the Sinai desert.
We would like to thank Prof. Goldwasser for a very insightful talk and for carrying us with her talk to a very interesting time in history!
Last author Jörg Menche and first author Sebastian Pirch (© Michael Sazel/CeMM)
Networks offer a powerful way to visualize and analyze complex systems. However, depending on the size and complexity of the network, many visualizations are limited. Protein interactions in the human body constitute such a complex system that can hardly be visualized. Jörg Menche, Adjunct Principal Investigator at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Professor at the University of Vienna and research group leader at Max Perutz Labs (Uni Wien/MedUni), and his team developed an immersive virtual reality (VR) platform that solves this problem. With the help of VR visualization of protein interactions, it will be possible in the future to better recognize correlations and identify those genetic aberrations that are responsible for rare diseases.
The larger and more complex networks are, the more difficult their visualization on the screen becomes. Conventional computer programs quickly reach their limits. This challenge was addressed by network scientist Jörg Menche and his research group at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. They developed a VR platform for exploring huge amounts of data and their complex interplay in a uniquely intuitive fashion.
The body as a network
The representation of complex data can be particularly important in the search for the cause of rare diseases, because the human body, with its approximately 20,000 proteins that are encoded in the human genome and interact with each other, represents a huge complex network. Whether movement or digestion – at the molecular level, all biological processes are based on the interaction between proteins. If the protein interactions are illustrated in a network, a barely representable picture of about 18,000 dots – proteins – and about 300,000 lines between these dots will be created. Menche and his research group used the virtual reality (VR) platform they developed to make this image “readable” and, in collaboration with St. Anna Children’s Cancer Research, succeeded in making the entirety of protein interactions visible for the first time. This makes it possible to interactively explore the vast and complex network.
Approaching the cause of rare immune diseases
For their study, published in Nature Communications, first author Sebastian Pirch and Menche’s research group identified connection patterns between different protein complexes in the human body and linked them to their biological functions. In addition, the scientists used global databases to identify specific protein complexes associated with a particular disease. “While conventional forms of representation would look like a proverbial ‘hairball’, the 3-dimensional representation enables the precise analysis and observation of the different protein complexes and their interactions,” says study author Pirch. This can be particularly important in the identification of rare genetic defects and crucial for therapeutic measures. “On the one hand, our study represents an important proof of concept of our VR platform; on the other hand, it directly demonstrates the enormous potential of visualizing molecular networks,” says project leader Menche. “Especially in rare diseases, severe immune diseases, protein complexes associated with specific clinical symptoms can be analyzed in more detail to develop hypotheses about their respective pathobiological mechanisms. This facilitates the approach to disease causes and subsequently the search for targeted therapeutic measures.”
About the VR platform
The platform developed by Menche’s research group is designed for maximum flexibility and extensibility. Key features include the import of user-defined code for data analysis, easy integration of external databases, and a high degree of design freedom for arbitrary elements of user interfaces. The researchers were able to draw on technology normally used in the development of 3D computer games, such as the globally popular game Fortnite. By publishing the source code, the researchers hope to convince other developers of the potential of virtual reality for analyzing scientific data.
The study "VRNetzer: A Virtual Reality Network Analysis Platform" was published in the journal Nature Communications on April 23, 2021. DOI: 10.1038/s41467-021-22570-w.
Authors: Sebastian Pirch, Felix Müller, Eugenia Iofinova, Julia Pazmandi, Christiane V. R. Hütter, Martin Chiettini, Celine Sin, Kaan Boztug, Iana Podkosova, Hannes Kaufmann & Jörg Menche
Funding: This work was supported by the Vienna Science and Technology Fund (WWTF) through projects VRG15-005 and NXT19-008, and by an Epic MegaGrant.
Artem Kalinichenko and Kaan Boztug. / © St. Anna Children's Cancer Research Institute.
Scientists from CeMM Adjunct PI Kaan Boztug's Group at St. Anna Children's Cancer Research Institute, together with their collaborators from Finland and Sweden, discover a novel subtype of a genetic disease: genetically determined deficiency of the protein RhoG abrogates the normal cytotoxic function of specific immune cells, causing hemophagocytic lymphohistiocytosis (HLH). These new findings may help with the genetic diagnosis for patients with a clinical suspicion of HLH. Published in the high-ranked scientific journal Blood, the study provides a basis for both a deeper understanding of the biology of HLH and the exploration of new therapeutic approaches.
As part of an international collaborative effort, the scientists illuminate a new etiology of a disease called familial hemophagocytic lymphohistiocytosis (HLH). Occurring usually in early childhood, familial or genetically-determined HLH is one of the most dramatic hematologic disorders. It is characterized by the inability of specific immune cells, namely T lymphocytes and natural killer (NK) cells, to kill an infected (e.g., virus-infected) target cell. As a consequence, the body may secrete biological messengers (so-called cytokines) that generate massive immune activation and hyperinflammation throughout the entire body. “If untreated, the hyperinflammation associated with HLH can be lethal in a short period of time”, says Kaan Boztug, MD, Scientific Director of St. Anna CCRI and senior author of the study.
Until recently, four subtypes of familial HLH had been known, caused by mutations in genes involved in regulating the immune defense. “Now we discovered a new type of this disease, caused by inherited mutations in the gene that encodes the protein RhoG”, explains the first author of the study, Artem Kalinichenko, PhD, Senior Postdoctoral researcher at St. Anna CCRI and Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD).
The researchers show how deficiency of RhoG specifically impairs the cytotoxic function of T lymphocytes and NK cells. This results in their uncontrolled activation and ultimately causes HLH.
In particular, RhoG deficiency impairs the process of exocytosis in specific immune cells and disables their killing ability. Immune cells like T and NK cells use exocytosis to release cytotoxic molecules to attack and kill infected or tumor cells. When RhoG deficiency abrogates this function in immune cells, they cannot kill their target cells as intended. “We will explore in more detail, how this potentially affects the propensity to develop cancer”, says Dr. Kalinichenko.
RhoG regulates lymphocyte cytotoxicity
In their study, the scientists investigated an infant who developed severe HLH at the age of four months. While the disease was associated with impaired cytotoxicity of T and NK cells, no mutations were found in known HLH-associated genes. Further genetic analysis revealed deleterious mutations in the gene encoding RhoG. By experimental ablation of RhoG, the scientists confirmed the previously unknown role of RhoG in the cytotoxic function of human lymphocytes. Despite a drastic and specific effect on cytotoxic function, RhoG deficiency does not affect other functions of immune cells that play an important role for the disease development.
“In our study we discovered a pivotal role of RhoG interaction with an exocytosis protein called Munc13-4, essential for anchoring of cytotoxic granules to the plasma membrane”, explains Dr. Boztug. This docking is a critical step in exocytosis. It is required for further fusion of the vesicles with the plasma membrane and the release of the cytotoxic granules.
“Thus, our study illuminates RhoG as a novel essential regulator of human lymphocyte cytotoxicity, and provides the molecular pathomechanism behind this previously unreported genetically determined form of hemophagocytic lymphohistiocytosis”, concludes Dr. Boztug.
Shorter screening process for patients
Based on the understanding of the underlying molecular mechanism of familial HLH, the researchers are looking forward to an improved prognosis and treatment of the disease in the long-term. As a short-term consequence, the here discovered RhoG deficiency can help HLH patients by enabling a genetic diagnosis. “We hope that our understanding of the molecular pathomechanisms of HLH may impact disease management and prognosis”, comments Dr. Boztug.
This study is an exciting breakthrough that brings up new important scientific questions. “The discovery of RhoG deficiency has opened up new insights into the molecular functions of this protein and revealed highly relevant questions. We have found that RhoG regulates both, the ‘cell skeleton’ and the exocytosis machinery. Now we are very keen to know how RhoG coordinates their activity in space and time”, says Dr. Kalinichenko.
Collaborative research on rare diseases
This scientific work was possible thanks to a collaboration of St. Anna CCRI with the LBI-RUD, the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, the Medical University of Vienna, and international partners. Special thanks go to the co-senior authors Janna Saarela (Institute for Molecular Medicine Finland, Helsinki, Finland and Centre for Molecular Medicine Norway, Oslo, Norway) and Mikko R.J. Seppänen (Rare Diseases Center, Children’s Hospital, University of Helsinki, Finland) as well as Yenan T. Bryceson (Karolinska Institute, Stockholm, Sweden). The patient was enrolled in the ongoing FINPIDD study series and is under medical treatment at the Helsinki University Hospital.
Publication:
"RhoG deficiency abrogates cytotoxicity of human lymphocytes and causes hemophagocytic lymphohistiocytosis" was publishd on Blood on 15 April 2021. DOI: https://doi.org/10.1182/blood.2020008738
Authors: Artem Kalinichenko, Giovanna Perinetti Casoni*, Loic Dupre*, Luca C. Trotta*, Jakob Huemer, Donatella Galgano, Yolla German, Ben Haladik, Julia Pazmandi, Marini Thian, Özlem Yüce Petronczki, Samuel C.C Chiang, Mervi H Taskinen, Anne Hekkala, Saila Kauppila, Outi Lindgren, Terhi Tapiainen, Michael J. Kraakman, Kim Vettenranta, Alexis J. Lomakin, Janna Saarela§ , Mikko R J Seppänen§, Yenan T Bryceson§, Kaan Boztug§‡
* these authors contributed equally
§ these authors contributed equally
Funding:
This work was supported by European Research Council through an ERC Consolidator Grant “iDysChart” (Kaan Boztug) and the Vienna Science and technology Fund (WWTF) through project LS14-031 (Kaan Boztug); Austrian Academy of Science (ÖAW) through DOC fellowship program 25365 (Jakob Huemer) and 25225 (Marini Thian); Finnish Foundation for Pediatric Research and Pediatric Research Center, Helsinki University Hospital (Mikko RJ. Seppänen), and Swedish Research Council, Cancer Foundation, Children's Cancer Foundation, and Knut and Alice Wallenberg Foundation to Yenan T. Bryceson.
CeMM South terrace with the new chairs (© Laura Alvarez / CeMM).
After 10 years in the CeMM building, we have made some renovations in the cafeteria and our iconic terrace overlooking Vienna’s historical center. Despite the challenging times we are living, it is a priority for CeMM to provide an inviting and comfortable space for safe interactions and cooperation not only among our colleagues but also our guests.
At the end of 2020, we launched the “One Chair One for CeMM” fundraising campaign to help support the acquisition of new, high quality outdoor chairs. The campaign was a success and we received donations to cover the costs of 48 chairs. Each chair is unique and includes a dedicated label chosen by the sponsor. We are happy to announce that the new chairs have arrived at the CeMM terrace and are now available for all our colleagues.
We would like to thank all our donors and supporters for their invaluable support to our institute and helping us to keep on providing the right space for our colleagues to do their work in the best possible conditions!
On the left, fluorescence microscopy images of the cell lines after treatment with solutions 1.5 μM in DMSO of quinoxalines (© Fabián Amaya Garcia & Miriam Unterlass). / On the right, authors of the study.
The discipline of chemistry deals with understanding (analysis) and making and transforming (synthesis) of matter. The size-range with which chemistry is most concerned with is that of molecules as building blocks of matter. Molecules are nothing but connected atoms, and when aiming at making, i.e. synthesizing, them, it is useful to chemists to subdivide them into subsets, which are so-called "functions" or "functional groups". Although every type of molecule is unique, it's subsets - the functional groups - will eventually be found in many other molecules. Therefore, approaches of generating a particular functional group may eventually benefit the synthesis of numerous molecules bearing ths functional group.
The research group of Miriam Unterlass, CeMM Adjunct Principal Investigator and Assistant Professor at the Technische Universität Wien, in collaboration with two other CeMM research groups, the Menche Lab and the Kubicek Lab, has now developed a novel synthesis for the so-called "quinoxaline" functional group, which is to date reported to be part of more than 100,000 molecules. Quinoxalines are highly important for especially pharmaceutical applications, where they are part of various drugs such as the antibiotic Echinomycin, or Brimonidine a drug to treat ocular hypertension. Furthermore, they display intriguing optoelectronic properties and therefore find application as e.g. dyes or electroluminescent materials. Classically, the quinoxaline function is made by rather harsh, harmful, and tedious routes (toxic organic solvents, expensive catalysts). In contrast, the new synthesis developed by Unterlass and colleagues employs 'hot water' as solvent and is therefore termed hydrothermal synthesis (HTS). Through the developed HTS, quinoxalines can be generated within only 10 minutes. In fact, the synthesis is the least harmful of all routes reported to date, as Amaya-García et al. show in their recently published manuscript, through a large-scale computational comparison with all existing alternatives. Moreover, the researchers show that the generated quinoxalines exhibit fluorescence and can be used to stain different cell lines.
* * *
The study "Green hydrothermal synthesis of fluorescent 2,3-diarylquinoxalines and large-scale computational comparison to existing alternatives" was published online ahead of print on ChemSusChem on 4 March 2021. DOI: https://doi.org/10.1002/cssc.202100433
Authors: Fabián Amaya-García, Michael Caldera, Anna Koren, Stefan Kubicek, Jörg Menche, Miriam M. Unterlass
Funding: This project was funded by the Austrian Science Fund (FWF) under grant no. START Y1037‐N28 and the Vienna Science and Technology Fund (WWTF) under grant number LS17‐051.
Sylvia Knapp and Christoph Binder (© Klaus Pichler / CeMM).
Sylvia Knapp and Christoph Binder have been CeMM pioneers and have been associated with their groups with us for 15 years. On 31 March 2021 their CeMM research contracts end and we would like to say a big heartfelt thank you for the scientific contributions, the networking and personal engagement.
Both joined CeMM at the first round of Principal Investigator hiring and have been critical in setting the stage for future directions and hires at CeMM ever since. Both embodied the very essence of how CeMM was trying to position itself, as a bridge between hard-core frontier research in biomedicine and the clinical world. After their MDs, both had gone to prestigious institutions abroad to also obtain a PhD, making them perfectly capable of navigating the medical and the basic research world with equal ease. Coincidentally, their respective fathers, Walter Knapp and Bernd R. Binder, were highly successful MedUni Professors and influential scientists themselves. Both were fervent advocators of molecular medicine and important early contributors to the CeMM project.
At CeMM, Sylvia Knapp and Christoph Binder, helped generation after generation of researchers to make connections to the relevant clinical departments at the Medical University while contributing to the creation of what can be defined the CeMM culture of international, collegial and highly collaborative spirit. Over the years both, Sylvia Knapp and Christoph Binder, successfully took up more and more responsibilities at the Medical University of Vienna, became inspiring professors, and now also filling important functions at yet other universities and funding organizations. They trained and accompanied a large number of students to finish their PhD. Equally critical for the CeMM mission, they both have, with their teams and often in collaboration with other CeMM researchers, published several high-impact papers. We are proud to have supported their scientific career early on and so contributed to their success. We hope that CeMM has also left a positive footprint in their personal development as researchers, mentors, and community leaders. Christoph once compared CeMM with a place where you are “heart-washed”. It is nice to think that people who leave the institute are taking along not only the recipe for scientific excellence, but also the collaborative spirit and the civil purpose of contributing to society.
CeMM has always been meant to be a career springboard. We do not offer tenure, so after a successful research period, we need to allow a new generation of PIs to join CeMM and freely develop their potential and scientific interests. Although it is sad to separate, we count on the well-established networks and research collaborations which will help us to stay connected with Sylvia and Christoph and their current teams and alumni, even without formal ties. Our companionship and collegiality cannot and will not be disturbed by any change of formal status, after having shared such a long and critical part of our scholarly journey together, as well as many fond memories. We anticipate that this next phase will actually bring new opportunities and dimensions to the relationship.
We would like to look back at some of the research highlights Sylvia, and Christoph and their teams have performed and published in collaboration with CeMM:
Sylvia Knapp studied Medicine in Vienna and Berlin, is a board-certified internist and obtained her PhD at the University of Amsterdam in the laboratory of Tom van der Poll. In 2006 she joined CeMM as Principal Investigator and until recently, she continued her clinical duties while also running her laboratory. In 2012 Sylvia became Professor for Infection Biology at the Medical University of Vienna. She is a member of the Academia.Net circle of excellent female scientists, corresponding member of the Austrian Academy of Sciences, was appointed to the Board of the Medical University of Graz, and is Vice President of the Ludwig Boltzmann Society. Sylvia’s research focuses on the innate immune response to infections. Among the highlights:
Christoph Binder obtained his MD degree from the University of Vienna, and his PhD degree from the University of California in San Diego while working with Joseph (Joe) L Witztum. He joined the Department of Laboratory Medicine of the Medical University of Vienna in 2005, where in 2009 he was appointed Professor of Atherosclerosis Research, and now is Deputy Head of Division. In 2006 he joined CeMM as Principal Investigator. Christoph won numerous prestigious fellowships and awards. He is a specialist in laboratory medicine and leads a research group focusing on the role of immune functions in atherosclerosis. Among the highlights in his research we find:
We wish Sylvia, Christoph and their team members many more successful research projects, publications and prizes, and all the best for the future! The members of CeMM are looking forward to personally thank them and their teams in a farewell ceremony as soon as it is safe to do so. Thank you, you have been important partners for the starting phase and development of CeMM!
The image shows a part of the reaction pathway, in which the catalyst is attached to the reacting molecule. This was achieved through quantum chemical calculations of the reaction. (© Giovanni Di Mauro / CeMM)
Among the many pharmaceuticals in use every day, one of the most well-recognized substances is the century-old pain killer Paracetamol. Paracetamol is part of a family of compounds, the so-called para-aminophenols, which also includes other biologically active molecules, such as Diloxanide Furoate, which is used against amoeba infections, or the beta blocker Practolol. These molecules are typically synthesised using harsh acids, in processes that involve the formation of considerable amounts of waste (in the form of undesired byproducts).
The research group of Nuno Maulide, CeMM Adjunct Principal Investigator and Professor at the University of Vienna, has now discovered a novel method of chemical synthesis to access Paracetamol and related molecules through a catalytic process that is extremely selective and generates little waste. This is enabled by a rearrangement reaction, in which specific atoms of a given molecule change positions, while no atoms are released as waste. Additionally, here, using an inexpensive selenium-based catalytic system avoids the use of expensive (and often scarce) metal catalysts.
While undertaking mechanistic studies to understand the exact pathway of the reaction at hand, the authors uncovered a complex yet organised cascade of elemental steps, in which the catalyst and the starting material exchange one atom back and forth without breaking their engagement. Then, after completing the transformation and yielding the final product, the catalyst is released and can engage another molecule of the starting material to be taken through the rearrangement sequence.
This newly developed method bears great potential in enabling chemists to rethink the way in which para-aminophenols are made, while simultaneously deepening their understanding of chemical reactivity. This broadly applicable, easy-to-use synthetic tool opens up wide perspectives for the preparation of valuable compounds under inexpensive and benign conditions.
* * *
The study "Redox‐Neutral Selenium‐Catalysed Isomerisation of para‐Hydroxamic Acids into para‐Aminophenols" was published online on Angewandte Chemie on 24 March 2021. DOI: https://doi.org/10.1002/anie.202100801
Authors: Hsiang‐Yu Chuang, Manuel Schupp, Ricardo Meyrelles, Boris Maryasin, Nuno Maulide.
Pictured from left to right: Science Minister Heinz Faßmann, Andreas Bergthaler (Project Manager at CeMM), Giulio Superti-Furga (CeMM Scientific Director), Anna Schedl (Project Coordinator at CeMM), Anita Ender (CeMM Administrative Director) and Gregor Weihs (FWF President). (Photo credit: FWF/Novotny)
CeMM congratulates our Principal Investigator Andreas Bergthaler: He is one of the four newly funded researchers who are further expanding their corona research with funding from the Austrian Science Fund (FWF).
With funding from the Austrian Science Fund (FWF), Austria’s top researchers have the opportunity to study the Corona pandemic and its consequences. In recent months, 19 research teams were able to get started under the SARS-CoV-2 urgent funding program, and now four more FWF-funded teams are joining them: physician Alice Assinger from the Medical University of Vienna, microbiologist Andreas Bergthaler from CeMM, educational scientist Oliver Koenig from Bertha von Suttner Private University in St. Pölten, and family sociologist Ulrike Zartler from the University of Vienna.
Identifying and understanding the pathways of SARS-CoV-2 spread
CeMM PI Andreas Bergthaler together with Christoph Bock lead the team that is carrying out large-scale sequencing of SARS-CoV-2 viruses in Austria and analyzing the spread of mutations. Back in autumn in 2020, the group published a highly-cited study on the mutational dynamics of SARS-COV-2 in the prestigious journal Science Translational Medicine (DOI: 10.1126/scitranslmed.abe2555), and their research provides information on how and where the coronavirus mutations spread within Austria. The FWF urgent funding will allow Andreas Bergthaler to further deepen his research in order to better understand the spread of the virus and its mutations. The findings will improve the knowledge base for future measures to contain the pandemic.
SARS-CoV-2 Project Website: www.sarscov2-austria.org
Basic research helps manage the pandemic
"We already know quite a bit about Corona, but by no means everything. Researchers like Andreas Bergthaler have been working tirelessly for weeks to close these gaps in our knowledge. His work and the expertise of countless colleagues from very different fields are helping us to better understand the virus, the crisis and its consequences." said Federal Minister Heinz Faßmann on the occasion of the latest funding allowance provided to top researchers by the Austrian Science Fund (FWF).
"We enable scientists from all disciplines to intensify their corona research at the highest quality level. Building on their findings, policymakers and society can find answers to the current crisis, but also for future challenges," said interim FWF President Gregor Weihs.
FWF urgent funding: accelerated procedure without compromising quality
As an immediate response to the Corona pandemic, the FWF initiated SARS-CoV-2 urgent funding in March 2020 - a fast-track procedure for research applications dealing with the prevention, early detection, containment as well as research of SARS-CoV-2, with a particular focus on international cooperation. In addition, projects that focus their research interest on technical, ecological, economic, political, legal, medical, cultural, psychological, or ethical implications of SARS-CoV-2 are encouraged to apply. The expertise of virtually all basic research disciplines is needed in the current situation. The fast-track process for research proposals addressing SARS-CoV-2 runs until the end of March 2021.
We thank the FWF for supporting CeMM in researching and combating SARS-CoV-2!
First authors Taras Afonyushkin (left) and Georg Obermayer (right) with Last author Christoph Binder (middle), © Laura Alvarez/CeMM.
Thrombotic occlusion of blood vessels, which leads to myocardial infarctions, strokes and venous thromboembolisms, is the major cause of death in the western hemisphere. Therefore, it is of critical importance to understand mechanisms preventing thrombus formation. A new study by the research group of Christoph Binder, Principal Investigator at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and Professor at the Medical University of Vienna, now explains the important role of immunoglobulin-M (IgM) antibodies in preventing thrombosis. The study published in the journal Blood shows that these antibodies recognize microvesicles, which are membrane blebs shed by cells and recognized for their critical role in thrombosis, and therefore prevent their pro-thrombotic effects. These results provide a novel approach to reduce the risk of thrombosis by using IgM antibodies.
Antibodies are an important component of the immune system. On the one hand, these proteins serve in the body to defend against microbes, and on the other hand to remove the body’s own “cell waste”. Naturally occurring antibodies which are present from birth and mostly of the immunoglobulin-M (IgM) type, play an essential role in these processes. In the context of thrombosis, earlier studies demonstrated that people with a low number of IgM antibodies have an increased risk of thrombosis. A research group led by Christoph Binder, Professor of Atherosclerosis Research at the Medical University of Vienna and Principal Investigator at CeMM , previously demonstrated in a study published in 2009 that a high percentage of natural IgM antibodies bind oxidation-specific epitopes, molecular structures that are present on dying cells and serve as “remove-me signals” for the immune system. In this study, Binder’s research group identified the mechanisms explaining anti-thrombotic effects of natural IgM antibodies.
IgM antibodies bind procoagulant microvesicles
Microvesicles, blebs shed from the membrane of cells, are critical mediators of blood coagulation and thrombus formation. The study authors Georg Obermayer and Taras Afonyushkin from Binder’s research group, both affiliated with CeMM and the Medical University of Vienna, have now demonstrated that natural IgM antibodies that bind oxidation-specific epitopes can prevent coagulation and thrombosis induced by microvesicles. This provides a mechanistic explanation for the previously published observation that low levels of these antibodies are associated with an increased risk of thrombosis. “We assume that natural IgM antibodies recognize microvesicles that are particularly proinflammatory and procoagulant,” say the scientists. Both in experiments on the mouse model and directly on human blood samples, the scientists were able to show that the addition of IgM antibodies inhibited blood clotting caused by specific microvesicles and protected mice from lung thrombosis. Conversely, it was also shown that depletion of the IgM antibodies increased blood clotting.
Possible starting point for future therapies
The study authors explain: “The study for the first time provides an explanation why people with a low number of natural IgM antibodies have an increased risk of thrombosis.” Project leader Christoph Binder adds: “The results offer high potential for novel treatments to reduce the risk of thrombosis. Influencing IgM antibody levels in high-risk patients could be a viable addition to the previously established blood thinning treatment, as this is also known to be associated with side effects such as an increased tendency to bleed in the case of injuries.” In addition, the study makes an important contribution to the basic understanding of factor modulating thrombus formation. “Microvesicles are already recognized as an important component of blood coagulation. However, our study created a novel possibility of targeting them therapeutically for the first time,” says Christoph Binder.
The study “Natural IgM antibodies inhibit microvesicle-driven coagulation and thrombosis” was published in the journal Blood, online on 8 December 2020. DOI: https://doi.org/10.1182/blood.2020007155.
Authors: Georg Obermayer*, Taras Afonyushkin*, Laura Göderle, Florian Puhm, Waltraud Schrottmaier, Soreen Taqi1, Michael Schwameis, Cihan Ay, Ingrid Pabinger, Bernd Jilma, Alice Assinger, Nigel Mackman, Christoph J. Binder;
* authors contributed equally
Funding: This study was supported by the SFB-54 “InThro” of the Austrian Science Fund (FWF), the Christian Doppler Laboratory for Innovative Therapy Approaches in Sepsis, and CCHD (Cell Communication in Health and Disease) of the FWF.
From L to R: Venugopal Gudipati, Johannes B. Huppa, Judith H. Aberle, Maximilian Koblischke Andreas Bergthaler, Benedikt Agerer (© Laura Alvarez / CeMM).
The body’s immune response plays a crucial role in the course of a SARS-CoV-2 infection. In addition to antibodies, the so-called T-killer cells, are also responsible for detecting viruses in the body and eliminating them. Scientists from the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and the Medical University of Vienna have now shown that SARS-CoV-2 can make itself unrecognizable to the immune response by T-killer cells through mutations. The findings of the research groups of Andreas Bergthaler, Judith Aberle and Johannes Huppa provide important clues for the further development of vaccines and were published in the journal Science Immunology.
After a year of the pandemic, an increasingly clear picture is emerging for science and medicine of how the immune response protects people from SARS-CoV-2. Two protagonists play central roles: antibodies and T-killer cells (also called cytotoxic CD8 T cells). While antibodies dock directly onto viruses to render them harmless, T-killer cells recognize viral protein fragments on infected cells and subsequently kill them to stop virus production. More and more studies show that SARS-CoV-2 can evade the antibody immune response through mutations and thus also impair the effectiveness of vaccines. Whether such mutations also affect T-killer cells in their function had not been clarified so far. Benedikt Agerer in the laboratory of Andreas Bergthaler (CeMM), Maximilian Koblischke and Venugopal Gudipati in the research groups of Judith Aberle and Johannes Huppa (both Medical University of Vienna) have now worked together closely to investigate the effect of viral mutations in so-called T cell epitopes, i.e., in regions recognized by T-killer cells. For this purpose, they sequenced 750 SARS-CoV-2 viral genomes from infected individuals and analyzed mutations for their potential to alter T cell epitopes. “Our results show that many mutations in SARS-CoV-2 are indeed capable of doing this. With the help of bioinformatic and biochemical investigations as well as laboratory experiments with blood cells from COVID-19 patients, we were able to show that mutated viruses can no longer be recognized by T-killer cells in these regions,” says Andreas Bergthaler.
Focus on spike protein might be too narrow
In most natural infections, several epitopes are available for recognition by T-killer cells. If the virus mutates in one place, it is likely that other epitopes indicate the presence of the virus.
Most of the current vaccines against SARS-CoV-2 are directed exclusively against the so-called spike protein, which is one of 26 virus proteins. This also reduces the number of epitopes that are available for recognition by T-killer cells. “The spike protein has, on average, one to six of these T cell epitopes in an infected person. If the virus mutates in one of these regions, the risk that the infected cells will not be recognized by the T-killer cells increases,” explains Johannes Huppa. Judith Aberle emphasizes: “Especially for the further development of vaccines, we therefore have to keep a close eye on how the virus mutates and which mutations prevail globally. Currently, we see few indications that mutations in T killer cell epitopes are increasingly spreading.”
The study authors see no reason in their data to believe that SARS-CoV-2 can completely evade the human immune response. However, these results provide important insights into how SARS-CoV-2 interacts with the immune system. “Furthermore, this knowledge helps to develop more effective vaccines with the potential to activate as many T-killer cells as possible via a variety of epitopes. The goal are vaccines that trigger neutralizing antibody and T killer cell responses for the broadest possible protection,” the study authors say.
The study “SARS-CoV-2 mutations in MHC-I restricted epitopes evade CD8+ T cell responses” was published in Science Immunology online on March 4, 2021.
DOI: 10.1126/sciimmunol.eabg6461
Authors: Benedikt Agerer*, Maximilian Koblischke*, Venugopal Gudipati*, Luis Fernando Montaño-Gutierrez, Mark Smyth, Alexandra Popa, Jakob-Wendelin Genger, Lukas Endler, David M. Florian, Vanessa Mühlgrabner, Marianne Graninger, Stephan W. Aberle, Anna-Maria Husa, Lisa Ellen Shaw, Alexander Lercher, Pia Gattinger, Ricard Torralba-Gombau, Doris Trapin, Thomas Penz, Daniele Barreca, Ingrid Fae, Sabine Wenda, Marianna Traungott, Gernot Walder, Winfried F. Pickl, Volker Thiel, Franz Allerberger, Hannes Stockinger, Elisabeth Puchhammer-Stöckl, Wolfgang Weninger, Gottfried Fischer, Wolfgang Hoepler, Erich Pawelka, Alexander Zoufaly, Rudolf Valenta, Christoph Bock, Wolfgang Paster, René Geyeregger, Matthias Farlik, Florian Halbritter, Johannes B. Huppa**, Judith H. Aberle**, Andreas Bergthaler**
*, **Equal contributions
Funding: This project was funded in part by two grants from the Vienna Science and Technology Fund (WWTF) as part of the WWTF COVID-19 Rapid Response Funding 2020 awarded to Andreas Bergthaler and René Geyeregger, respectively.
Benedikt Agerer was supported by the Austrian Science Fund (FWF) DK W1212. Mark Smyth and Alexander Lercher were supported by DOC fellowships of the Austrian Academy of Sciences (No. 24813, No. 24158 and No. 24955 respectively). Venugopal Gudipati, Vanessa Mühlgrabner and Johannes B. Huppa received support from the Vienna Science and Technology Fund
(WWTF, LS14-031). Judith H. Abele was supported by the Medical-Scientific fund of the Mayor of the federal capital Vienna (grant COVID003). Winfried F. Pickl. was supported by the Medical-Scientific fund of the Mayor of the federal capital Vienna (grant COVID006). Christoph Bock and Andreas Bergthaler were supported by ERC Starting Grants (European Union’s Horizon 2020 research and innovation program, grant agreement numbers 679146 respectively 677006).
