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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.
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 lab participates in the EU FP7-funded Marie Curie Initial Training Network INBIONET
Title: “Function of CDK8 in STAT1-Regulated Transcription and Cytokine Responses”