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Our research aims at understanding of how immune homeostasis is maintained and how a robust but not exaggerated immune response is accomplished. Defense against infectious agents and damaging cues requires efficient activation of inflammatory response and timely re-establishment of immune homeostasis once the hostile microbial or sterile cues have been eliminated. Unproductive responses result in infectious disease whereas failures in homeostatic processes cause tissue damage and prevent healing. Thus, inflammatory response needs to be strong but quantitatively and timely restricted. Although many of the inflammation-promoting and –controlling processes are known, the basic question of how these processes are coordinated in the context of balanced tissue-protective immune responses remains poorly understood. We study the molecular wiring of robust yet controlled inflammation at the level of transcription, mRNA decay and signaling.
Not Too Little, Not Too Much, Just Right: We investigate immune homeostasis and balanced immune responses in 3 areas:
1) mRNA decay in maintenance of immune homeostasis. mRNA decay is fundamental for immune homeostasis and control of inflammation. We employ genome-wide approaches, systems biology and animal models to reveal mechanisms defining the timely and selective removal of inflammation-associated mRNAs.
2) Mediator kinases in transcriptional responses to cytokines. We investigate how Mediator kinases - enigmatic positive and negative general transcription regulators – tune responses to cytokines. Approach: biochemistry, proteomics and genome-wide assays (GRO-Seq, PRO-Seq, ChIP-Seq etc.).
3) Cytokine signaling in resistance and resilience to infections. Using animal models of infection combined with metabolomics, transcriptomics and cell biology we investigate the key question of how cytokines regulate both elimination of pathogens (resistance) and tissue protection (resilience).
Pavel Kovarik studied molecular biology and biochemistry at universities in Brno and Vienna. He received his PhD in biochemistry from the University of Vienna in 1995. In 2003 he became associate professor at Max F. Perutz Laboratories, University of Vienna, where he was promoted to full Professor of Immunobiology in 2012. He has coordinated several national and European research projects.
IL-1α and IL-1β are pro-inflammatory cytokines that use the same receptor and elicit same cellular responses. Why are then both maintained in mammalian genomes? We were able to define essential and non-redundant functions of IL-1α and IL-1β in protection against bacterial infections: IL-1α drives pathways preventing tissue damage, hence tolerance, while IL-1β is essential for pathogen clearance, thus resistance. See our publication Eislmayr et al, Science Advances 2022.
The Mediator kinase is an enigmatic transcription regulator. Our recent study showed that the Mediator kinase controls Pol II pause release (Steinparzer et al, Molecular Cell 2019). Moreover, the Mediator kinases CDK8 and CDK19 (originally thought to be functionally redundant) fulfil mechanistically distinct functions and activate different gene sets in the interferon-induced anti-viral response.
The lifespan of neutrophils co-determines the duration of immune responses. We showed that TTP-driven mRNA decay is a selective promoter of apoptosis of pathogen-engaged neutrophils: TTP subdues anti-apoptotic (Ebner et al., J Clin Invest 2017). Intriguingly, TTP deletion augments neutrophil response and blunts bacterial infection.
Klebsiella is a significant bacterial pathogen owing to its frequent antibiotic resistance. We discovered an efficient defense mechanism against Klebsiella: it is driven by a feed-forward communication loop between natural killer cells and macrophages that culminates in macrophages-driven antibacterial program (Ivin et al., Plos Pathogens 2017).
The mRNA-destabilizing protein TTP is a key factor in elimination of cytokine mRNAs. By using PAR-iCLIP and mRNA stability assays we established the TTP Atlas, a nucleotide resolution map of functionally annotated TTP binding sites in the macrophage transcriptome (Sedlyarov et al., Mol Syst Biol 2016).
Our study on infection with Streptococcus pyogenes revealed that type I interferon signaling is essential for preventing lethal hyperinflammation – it ensures that the production of the essential pro-inflammatory cytokine IL-1ß reaches protective not destructive levels (Castiglia et al., Cell Host & Microbe 2016).
Transcriptional Responses to IFN-gamma Require Mediator Kinase-Dependent Pause Release and Mechanistically Distinct CDK8 and CDK19 Functions.
Steinparzer, Iris; Sedlyarov, Vitaly; Rubin, Jonathan D; Eislmayr, Kevin; Galbraith, Matthew D; Levandowski, Cecilia B; Vcelkova, Terezia; Sneezum, Lucy; Wascher, Florian; Amman, Fabian; Kleinova, Renata; Bender, Heather; Andrysik, Zdenek; Espinosa, Joaquin M; Superti-Furga, Giulio; Dowell, Robin D; Taatjes, Dylan J; Kovarik, Pavel
The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection.
Ebner F, Sedlyarov V, Tasciyan S, Ivin M, Kratochvill F, Gratz N, Kenner L, Villunger A, Sixt M, Kovarik P
Natural killer cell-intrinsic type I IFN signaling controls Klebsiella pneumoniae growth during lung infection
Masa Ivin, Amy Dumigan, Filipe N. de Vasconcelos, Florian Ebner, Martina Borroni, Anoop Kavirayani, Kornelia N. Przybyszewska, Rebecca J. Ingram, Stefan Lienenklaus, Ulrich Kalinke, Dagmar Stoiber, Jose A. Bengoechea, Pavel Kovarik
The Group Kovarik participates in the special research program “RNA-regulation of the transcriptome” funded by the Austrian Research Fund FWF.
The lab participates in the EU FP7-funded Marie Curie Initial Training Network INBIONET
Pavel Kovarik coordinates the University of Vienna-funded research platform “Decoding mRNA decay in inflammation”
The Kovarik lab participates in the transnational Infect-ERA project HAPLOINFECT funded by FWF and EU FP7.
Title: “Function of CDK8 in STAT1-Regulated Transcription and Cytokine Responses”
Voyage of the Starships: giant transposons as crucibles of evolution
Parthenogenesis, cryptobiosis, and the survival in extreme environmental conditions
Evading ageing: Mitochondrial and proteostatic adaptations in oocytes
Genomes in Rhodnius prolixus symbiotic system
Stem cells, immune evasion and metastasis in colorectal cancer
Ubiquitin & Friends Symposium 2024
The Ubiquitin & Friends Symposium is an annual international meeting taking place in the beautiful capital of Austria, aiming to bring together scholars from various fields studying ubiquitin/Ubl biology and protein degradation in a personal, family-like atmosphere, as suggested by the name.
The evolution and development of mollusc shells
Unraveling the Complexity of Crossover Regulation in C. elegans
Dynamics of 3D Genome Structure and Function
How superworms can help to solve our plastic waste crisis
Title to be announced
New players in an old pathway: biology of methanogens of the TACK superphylum
Shaping morphogen gradients: from molecules to tissues and back
Title to be announced
Studying stressed cells by in situ structural biology
Exploring Microbial Resilience: Unravelling Escherichia coliand#x27;s Stress Response at the Level of Protein Synthesis
Arbuscular mycorrhiza development and function
Deep homology and deep diversity: Evolving genetic toolkits for making and sensing light
The evolution of cell type identity and tissue microecology at the fetal-maternal interface
The unanticipated roles of PICIs and phages in bacterial evolution
Chemical targeting of subcellular protein localization
Origin and diversification of gut-derived organs in chordates
Job's Dilemma for the Genome: Why Bad Things Happen to Good Chromosomes
Connections between carbon and nitrogen cycling in the ocean
Understanding how the DNA-loop-extruding protein complex Condensin folds a chromatinized genome into mitotic chromosomes
DrugMap: A quantitative pan-cancer analysis of cysteine ligandability
From Roads to Rivers? Occurrence and environmental fate of tire and road wear particles and of tire-related chemicals
FENS 2024 Satellite event: Home cage behavior monitoring at the interface of animal welfare and neuroscience
Striking physiology and cell biology of (marine) environmental microorganisms
Mechanisms controlling maintenance of cohesin dependent loops
Title to be announced