We used conditional ablation of STAT1 in macrophages, monocytes and granulocytes of mice and showed that myeloid STAT1 protects from early murine cytomegalovirus replication and pathology in spleen. Unexpectedly, we found that myeloid STAT1 drives extramedullary haematopoiesis (EMH). STAT1 promotes EMH not only after virus infection but also upon sterile inflammation induced by CpG oligodeoxynucleotides. Using additional genetically engineered mice we analysed the impact of upstream signals known to activate STAT1 and observed that virus-induced EMH does not rely on type I or type II IFN signaling in myeloid cells or IL-27 signaling in all cell types. Our studies provide the first genetic evidence that STAT1-dependent signaling in myeloid cells restricts MCMV at early time points post infection and induces compensatory (stress-induced) haematopoiesis in the spleen.

Publication in Cell Reports

Riem Gawish*, Tanja Bulat*, Mario Biaggio*, Caroline Lassnig, Zsuzsanna Bago-Horvath, Sabine Macho-Maschler, Andrea Poelzl, Natalija Simonović, Michaela Prchal-Murphy, Rita Rom, Lena Amenitsch, Luca Ferrarese, Juliana Kornhoff, Therese Lederer, Jasmin Svinka, Robert Eferl, Markus Bosmann, Ulrich Kalinke, Dagmar Stoiber, Veronika Sexl, Astrid Krmpotić, Stipan Jonjić, Mathias Müller, and Birgit Strobl

*equal author contribution

Myeloid Cells Restrict MCMV and Drive Stress-Induced Extramedullary Hematopoiesis through STAT1 (2019); Doi: https://doi.org/10.1016/j.celrep.2019.02.017

We used conditional ablation of TYK2 in mice and showed that TYK2 promotes NK cell activity in tumour surveillance and the defence against Listeria monocytogenes infection through cell-extrinsic and -intrinsic mechanisms. The key discoveries are as follows: NK cell-extrinsic TYK2 drives peripheral NK cell maturation, demethylation of the Ifng locus, activating receptor-induced IFNg production, cytotoxicity and anti-tumour activity; the NK cell defects observed in Tyk2-/- mice can be restored by recombinant IL-15/IL-15Rα treatment; NK cell-intrinsic TYK2 signalling mediates infection-induced IFNg production and acts protective during Listeria monocytogenes infection.

Collectively, our study disclosed TYK2 functions that remained unrecognized in mice with complete TYK2 deficiency. Our findings that cytotoxic defects of Tyk2-/- NK cells can be rescued by IL-15/IL-15Rα treatment suggest that unwanted effects of TYK2 inhibitors in tumour therapy may be overcome by boosting NK cell activity.

Publication in Journal of Immunology

Natalija Simonović * , Agnieszka Witalisz-Siepracka *, Katrin Meissl, Caroline Lassnig, Ursula Reichart,  Thomas Kolbe,  Matthias Farlik, Christoph Bock, Veronika Sexl, Mathias Müller, and Birgit Strobl

*equal author contribution

NK Cells Require Cell-Extrinsic and -Intrinsic TYK2 for Full Functionality in Tumor Surveillance and Antibacterial Immunity (2019); Doi:

https://doi.org/10.4049/jimmunol.1701649

The symposium will be held at the Vetmeduni Vienna on January 31 and February 01, 2019. The symposium invited speakers from the Vienna Life Science community and from the Vetmeduni Vienna who work in basic and translational biomedical sciences to pave the road for new therapeutic concepts. Their research contributions serve as role models for students and early career scientists. We train students of the MSc program ‘Comparative Biomedicine’on our campus under the principle of “One Health – One Medicine”. The symposium is organized and supported by SFB F61 JakStat Monarchies.

Link to PDF of Program

An international research team led by Veronika Sexl from Vetmeduni Vienna and supported by other members of SFB ‚JakStat Monarchies‘ have made an important discovery that could lead to a better understanding of lymphocytic leukemia: the STAT5B protein – but not the highly related STAT5A isoform – is crucial for disease development by suppressing interferon signals during leukemic transformation. Our findings will enable novel therapeutic approaches in precision medicine.

Publication in Leukemia:

Sebastian Kollmann, Eva Grundschober, Barbara Maurer, Wolfgang Warsch, Reinhard Grausenburger, Leo Edlinger, Jani Huuhtanen, Sabine Lagger, Lothar Hennighausen, Peter Valent, Thomas Decker, Birgit Strobl, Mathias Mueller, Satu Mustjoki, Andrea Hoelbl-Kovacic and Veronika Sexl

Twins with different personalities: STAT5B—but not STAT5A—has a key role in BCR/ABL-induced leukemia (2019), https://doi.org/10.1038/s41375-018-0369-5

Facial tumours of Tasmanian devils belong to rare cases of transmissible cancers. More than 90% of the population of devils is extinct due to two distinct Schwannoma cell lines that spread among the species. They are of great interest for biomedical research, as they allow the study of fundamental properties of cancer cells and how they escape the host´s immune system. Using cutting-edge technologies, scientists of the group of Andreas Bergthaler at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and members of the groups of Richard Moriggl and Christoph Bock, both SFB JakStat Monarchies at the Vienna University of Veterinary Medicine together with international collaborators identified the ERBB receptor-STAT3 axis as key molecular mechanisms allowing for the transmissibility of the tumour cells. Importantly, the consortium showed that the inhibition of ERBB receptors with a selective tyrosine kinase inhibitor or pharmacologic intervention of STAT3 could selectively kill the transmissible cancer cells upregulating MHC class I allowing for immune cell recognition. This could play an important role for the treatment and understanding of the disease to rescue the Tasmanian devil in the isolated island from extinction.

Publication in Cancer Cell:

Lindsay Kosack, Bettina Wingelhofer, Alexandra Popa, Anna Orlova, Benedikt Agerer, Bojan Vilagos, Peter Majek, Katja Parapatics, Alexander Lercher, Anna Ringler, Johanna Klughammer, Mark Smyth, Kseniya Khamina, Hatoon Baazim, Elvin D. de Araujo, David A. Rosa, Jisung Park, Gary Tin, Siawash Ahmar, Patrick T. Gunning, Christoph Bock, Hannah V. Siddle, Gregory M. Woods, Stefan Kubicek, Elisabeth P. Murchison, Keiryn L. Bennett, Richard Moriggl and Andreas Bergthaler

The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease (2019) DOI:https://doi.org/10.1016/j.ccell.2018.11.018

See also “The Deadly Bite of STAT3” mini review Cancer Cell by Hagen Schwenzer and Ariberto Fassati: DOI:https://doi.org/10.1016/j.ccell.2018.12.004

The Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway is critical in tuning immune responses and its dysregulation is tightly associated with cancer and immune disorders. Disruption of interleukin (IL)-15/STAT5 signaling pathway due to the loss of IL-15 receptor chains, JAK3 or STAT5 leads to immune deficiencies with natural killer (NK) cell abnormalities. JAK1, together with JAK3 transmits signals downstream of IL-15, but the exact contribution of JAK1 to NK cell biology remains to be elucidated. In this study we show that deletion of NK cell-intrinsic JAK1 leads to an almost complete loss of NK cells in the spleen, blood, and liver, proving a crucial role of JAK1 in peripheral NK cells. The absence of one allele of Jak1 suffices to drastically impair NK cell function whereas the deletion of JAK2 in NK cells has no impact on their survival or maturation. We thus propose that in contrast to currently used JAK1/JAK2 inhibitors, the use of JAK2-specific inhibitors would be advantageous for the cancer patients by leaving NK cells intact.

Publication in Frontiers in Immunology

Agnieszka Witalisz-Siepracka, Klara Klein, Daniela Prinz, Nicoletta Leidenfrost, Gernot Schabbauer, Alexander Dohnal and Veronika Sexl

Loss of JAK1 Drives Innate Immune Deficiency (2019), doi: 10.3389/fimmu.2018.03108

See also Video:  https://drive.google.com/open?id=1lUNFRP4aLRZxr4-9VQkKV30IwV2EppKh

STAT1 exists as two alternatively spliced isoforms, STAT1α and STAT1β; the latter lacks the C-terminal transactivation domain (TAD). Our previous study with gene-modified mice expressing only the STAT1β isoform (Stat1β/β) demonstrated that STAT1β is capable of inducing a subset of IFNγ-responsive genes but the reason for the gene-selectivity remained unclear. In this study we used primary macrophages form wild-type and Stat1β/β mice to characterize the role of the C-terminal TAD in the transactivation and cofactor recruitment to paradigmatic IFNγ-responsive genes. Our key discoveries are that the STAT1β isoform is differentially required for (i) the recruitment of the Mediator coactivator complex and the transition of poised RNA polymerase II (Pol II) into productive elongation, (ii) the association of the general transcription factors TFIIH and p-TEFb to promoter elements specifically at late time points after stimulation or (iii) the establishment of active histone marks and the recruitment of Pol II to the STAT1 and IRF1 co-regulated gene promoters.

Collectively, our results shed new light on the communication of STAT1 with the transcriptional machinery and provide mechanistic insights into isoform-specific transcriptional activities of STAT1.

Publication in Frontiers in Immunology

Matthias Parrini, Katrin Meissl, Mojoyinola Joanna Ola, Therese Lederer, Ana Puga, Sebastian Wienerroither, Pavel Kovarik, Thomas Decker, Mathias Müller  and Birgit Strobl

The C-Terminal Transactivation Domain of STAT1 Has a Gene-Specific Role in Transativation and Cofactor Recruitment (2018), doi: 10.3389/fimmu.2018.02879

RNA helicase DDX3X is important for many aspects of RNA metabolism and RNA translation. In addition, several publications have highlighted a role for DDX3X in immunity, as it contributes to the induction of type I IFNs. However, the in vivo relevance of DDX3X in cells of hematopoietic origin remains unexplored. Using mouse genetics, we demonstrate that DDX3X makes important contributions to innate immunity against pathogens beyond its role in IFN induction, by influencing hematopoiesis as well as the transcription of many antimicrobial genes. By comparison between cells from male or female animals we show that DDX3X functions are in part compensated by its Y-chromosomal homologue DDX3Y. This suggests that DDX3X may be one of the factors contributing to well-established differences of the male and female immune systems. 

Publication in PLoS Pathogens

Daniel Szappanos, Roland Tschismarov, Thomas Perlot, Sandra Westermayer, Katrin Fischer, Ekaterini Platanitis, Fabian Kallinger, Maria Novatchkova, Caroline Lassnig, Mathias Müller, Veronika Sexl, Keiryn L. Bennett, Michelle Foong-Sobis, Josef M. Penninger and Thomas Decker

The RNA helicase DDX3X is an essential mediator of innate antimicrobial immunity (2018), https://doi.org/10.1371/journal.ppat.1007397

The conference will be held at the Sheraton Resort, Rhodes, Greece on June 2-7, 2019.

Organizing committee: Belinda Parker, Leonidas Platanias, Mathias Müller and Serge Y Fuchs.

The Conference is under the sponsorship of Aegean Conferences, a non-profit educational organization promoting science through focused scientific conferences (www.aegeanconferences.org). Registration will be limited to 80-110 participants for this meeting; therefore, there should be ample opportunities for interactions and discussions.

The conference sessions present subject areas focused on:

Role of cytokines in tumor initiation, progression and metastatic disease

Anti-tumorigenic effects of interferons and other cytokines

Cytokine-mediated immune regulation and tumor microenvironment

Cytokines and cancer stem cells

Targeting cytokine pathways for anti-cancer treatment and therapeutic use of cytokines

The program details will be presented soon. Click here to download the flyer

https://www.aegeanconferences.org/src/App/conferences/view/139

The invitation only meeting on May 6-9, 2018 boasts an outstanding scientific programme and will take place in a beautiful location and inspiring atmosphere. We have invited international experts to complement the scientific programme of the two SFBs, including: Jacqueline Bromberg, New York; Gerard Evan, Cambridge; Thomas Graf, Barcelona; Nancy Hynes, Basel; Shai Izraeli, Tel Aviv; David Levy, New York; A. Tom Look, Harvard;  Tak Mak, Toronto

A cooperation of Ludwig Boltzmann Institute for Cancer Research, Ludwig Boltzmann Cluster Oncology, SFB-F47, and SFB-F61

Figure: The meeting will be held at Seggau Castle in Styria, close to the city of Leibnitz