December 21, 2020

Mutational Dynamics of SARS-CoV-2 in Austria

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Following its quest to create the molecular basis for precision medicine and wishing to contribute to fight the COVID-19 pandemia, scientists at CeMM have been sequencing the SARS-CoV-2 genome since March 2020. An interdisciplinary team led by Andreas Bergthaler and Christoph Bock have since obtained more than 1100 samples from Austria, of which 747 resulted in full-length high quality SARS-CoV-2 genomes. These are deposited in the public database GISAID, and the platform is updated on a regular basis with additional sequences, in order to learn more about the molecular understanding of the COVID-19 pandemic and the causative pathogen. Additional information can be found at https://www.sarscov2-austria.org/

Over the last few weeks, the United Kingdom has faced a rapid increase in COVID-19 cases leading to enhanced epidemiological and virological investigations. Analysis of viral genome sequence data identified a sizeable proportion of cases belonging to a new single phylogenetic cluster (B.1.1.7 lineage). The new SARS-CoV-2 variant is defined by 17 nonsynonymous, several of which are found in the viral spike protein, and still of uncertain functional significance. While it is known that viruses constantly change through mutation, and seldom does it lead to biological changes, the variant now increasingly observed in the UK may be associated with increased infectivity, although mechanistic data is still lacking.

The researcher at CeMM in collaboration with the Austrian Agency for Health and Food Safety (AGES), are now looking for this specific SARS-CoV-2 variant with multiple spike protein mutations by sequencing additional virus samples in Austria. Among the latest sequenced and analyzed more than 150 virus samples since September (data still to be uploaded to GISAID), there was no evidence yet that the UK variant had already spread in Austria. However, this may change when new viral isolates are sequenced. This requires additional sequencing efforts, as well as continuing the strict compliance with existing safety measures.

CeMM is proud to be able to provide this important analysis of SARS-CoV-2 sequences for Austria and the international scientific community as quickly as possible, commensurate to the available means. CeMM, however, abstains from any speculative interpretation on the data it produces or from suggestions on policy measures. 

December 10, 2020

Hematoxylin as a killer of CALR mutant cancer cells: New therapeutic approach for the treatment of primary myelofibrosis

Ruochen Jia and Robert Kralovics ( (c) Laura Alvarez / CeMM)

Patients with myeloproliferative neoplasm (MPN), a group of malignant diseases of the bone marrow, often have a carcinogenic mutated form of the calreticulin gene (CALR). Scientists of the research group of Robert Kralovics, Adjunct Principal Investigator at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and group leader at the Medical University of Vienna, have now identified hematoxylin as a novel CALR inhibitor. The study, published in the renowned journal Blood, shows how hematoxylin compounds affect a specific domain of CALR and selectively kill those CALR mutant cells that have been identified as the cause of disease in MPN patients. The discovery has enormous therapeutic potential and gives hope for new treatment options.

In medicine, a group of malignant diseases of the bone marrow is known as myeloproliferative neoplasms. This special type of blood cancer is characterised by increased formation of blood cells, vulnerability to thrombosis and frequent transformation to acute leukaemia. In the laboratory of Robert Kralovics it was discovered as early as 2013 that carcinogenic mutations of the gene calreticulin (CALR) were frequently found in affected patients and are now used clinically as diagnostic and prognostic markers. The mechanism by which the mutated CALR functions as an oncogene, which can lead to myeloid leukaemia, has also been scientifically identified since then. The carcinogenic effect of CALR mutations is based on the interaction of the N-glycan binding domain (GBD) of CALR with the thrombopoietin receptor. Ruochen Jia from the research group of Robert Kralovics at CeMM was looking for a way to stop this interaction and prevent one of the growth advantages of CALR mutated cells. It became evident that a group of chemicals, most notably hematoxylin, can selectively kill mutated CALR cells. The results thus provide extremely valuable information for potential treatment approaches for myeloproliferative neoplasms.

Hematoxylin compounds kill CALR mutated cells

Robert Kralovics, head of the study, explains: “In our study we tried to identify small molecules that might block the interaction between the mutated CALR and the receptor.” The scientists used so-called in-silico docking studies for this purpose. “Basically, these are computer-based simulations of biochemical processes – virtual ‘screenings’ that enable increasingly accurate predictions,” says study author Ruochen Jia. The results showed a group of chemicals as binders for a specific domain of calreticulin, which selectively kill the mutated CALR cells. “Our data suggest that small molecules targeting the N-glycan binding domain of CALR can selectively kill CALR-mutated cells by disrupting the interaction between CALR and the thrombopoietin receptor and inhibiting oncogenic signal transmission,” said the study author. A hematoxylin compound proved to be particularly efficient. So far, hematoxylin has been used as a dye especially in histological staining processes.

Ray of hope for primary myelofibrosis therapy

“Our study demonstrates the enormous therapeutic potential of CALR inhibitor therapy,” says Kralovics. “The treatment of patients with primary myelofibrosis (PMF) continues to produce poor clinical outcomes. They have the clearest tendency to develop acute myeloid leukaemia. Since about one third of PMF patients have a CALR mutation, they could particularly benefit from the new therapeutic approach.”

The study “Hematoxylin binds to mutant calreticulin and disrupts its abnormal interaction with thrombopoietin receptor” was published in the journal Blood on 17 November 2020. DOI: doi.org/10.1182/blood.2020006264.

Authors: Ruochen Jia, Thomas Balligand, Vasyl Atamanyuk, Harini Nivarthi, Erica Xu, Leon Kutzner, Jakob Weinzierl, Audrey Nedelec, Stefan Kubicek, Roman Lesyk, Oleh Zagrijtschuk, Stefan N Constantinescu, Robert Kralovics;

Funding: This study was supported by the Austrian Science Fund FWF (FWF SFB F4702, P29018-B30, FWF Stand-Alone P 30041-B26).

December 09, 2020

ERC Consolidator Grant awarded to CeMM Principal Investigator Christoph Bock

Christoph Bock, CeMM Principal Investigator (© Klaus Pichler / CeMM).

We congratulate Christoph Bock, Principal Investigator at CeMM and Guest Professor at the Medical University of Vienna, for receiving a prestigious and well-endowed ERC Consolidator Grant of the European Research Council.

ERC Consolidator Grants are awarded to outstanding researchers of any nationality and age, with seven to twelve years of experience after PhD, and a scientific track record showing great promise and achievement. Christoph Bock and his research team receive funding worth EUR 2 million for a period of five years to pursue a highly ambitious biomedical research project.

In his project, Christoph will focus on the epigenetic regulation in CAR T cell therapy – an important but underappreciated aspect of cell-based therapies. “We will investigate the regulatory dynamics during CAR T cell therapy in unprecedented molecular detail, by following patients diagnosed with blood cancers. Moreover, we will use CRISPR technology to advance CAR T cell therapy for solid tumors. Our project aims to uncover key roles of epigenetic regulation in CAR T cells and eventually establish new therapies for hard-to-treat cancers” says Christoph Bock.

This is not the first ERC grant to be awarded to Christoph Bock. In 2016, Christoph Bock successfully applied for an ERC Starting Grant. This work led to groundbreaking molecular technologies that the new grant will apply with the goal of advancing cell-based cancer therapy.

Christoph Bock joined CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, as Principal Investigator in 2012. He pursues interdisciplinary research aimed at understanding the epigenetic basis of cancer and advancing precision medicine with genomics technology. His research group combines experimental biology (high-throughput sequencing, epigenetics, CRISPR screening, synthetic biology) with computer science (bioinformatics, machine learning, artificial intelligence). He is guest professor at the Medical University of Vienna, scientific coordinator of the Biomedical Sequencing Facility at CeMM, and group leader at the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases. He coordinates an EU Horizon 2020 project on the single-cell analysis of human organoids as a contribution to the Human Cell Atlas and co-leads a project on the mutational dynamics of SARS-CoV-2 in Austria. Christoph Bock is an elected member of the Young Academy of the Austrian Academy of Sciences and has received major research awards, including the Max Planck Society’s Otto Hahn Medal (2009), and the Overton Prize of the International Society of Computational Biology (2017).

December 07, 2020

CeMM's spin-off Proxygen enters new partnership with Boehringer Ingelheim to explore molecular glue degraders

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Photo credit: Proxygen

CeMM congratulates its spin-off Proxygen on its new collaboration and license agreement with Boehringer Ingelheim. Their new partnership announced today will enable the identification of molecular glue degraders in the aim of degrading cancer drivers that were previously considered undruggable. The collaboration combines Proxygen’s unique molecular glue degrader discovery platform and its expertise in targeted protein degradation with Boehringer Ingelheim’s long-term strategy to provide first-in-class, breakthrough therapies for cancer patients.

Molecular glue degraders and PROTACs harness the power of the cell’s recycling machinery to selectively eliminate disease-causing proteins. Molecular glue degraders achieve this by specifically bridging the distance between target proteins and ubiquitin ligases, which consequently flag the target proteins for rapid degradation. Molecular glues orchestrate this protein-protein proximity through highly cooperative binding. They circumvent the need for a defined binding pocket on the surface of the target protein, a requirement for conventional small molecule drugs, allowing pharmaceutical intervention on proteins that were previously considered undruggable.

This successful partnership will create a new avenue towards an improved identification of molecular glue degraders candidates, and, hence, the development of future therapies to treat cancer effectively.

Read the full press release here.

 

 

December 04, 2020

Thomas Krausgruber awarded the ÖGAI Karl Landsteiner Prize for Basic Research in Immunology 2020

Senior Postdoctoral Fellow Thomas Krausgruber (© Klaus Pichler / CeMM)

Congratulations to Thomas Krausgruber, Senior Postdoctoral Fellow in Christoph Bock’s Group at CeMM, who has received the Karl Landsteiner Prize for Basic Research in Immunology 2020!

Every year the Karl Landsteiner and Eisler-Terramare Foudation Commemoration Trust and the Austrian Society for Allergology and Immunology (ÖGAI) offer a prize of 4,000 € to recognize excellent publications in the field of basic immunology research. The publications must have been published in the last two years and must have been carried out predominantly at an Austrian institution. This year, the ÖGAI award ceremony took place in an online format on 4 December 2020.

The prize recognizes Thomas’ outstanding research on structural cells in relation to the body’s immune function. In a recent paper published in the renowned scientific journal Nature (Nature. 2020 Jul;583(7815):296-302. doi: 10.1038/s41586-020-2424-4), Thomas and colleagues analyzed the epigenetic and transcriptional regulation in structural cells, including epithelium, endothelium, and fibroblasts. They found widespread activity of immune genes, suggesting that structural cells are deeply involved in the body’s response to pathogens. Moreover, the study uncovered an “epigenetic potential” that pre-programs structural cells to engage in the immune response against pathogens.

December 03, 2020

Cancer in children with rare inborn immune defect: High cure rate if treated early

Sevgi Köstel Bal and Kaan Boztug (© St. Anna Children’s Cancer Research Institute).

New research data highlight a marked predisposition to lymphoma, a type of cancer, in children harboring specific gene mutations. A significant fraction of these rare mutations also cause inborn immune defects associated with recurrent infections. Under the leadership of Kaan Boztug, LBI-RUD and CCRI Director and CeMM Adjunct Principal Investigator, and collaborating closely with leading centers across the world, researchers investigated patients bearing recently identified defects in two molecules termed CD27 and CD70. In contrast to previously reported high mortality rates associated with lymphoma in a part of this population, the present results are encouraging: a high cure rate was achieved if patients received stem cell transplantation soon after diagnosis. Published in the Journal Blood, the study gives insights into clinical course and early immunological parameters as well as treatment response in the largest group of children with CD27 or CD70 deficiency to date.

A worldwide study may contribute to cure children with specific inborn mutations, by providing unprecedented insights into disease characteristics. The underlying mutations, namely in the genes encoding CD27 and CD70, cause inborn errors of the immune system (immunodeficiencies). A major threat to these immuno-compromised patients are infections, primarily with Epstein-Barr virus (EBV). The impaired immune system cannot cope with this infection, and the virus persists in the blood. Subsequently it causes severe disease, including lymphoma. This is a type of cancer originating from infection-fighting cells of the immune system, termed lymphocytes.

Given the rarity of these mutations, no consensus on how to treat affected children exists. Previous observations had shown that patients with CD27 or CD70 deficiencies have a significantly increased risk of death during the first occurrence of lymphoma. To improve outcome, the recently published study for the first time reports in-depth clinical and immunological characterization of the largest patient cohort (n=49) with CD27 or CD70 deficiency reported to date.

Remarkable results in a rare disease
The new data highlight the marked predisposition to lymphoma of both CD27 and CD70 deficient patients. For children with severe Epstein-Barr virus associated disease, or lymphoma, genetic investigation of CD27 and CD70 is essential. This could optimize clinical management and most importantly support in making a timely decision for curative hematopoietic stem cell transplantation.

“In our study population we report excellent outcome following hematopoietic stem cell transplantation in patients with severe disease manifestations, predominantly lymphoma”, study senior author Assoc.-Prof. Kaan Boztug, MD, comments. 18 out of 19 (95%) patients who received stem cell transplantation just after their first malignant event could be cured. This means they are cancer free after a median follow-up of two years. Co-first author Sevgi Köstel Bal, MD, PhD, adds, “Our results provide a strong rationale for timely use of this curative treatment in patients with CD27 or CD70 deficiencies upon lymphoma diagnosis.”

Consider immune defect in children with cancer
Designed as a retrospective analysis, the study included clinical information of 49 patients from 20 centers all over the world. 33 patients presented with CD27 and 16 with CD70 deficiency.

The majority (90%) of patients had an Epstein-Barr virus infection at diagnosis of CD27 or CD70 deficiency. 36% of CD27 deficient patients and 56% of CD70-deficient patients developed lymphoma at a median age of 8.5 or three years, respectively. Another frequent event was autoinflammation, which appeared in various forms in 21 patients (43%). Autoinflammation is an aberrant inflammatory reaction affecting the body’s own tissues that derives from the innate immune system.

Major findings relate to immunological characteristics, mechanisms of disease pathogenesis and clinical course of individual patients undergoing various treatments. These findings highlight the critical role of CD27-CD70 interaction in regulating immunity, especially in the context of Epstein-Barr virus control and formation of lymphoma. The new data underline that an immune defect should be considered as underlying cause when children present with cancer, in particular if there is a history of recurrent infections or inability to control Epstein-Barr virus.

Largest cohort due to world-wide approach
Performed in close collaboration with the Inborn Errors Working Party of the European Society for Immunodeficiencies (ESID) and the European Society for Bone and Marrow Transplantation (EBMT), this study reports the to date world’s largest cohort of patients with mutations in either CD27 or CD70. This was only possible in a multicenter effort, led by the study centers in Vienna, Sydney, Düsseldorf, Leiden, Tehran, and Ankara.

Publication:
Extended Clinical and Immunological Phenotype and Transplant Outcome in CD27 and CD70 Deficiency.
S Ghosh*, S Köstel Bal*, E S J Edwards*, B Pillay, R Jimenez-Heredia, G Rao, F Erol Cipe, E Salzer, S Zoghi, H Abolhassani, T Momen, E Gostick, D A Price, Y Zhang, A J Oler, C Gonzaga-Jauregui, B Erman, A Metin, I Ilhan, S Haskologlu, C Islamoglu, K Baskin, S Ceylaner, E Yilmaz, E Unal, M Karakukcu, D Berghuis, T Cole, A Kumar Gupta, F Hauck, A Hoepelman, S Baris, E Karakoc-Aydiner, A Ozen, L Kager, D Holzinger, M Paulussen, R Krüger, R Meisel, P Thomas Oommen, E C Morris, B Neven, A J J Worth, J M van Montfrans, P Fraaij, S Choo, F Dogu, E G Davies, S Burns, G Dueckers, R Perez Becker, H von Bernuth, S Latour, M Faraci, M Gattorno, H Su, Q Pan-Hammarström, L Hammarström, M J Lenardo, C S Ma, T Niehues, A Aghamohammadi, N Rezaei**, A Ikinciogullari**, S G Tangye**, A C Lankester**, K Boztug**
Blood. 2020 Jun 30; blood.2020006738. doi: 10.1182/blood.2020006738. Online ahead of print. PMID: 32603431
* S.G, S.K.B and E.J.E contributed equally.
** N.R., A.I., S.G.T., A.C.L. and K.B. contributed equally.
Corresponding authors: K.B., A.C.L. and S.G.T.
Link: https://doi.org/10.1182/blood.2020006738

Funding:
This work was funded by the European Research Council (ERC), the Austrian Science Fund (FWF), The Susan and John Freeman Cancer Research Grant from Cancer Council NSW (Australia), the National Health and Medical Research Council of Australia, the Wellcome Trust Senior Investigator Award, a Mid-Career Research Fellowship awarded by the Office of Health and Medical Research of the New South Wales Government of Australia, a Principal Research Fellowship and a Peter Doherty Leadership Grant awarded from the National Health and Medical Research Council, the German Centre for Infection Research, the Else Kröner-Fresenius Stiftung, and the German Federal Ministry of Education and Research, the UK National Institute of Health Research and the Great Ormond Street Hospital Biomedical Research Centre and by funds from the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH).

December 01, 2020

SLC25A51 regulates the transport of the coenzyme NAD into the mitochondria

Last author Giulio Superti-Furga and first author Enrico Girardi (© Klaus Pichler / CeMM)

Previously poorly characterized gene proved to be an important regulator with potential for the development of new metabolic therapies against ageing and cancer.

For their growth, cells need various nutrients and vitamins. So-called solute carriers (SLC), proteins that can transport such substances across the boundaries of cellular membranes, play a central role in metabolism. Scientists in Giulio Superti-Furga’s research group at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences have now discovered that the previously uncharacterized protein SLC25A51 acts as a transporter into the mitochondria for the coenzyme NAD. This molecule has already been associated with numerous physiological and pathological processes such as ageing, neurological diseases and the metabolism of cancer cells. Therefore, the results of this study not only open up new possibilities to study the biological role of NAD but also potentially provide the basis for new therapeutic approaches. The work has now been published in the journal Nature Communications.

Solute carriers (SLC) are proteins that act as transporters and enable the entry and exit of nutrients and waste products into and from the cell and its organelles. Many of these transporter proteins are still relatively poorly studied and the question of how some nutrients enter and leave cells often remains unanswered. So far, it has not yet been clarified how mitochondria gain access to an important cofactor of our metabolism, the so-called NAD (nicotinamide adenine dinucleotide). In scientific literature, there were only references to mitochondrial NAD transporters in plants and yeast. Lead author Enrico Girardi and the research group of CeMM Scientific Director Giulio Superti-Furga, in cooperation with scientists from the University of Bari (Italy), have now identified the protein responsible for the important transport of NAD into mitochondria: SLC25A51.

Measurement of nutrient pathways provided evidence

For their studies, the scientists used a specially created cell line library, which allows investigating pairwise genetic interactions of two SLCs. Their genes are deactivated both individually and in pairs; the effects of these interventions on cell growth can then be measured. Among the combination-related large number of interactions measured, some around the previously uncharacterized gene SLC25A51 stood out. The other interacting SLCs transport various nutrients, but all of them could be associated with NAD via known metabolic processes. “By accurately quantitatively measuring certain nutrients in the cells, we found that the presence of SLC25A51 correlated with the amount of NAD and that cells lacking SLC25A51 had extremely low levels of this molecule in their mitochondria,” explains senior author Giulio Superti-Furga. “In our study we also show that the already known NAD transporter in yeast and SLC25A51 play a similar role in the human cell.”

Important part of the scientific puzzle

The question of the existence of a mitochondrial NAD transporter in humans has been discussed for some time. Giulio Superti-Furga also explains: “The results of our research, which have also been confirmed in two other independent studies by US laboratories, provide an important answer to this question and open up the opportunity of influencing the NAD content in this key organelle. NAD is associated with many physiological and pathological processes such as ageing, neurological diseases and the metabolism of cancer cells. Our study therefore represents an important contribution to understanding the biological role of this molecule. At the same time, we also see the enormous therapeutic potential arising from the possibility of a possible modulation of the NAD content in mitochondria by the transporter SLC25A51.”

The study "Epistasis-driven identification of SLC25A51 as a regulator of human mitochondrial NAD import" was published in Nature Communications on 1 December 2020. DOI: 10.1038/s41467-020-19871-x  

Authors: Enrico Girardi, Gennaro Agrimi, Ulrich Goldmann, Giuseppe Fiume, Sabrina Lindinger, Vitaly Sedlyarov, Ismet Srndic, Bettina Gürtl, Benedikt Agerer, Felix Kartnig, Pasquale Scarcia, Maria Antonietta Di Noia, Eva Liñeiro, Manuele Rebsamen, Tabea Wiedmer, Andreas Bergthaler, Luigi Palmieri, Giulio Superti-Furga

Funding: The study was funded with support by the Austrian Academy of Sciences, the European Research Council (ERC) (AdG 695214, StG 677006) and the Austrian Science Fund (FWF P29250-B30, FWF DK W1212).

November 23, 2020

Austrian study provides deep insights into transmission and mutation properties of SARS-CoV-2

The analysis of epidemiologically-validated chains of infections in Austrian superspreading events found that a relatively large average dose of 1000 infectious viral particles is transmitted (© CeMM).

Learning from past SARS-CoV-2 outbreaks for future pandemic control

In the COVID-19 pandemic, 57 million people have already been infected worldwide. In the search for vaccines and therapies, a precise understanding of the virus, its mutations and transmission mechanisms is crucial. A recent study by the research group of Principal Investigator Andreas Bergthaler at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, in the renowned journal Science Translational Medicine, makes an important contribution to this. The high quality of epidemiological data in Austria, together with state-of-the-art virus genome sequencing, has supported unprecedented insights of the mutation behaviour and transmission of the SARS-CoV-2 virus.

The project “Mutational dynamics of SARS-CoV-2 in Austria” was launched by CeMM in close cooperation with the Medical University of Vienna at the end of March. Together with the Austrian Agency for Health and Food Safety (AGES) and in cooperation with numerous universities and hospitals all over Austria, scientists are working on drawing a more precise picture of the virus mutations and transmissions that occur by genome sequencing of SARS-CoV-2 viruses. Under the leadership of CeMM Principal Investigators Andreas Bergthaler and Christoph Bock, 750 samples from important SARS-CoV-2 infection clusters in Austria such as the tourist town of Ischgl and Vienna were phylogenetically and epidemiologically reconstructed and their role in transcontinental virus spread was analysed. The results also provide important information on transmission and the development of mutations in the SARS-CoV-2 virus.

Mutation analyses revealed correlations between clusters 

Based on epidemiological data, the scientists used mutation analyses to reconstruct a SARS-CoV-2 cluster consisting of 76 cases and to uncover a cryptic link between two epidemiological clusters. “This example illustrates how contact tracing and virus mutation analysis together provide a strong pillar of modern pandemic control,” says project leader Andreas Bergthaler. Franz Allerberger, Head of the Public Health Division of AGES and co-author of the study, agrees: “The modern techniques of virus genome sequencing support epidemiological contact tracing and offer high-resolution insights of the ongoing pandemic.”

Researchers observe the development of new mutations

A special feature of the study is that a chain of eight consecutive transmissions was analysed. “The transmission chain started with a returnee from Italy. Within 24 days, the SARS-CoV-2 virus spread in the greater Vienna region via public and social events in closed rooms”, say the CeMM study authors Alexandra Popa and Jakob-Wendelin Genger. The precise breakdown of the transmission chain enabled the scientists to closely observe the development of a new mutation of SARS-CoV-2. “Thanks to excellent epidemiological and our deep virus sequencing data, we could follow how the SARS-CoV-2 virus mutated in one individual and was then transmitted to others,” explains Andreas Bergthaler. In addition, the scientists observed the mutation behaviour of the virus during the course of the disease in 31 patients. This may help in the future to assess whether treatments influence the mutation characteristics of the virus.

On average 1,000 virus particles are transmitted during an infection

The results of the current analyses also show that on average 1000 infectious virus particles are transmitted from one infected person to the next. These values are overall considerably higher than for other viruses such as HIV or noroviruses. Andreas Bergthaler adds: “Yet, occasionally we also found infected people who apparently came into contact with fewer virus particles and still became infected. We suspect that parameters such as the application of protective measures, the transmission route or the immune system may play a decisive role here.” These results raise important new questions and hypotheses. Reducing the viral load of infected individuals by a combination of measures such as mouth-nose protection, physical distance and adequate indoor air exchange could play a key role in both preventing the spread of the virus and possibly even influence the course of the disease.

The current study based on data collected during the early phase of the SARS-CoV-2 pandemic in spring 2020, provides important insights into the fundamental dynamics of SARS-CoV-2 mutations within patients and during transmission events. These results support other ongoing research projects aiming at a better understanding and controlling the pandemic.

Find out more about the project: www.sarscov2-austria.org

The study “Genomic epidemiology of superspreading events reveals mutational dynamics and transmission properties of SARS-CoV-2” was published in the journal Science Translational Medicine on 23 November 2020. DOI: 10.1126/scitranslmed.abe2555

Authors:
Alexandra Popa, Jakob-Wendelin Genger, Michael D. Nicholson, Thomas Penz, Daniela Schmid, Stephan W. Aberle, Benedikt Agerer, Alexander Lercher, Lukas Endler, Henrique Colaço, Mark Smyth, Michael Schuster, Miguel L. Grau, Francisco Martínez-Jiménez, Oriol Pich, Wegene Borena, Erich Pawelka, Zsofia Keszei, Martin Senekowitsch, Jan Laine, Judith H. Aberle, Monika Redlberger-Fritz, Mario Karolyi, Alexander Zoufaly, Sabine Maritschnik, Martin Borkovec, Peter Hufnagl, Manfred Nairz, Günter Weiss, Michael T. Wolfinger, Dorothee von Laer, Giulio Superti-Furga, Nuria Lopez-Bigas, Elisabeth Puchhammer-Stöckl, Franz Allerberger, Franziska Michor, Christoph Bock, Andreas Bergthaler 


Funding:
The project is co-financed by a COVID-Rapid Response grant from the Vienna Science and Technology Fund (WWTF) and by contributions in kind from CeMM, the Austrian Academy of Sciences, the Medical University of Vienna and their respective partners.

 

 

November 19, 2020

Christoph Bock among the world's most highly-cited scientists in 2020

CeMM PI Christoph Bock (© Klaus Pichler / CeMM)

Every year the “Highly Cited Researchers” list provided by Clarivate Analytics recognizes the most influential researchers with highly-cited papers that rank in the top 1% by citation in different scientific fields. This year 39 researchers in the list are working in Austria. Among them, CeMM PI Christoph Bock, who has been included in the cross-field category, highlighting the interdisciplinary nature of his work.

Christoph  Bock  joined  CeMM  as  Principal  Investigator  in  2012.  He  pursues  interdisciplinary  research aimed at understanding the epigenetic and gene-regulatory basis of cancer, and advancing precision medicine with genomics technology. His research group combines experimental biology (high-throughput  sequencing,  epigenetics,  CRISPR  screening,  synthetic  biology)  with  computer  science (bioinformatics, machine learning, artificial intelligence). He is also a guest professor at the Medical University of Vienna, scientific coordinator of the Biomedical Sequencing Facility (BSF) at CeMM, and key researcher at the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases. He  coordinates  the EU  Horizon  2020 HCA|Organoid project  on  the  single-cell  analysis  of  human  organoids  as  a  contribution to the Human Cell Atlas.

Congratulations to Christoph for being among the world’s most highly-cited scientists in 2020!

Check the full list of "Highly Cited Researchers" here.

November 18, 2020

Stem cell transplantation: undesirable rejection mechanism identified

CeMM Adjunct PI Georg Stary (LBI-RUd/MedUni Wien) © Klaus Pichler / CeMM

In the treatment of leukaemia, stem cell transplantation subsequent to chemotherapy and radiation can often engender severe adverse inflammatory reactions – especially in the skin or in the gut, since these so-called barrier organs are more frequently affected. Up until now, the reason for this was unclear. A MedUni Vienna team led by Georg Stary and Johanna Strobl from MedUni Vienna's Department of Dermatology, the CeMM (Research Center for Molecular Medicine of the Austrian Academy of Sciences) and the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases has now identified an immune mechanism that is partially responsible for this. The results have now been published in the leading journal "Science Translational Medicine".  

The term leukaemia is used to describe a group of malignant diseases of the haematopoietic system, in which precursors of the white blood cells (leucocytes) proliferate uncontrollably. Chemotherapy and radiotherapy are used to destroy the abnormal blood cells, which are then replaced by means of a stem cell transplant. In leukaemia, the transplantation of healthy bone marrow stem cells or haematopoietic stem cells is often the only hope of recovery for patients. The process involves "replacing" all the recipient's blood cells that were previously destroyed by the treatment with donor cells.

However, the MedUni Vienna dermatologists have now found that there are so-called skin-resident and inactive T cells in the endogenous immune system that survive chemotherapy and radiotherapy intact and go on to survive for a further ten years between and beneath the epithelial cells of the skin, while the circulating T cells are destroyed.

"We were able to demonstrate that T cells surviving in the skin tissue are responsible for the inflammatory reaction following a stem cell transplant. These phenomena often occur within the first 100 days and can cause anything from mild eczema through to extensive fibrosis, hardening of the tissue, or blistering on the surface of the skin. In other words, the endogenous T cells attack the recipient (host) following stem cell transplantation." In specialist jargon, the condition is also referred to as Graft versus Host Disease (GvHD), and, for the first time, this study identified an inverse "Host-versus-graft reaction".

There were also cases in which the donor T cells further "supported", and thus intensified, this reaction. Affected patients are treated with cortisone, which causes an additional burden for patients who are already immunosuppressed following the transplantation. The study found that in patients who do not develop graft-versus-host disease, tissue-resident T cells remaining after treatment even proved to be beneficial to the recipient, in that they assumed their role in immune defence and protecting against infection.

In the future, the exemplary study results could lead to new treatment strategies that help to avoid, or at least to minimise, undesirable and violent inflammatory reactions following stem cell transplants by manipulating the recipient's inactive T cells in advance. In addition, the manipulation of tissue-resident T cells might lead to new therapeutic approaches for other chronic inflammatory skin diseases, such as psoriasis or neurodermatitis.

Service: Science Translational Medicine
"Long-term skin-resident memory T cells proliferate in situ and are involved in human graft-versus-host disease" Johanna Strobl, Ram Vinay Pandey, Thomas Krausgruber, Nadine Bayer, Lisa Kleissl, Bärbel Reininger, Pablo Vieyra-Garcia, Peter Wolf, Maaia-Margo Jentus, Margit Mitterbauer, Philipp Wohlfarth, Werner Rabitsch, Georg Stingl, Christoph Bock, Georg Stary.

DOI: 10.1126/scitranslmed.abb7028