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Tyk2 in the innate immune response during sepsis

Abstract
Sepsis is a systemic inflammatory reaction initiated by the presence of bacteria, or their products (e.g. endotoxins), in the bloodstream and may lead to septic shock and multi-organ failure. The pathogenesis is incompletely understood and sepsis still represents a major problem in health care due to high mortality rates. Absence of Tyk2 in mice results in an increased resistance against lipopolysaccharide (LPS)-induced endotoxin shock, an experimental model for severe sepsis. Tyk2 belongs to the Janus kinase family of receptor-associated tyrosine kinases and is an integral part of signalling cascades initiated by multiple cytokines. Most of the Tyk2-utilizing cytokines are involved in the regulation of innate and/or adaptive immune responses, although with often opposing functions. It is currently unclear how Tyk2 contributes to the development of endotoxin shock and little is known about its role in sepsis induced by live bacteria. The proposed project is based on the availability of newly generated gene-modified mice, including knockin mice expressing kinase-inactive Tyk2 and conditional Tyk2 knockout mice. This will for the first time allow the study of whether kinase-inactivation of Tyk2 suffices to protect from LPS-induced endotoxin shock and will enable us to assess the contribution of Tyk2 in distinct cell populations to immune responses during sepsis. Within the proposed project we aim to further characterize Tyk2 functions during endotoxemia and to extend these studies to an experimental model of sepsis induced by live bacteria. The results generated will help us to understand the complex network of signalling cascades involved in the pathogenesis of sepsis and may contribute to the design of new therapeutic strategies.
Statistik Austria science classification
106023         Molecular biology
402018         Laboratory animal science
403016         Veterinary immunology
403024         Veterinary pathology
Lemma
Tyk2 während Sepsis
Project leader
Strobl Birgit
Duration
01.07.13-31.01.17
Type of Research
Basic research
Vetmed Research Units
Institute of Animal Breeding and Genetics, Unit of Molecular Genetics
Funded by
FWF - Fonds zur Förderung der wissenschaftlichen Forschung, Wien, Austria

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8 Publications

Poelzl, A; Lassnig, C; Tangermann, S; Hromadová, D; Reichart, U; Gawish, R; Mueller, K; Moriggl, R; Linkermann, A; Glösmann, M; Kenner, L; Mueller, M; Strobl, B (2021): TYK2 licenses non-canonical inflammasome activation during endotoxemia. Cell Death Differ. 2021 28 (2) 748-763.

Gawish, R; Bulat, T; Biaggio, M; Lassnig, C; Bago-Horvath, Z; Macho-Maschler, S; Poelzl, A; Simonović, N; Prchal-Murphy, M; Rom, R; Amenitsch, L; Ferrarese, L; Kornhoff, J; Lederer, T; Svinka, J [and 9 others] (2019): Myeloid Cells Restrict MCMV and Drive Stress-Induced Extramedullary Hematopoiesis through STAT1. Cell Rep. 2019; 26(9):2394-2406.e5
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Simonović, N; Witalisz-Siepracka, A; Meissl, K; Lassnig, C; Reichart, U; Kolbe, T; Farlik, M; Bock, C; Sexl, V; Müller, M; Strobl, B (2019): NK Cells Require Cell-Extrinsic and -Intrinsic TYK2 for Full Functionality in Tumor Surveillance and Antibacterial Immunity. J Immunol. 2019; 202(6):1724-1734
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Parrini, M; Meissl, K; Ola, MJ; Lederer, T; Puga, A; Wienerroither, S; Kovarik, P; Decker, T; Müller, M; Strobl, B (2018): The C-Terminal Transactivation Domain of STAT1 Has a Gene-Specific Role in Transactivation and Cofactor Recruitment. Front Immunol. 2018; 9:2879
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Floss, DM; Klöcker, T; Schröder, J; Lamertz, L; Mrotzek, S; Strobl, B; Hermanns, H; Scheller, J (2016): Defining the functional binding sites of interleukin 12 receptor β1 and interleukin 23 receptor to Janus kinases. Mol Biol Cell. 2016; 27(14):2301-2316
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Leitner, NR; Witalisz-Siepracka, A; Strobl, B; Müller, M (2017): Tyrosine kinase 2 - Surveillant of tumours and bona fide oncogene. Cytokine. 2017; 89:209-218
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Meissl, K; Macho-Maschler, S; Müller, M; Strobl, B (2017): The good and the bad faces of STAT1 in solid tumours. Cytokine. 2017; 89:12-20
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Prchal-Murphy, M; Witalisz-Siepracka, A; Bednarik, KT; Putz, EM; Gotthardt, D; Meissl, K; Sexl, V; Müller, M; Strobl, B (2015): In vivo tumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity. Oncoimmunology. 2015; 4(11):e1047579
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