Vaccine boosts innate immunity in people with dormant immune cells

Bacillus Calmette-Guérin (BCG) is one of the world’s oldest and most widely used vaccines. It was developed in the early 20th century to provide protection from tuberculosis. Surprisingly, this vaccine protects not only against tuberculosis but also reduces the risk for various other infections, through a mechanism called trained immunity. A new study led by SFB member Christoph Bock and Mihai Netea found that epigenetic cell states predict whether or not an individual profits from the “wake-up call” to the innate immune system that is provided by the BCG vaccine. This discovery contributes to the development of future therapeutics that induce protective trained immunity.

Published in Immunity

Simone J C F M Moorlag, Lukas Folkman, Rob Ter Horst, Thomas Krausgruber, Daniele Barreca, Linda C Schuster, Victoria Fife, Vasiliki Matzaraki, Wenchao Li, Stephan Reichl, Vera P Mourits, Valerie A C M Koeken, L Charlotte J de Bree, Helga Dijkstra, Heidi Lemmers, Bram van Cranenbroek, Esther van Rijssen, Hans J P M Koenen, Irma Joosten, Cheng-Jian Xu, Yang Li, Leo A B Joosten, Reinout van Crevel, Mihai G Netea, Christoph Bock

Multi-omics analysis of innate and adaptive responses to BCG vaccination reveals epigenetic cell states that predict trained immunity

https://doi.org/10.1016/j.immuni.2023.12.005

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CeMM team leading the data analysis: Christoph Bock, Rob ter Horst, Thomas Krausgruber, Lukas Folkmann (from left to right; ©CeMM)

DOC scholarships from the Austrian Academy of Sciences (ÖAW) for young scientists at the Vetmeduni Vienna.

Myint Aung (group Heidi Neubauer) and Jonatan Kendler (group Richard Moriggl) were each awarded one of the coveted DOC scholarships of the Austrian Academy of Sciences (ÖAW, https://stipendien.oeaw.ac.at/en/fellowships/doc). The scholarships are awarded to outstanding young scientists in a highly competitive selection process.

Myint will use preclinical mouse modelst o investigate the oncogenic STAT5B-driven disease mechanisms and druggabilities in γδ T cell lymphoma.

Jonatan aims to unravel the interplay of CDK6 and STAT5B in NPM/ALK-driven haematopoietic malignancies to define therapeutic vulanerabilities. Both scholarships will start in 2024.

The SFB members congratulate!

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Sylvia Knapp receives Prize of the City of Vienna

On 16 May 2023 Sylvia Knapp, Professor of Infection Biology at the Medical University of Vienna and PI of SFB F61, was awarded the Prize of the City of Vienna in the category Medical Sciences. The awards for outstanding achievements in culture and science were presented by the City Councillor for Culture and Science, Veronica Kaup-Hasler, in a festive ceremony in the ballroom of Vienna City Hall.

For further information see:

https://www.meduniwien.ac.at/web/en/about-us/news/2023/news-in-may-2023/sylvia-knapp-erhaelt-preis-der-stadt-wien/

https://presse.wien.gv.at/2022/12/09/preise-der-stadt-wien-2022-fuer-herausragende-leistungen-in-kultur-und-wissenschaft

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The SFB members Anna Orlova and Richard Moriggl are co-founders of the pharmaceutical start-up RIANA Therapeutics spun out of Vetmeduni Vienna in February 2023. RIANA Therapeutics focuses on developing novel anti-cancer treatments with hope to improve life of cancer patients.

For further information see https://www.vetmeduni.ac.at/en/universitaet/infoservice/presseinformationen/presseinformationen-2023/riana-viennese-start-up-develops-novel-precise-anti-cancer-drugs

Foto credit Thomas Suchanek/Vetmeduni Vienna

The SFB Jak-Stat subproject leader Veronika Sexl took the lead of the University of Innsbruck (https://www.uibk.ac.at/en/) in March 2023. Veronika was appointed head of the rectorate in an international selection process for a period of four years. The SFB members congratulate Veronika to this highly responsible and prestigious position. We will miss Veronika’s scientific excellence and spirit in our team and wish her a successful and fruitful time in Innsbruck.

Richard Moriggl – a long-term member of the SFB – will take over the leadership of the subproject ‘Partners in Crime: STAT3 and CDK6 Control Transformation in Hematopoietic Cells’. We highly appreciate the commitment of Richard and look forward to exciting interactions.

Foto credit Michael Bernkopf/Vetmeduni Vienna

Interferons (IFNs) activate cell-intrinsic defence mechanisms to fight infections. The innate immune response to infections overlaps and cooperates with cellular stress signalling governed by the mitogen-activated protein kinase (MAPK) p38. Laura Boccuni in the group of Thomas Decker unravelled the molecular mechanism how macrophages merge the IFN JAK-STAT and the stress p38 MAPK pathways to enhance the beneficial but also the detrimental effects of the innate and inflammatory responses. With the exception of one, all SFB groups contributed to this SFB-financed publication.

Published in Science Signaling

Laura Boccuni, Elke Podgorschek, Moritz Schmiedeberg, Ekaterini Platanitis, Peter Traxler, Philipp Fischer, Alessia Schirripa, Philipp Novoszel, Angel R. Nebreda, J. Simon C. Arthur, Nikolaus Fortelny, Matthias Farlik, Veronika Sexl, Christoph Bock, Maria Sibilia, Pavel Kovarik, Mathias Müller, Thomas Decker

Stress signaling boosts interferon-induced gene transcription in macrophages
https://doi.org/10.1126/scisignal.abq5389

See also for RELATED FOCUS: Rewiring the logic board of IFN signaling, by John D. MacMicking John D. MacMicking
https://doi.org/10.1126/scisignal.adf0778

The JAK-STAT signaling pioneers James E Darnell, John J O‘Shea and George R Stark and former or current co-workers in their labs co-author a comprehensive review on the current knowledge on the cellular and systemic activities of JAKs and STATs and possibilities of their therapeutic targeting in disease settings (see https://doi.org/10.1016/j.cell.2022.09.023).

The Viennese JAK-STAT community congratulates this fascinating pathway to its 30ies anniversary!

Katarzyna Sitnik wins Merit Award of CMV Conference

  https://www.cmv2022.org Abstract of Oral Presentation Pdgfra-positive fibroblasts are a major site of mouse cytomegalovirus latency in vivo. Latent cytomegalovirus (CMV) infections pertain to most of the human population, yet our understanding of the cell types that carry latent CMV in vivo remains limited. While endothelial cells and macrophages have been identified previously as sites […]

Innate immunity to viral infection is achieved by a group of polypeptide mediators, the interferons (IFN). By binding to cell surface receptors they initiate signal transduction via Janus kinases (JAK) that the STATs target, a group of transcription factors. STATs combine to form a transcription factor, ISGF3, that activates transcription of a large number of IFN-induced genes (ISG) encoding antiviral proteins and establishing an antiviral state.
We show that the transcription of antiviral genes includes important changes of chromatin structure (see below). First, ISGF3 binds to the control region of ISG to induce a rearrangement of nucleosomes that creates maximal accessibility of the promoter (below middle panel). Second, ISG that are arranged in chromosomal clusters change their chromatin loop structure to increase the interaction of regulatory elements (below right panel). The molecular model emerging from the study posits that interaction in the 3-dimensional space creates regulatory hubs with the ability to influence the expression of several clustered genes simultaneously. This may help to both coordinate, accelerate and strengthen the establishment of the antiviral state.

IFN stimulus alters the 3-dimensional chromatin architecture at antiviral gene clusters

Published in iScience

Ekaterini Platanitis, Sthephan Gruener, Aarathy Ravi Sundar Jose Geetha, Laura Boccuni, Alexander Vogt, Maria Novatchkova, Andreas Sommer, Iros Barozzi, Mathias Müller, Thomas Decker

Interferons reshape the 3D conformation and accessibility of macrophage chromatin

https://doi.org/10.1016/j.isci.2022.103840

Our work builds on a previously published paper (https://doi.org/10.1038/leu.2016.277) describing germ-line TYK2 gain-of-function (GOF) mutations identified in childhood leukemia. In close collaboration with the Dutch pediatric oncologists we studied the oncogenic and druggable properties of the two activating mutations of this JAK family member tyrosine kinase. We demonstrate the transformation capacity of the potent TYK2P760L mutation in various hematopoietic cell systems and its tumorigenic potential upon transplantation into mouse models. The highly selective TYK2 inhibitor deucravacitinib blocked GOF TYK2 activity. A screen for kinase pathways co-operating with oncogenic TYK2 identified the PI3K/AKT/mTOR and CDK4/6 pathways as top hits. Combinatorial treatment of the TYK2inib with blockers of these pathways turned out to be more efficacious than single treatments and could be successfully translated to PDX cells derived from the TYK2P760L mutation carrying patient. The original work with contributions from the SFB members Birgit Strobl, Veronika Sexl, Richard Moriggl and Mathias Müller establishes novel treatment options for acute leukemia in patients harboring GOF TYK2 mutations and has not been submitted to publication elsewhere.

Published in Haematologica

Katharina Wöss, Sabine Macho-Maschler, Dorette S. Van Ingen Schenau, Miriam Butler, Caroline Lassnig, Daniel Valcanover, Andrea Poelzl, Katrin Meissl, Barbara Maurer, Tania Brandstoetter, Claus Vogl, Anna Koren, Stefan Kubicek, Anna Orlova, Richard Moriggl, Birgit Strobl, Veronika Sexl, Frank N Van Leeuwen, Roland P Kuiper, Mathias Müller

Oncogenic TYK2P760L kinase is effectively targeted by combinatorial TYK2, mTOR and CDK4/6 kinase blockade

https://doi.org/10.3324/haematol.2021.279848