TF-PAR2 signaling in TLR3-induced lung inflammation and Coxsackievirus infection

Abstract:

Activation of protease activated receptors (PARs) by coagulation proteases influences the innate immune responses in viral infection. Tissue factor (TF) orchestrates PAR2 cleavage by coagulation factor VIIa or Xa, but the specific roles of these PAR2 activating proteases in immunity are incompletely understood. This project aims at defining the role of TF-FVIIa-PAR2 signaling in antiviral and TLR3 responses and at contrasting these results to the contributions of TF-PAR2 coagulation signaling to tumor escape mechanisms. The results from these studies will yield novel insights into beneficial effects of protease-selective anticoagulants on anti-viral immunity.

Principal investigators:

Univ.-Prof. Dr. med. Antje Beling (née Voigt)
Institut für Biochemie, CharitéCentrum Grundlagenmedizin CC2
Charité - Universitätsmedizin Berlin
Charitéplatz 1, 10117 Berlin
Phone: +49 (0)30 450 528 187
E-mail: antje.beling@charite.de
Web: https://biochemie.charite.de / https://www.researchgate.net/profile/Antje_Beling

Univ.-Prof. Dr. med. Wolfram Ruf
Centrum für Thrombose und Hämostase
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
Langenbeckstraße 1, 55131 Mainz
Phone: +49 (0)6131 17-8222
E-mail: ruf@uni-mainz.de
Web: http://www.unimedizin-mainz.de/cth/professorships-work-groups/prof-ruf.html?L=1

Doctoral candidates:

Kristin Grunz

Meike Kespohl

 

Project-related publications:

Subramaniam S, Jurk K, Hobohm L, Jäckel S, Saffarzadeh M, Schwierczek K, Wenzel P, Langer F, Reinhardt C, Ruf W (2017) Distinct contributions of complement factors to platelet activation and fibrin formation in venous thrombus development. Blood, 129:2291-2302

Paeschke A, Possehl A, Klingel K, Voss M, Voss K, Kesphol M, Sauter M, Overkleeft HS, Althof N, Garlanda C, Voigt A (2016) The availability of the cardio-protective pattern recognition molecule Pentraxin3 is controlled by the immunoproteasome. Eur. J. Immunol. 46:619-633

Rothmeier AS, Marchese P, Petrich BG, Furlan-Freguia C, Ginsberg MH, Ruggeri ZM, Ruf W (2015) Caspase-1-mediated pathway promotes generation of thromboinflammatory microparticles. J. Clin. Invest. 125:1471-84

Liang HP, Kerschen EJ, Hernandez I, Basu S, Zogg M, Botros F, Jia S, Hessner MJ, Griffin JH, Ruf W, and Weiler H (2015) EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice. Blood, 125:2845-54

Rahnefeld A, Klingel K, Schuermann A, Diny NL, Althof N, Lindner A, Bleienheuft P, Savvatis K, Respondek D, Opitz E, Ketscher L, Sauter M, Seifert U, Tschope C, Poller W, Knobeloch KP and Voigt A (2014) Ubiquitin-Like Protein ISG15 (Interferon-Stimulated Gene of 15 kDa) in Host Defense Against Heart Failure in a Mouse Model of Virus-Induced Cardiomyopathy. Circulation. 130:1589-600

Sutherland MR, Ruf W, Pryzdial ELG (2012) Tissue factor and glycoprotein C on herpes simplex virus type 1 are protease activated receptor 2 cofactors that enhance infection. Blood, 119:3638-3645

Opitz E, Koch A, Klingel K, Schmidt F, Prokop S, Rahnefeld A, Sauter M, Heppner FL, Volker U, Kandolf R, Kuckelkorn U, Stangl K, Kruger E, Kloetzel PM and Voigt A (2011) Impairment of immunoproteasome function by beta5i/LMP7 subunit deficiency results in severe enterovirus myocarditis. PLoS Pathogens. 7:1-13

Rahnefeld A, Ebstein F, Albrecht N, Opitz E, Kuckelkorn U, Stangl K, Rehm A, Kloetzel PM and Voigt A (2011) Antigen-presentation capacity of dendritic cells is impaired in ongoing enterovirus myocarditis. Eur. J. Immunol. 41:2774-2781

Jakel S, Kuckelkorn U, Szalay G, Plotz M, Textoris-Taube K, Opitz E, Klingel K, Stevanovic S, Kandolf R, Kotsch K, Stangl K, Kloetzel PM and Voigt A (2009) Differential Interferon Responses Enhance Viral Epitope Generation by Myocardial Immunoproteasomes in Murine Enterovirus Myocarditis. Amer. J. Pathol. 175:510-518

Ahamed J, Niessen F, Kurokawa T, Lee YK, Bhattacharjee G, Morrissey JH, Ruf W (2008) Regulation of macrophage LPS signaling by the tissue factor cytoplasmic domain. Blood, 109:5251-59