RNA Viruses: The genetic structure of RNA viral populations (quasi-species) determine their intra-host evolution, rapid adaptation and hence their pathogenesis. Host immune pressure plays a unique role in RNA virus evolution. Viruses such as hepatitis C (HCV) evolve multiple mechanisms to disrupt immune signaling cascades with a net multilayered effect leading to immune escape and/or immune modulation. Such mechanisms are pivotal for viral persistence, treatment failure and ongoing liver injury probably even after apparent successful viral eradication. Our goal is to identify and characterize molecular principles that explain dynamic changes in viral quasi-species and adaptation on host factors to explore basic aspects of immune modulation and escape from immune and/or drug pressure in RNA virus infection.
Welsch et al., J Hepatol 2015; 2015 Apr;62(4):779-84.
(I) Adaptation at Protein-Lipid Interfaces: Folding, structure and function of membrane-bound proteins are influenced by their lipid environments with proteins binding lipids selectively to modulate their structure and respective function. Interference with protein–lipid interactions represents attractive opportunities for the development of novel therapies in various diseases. Using infectious cell culture and biophysics assays we characterize mechanistic details that enable perturbations at protein-lipid interfaces to initiate conformational changes.
Funding: Else Kröner-Fresenius Foundation (EKFS), Research Training Group Translational Research Innovation - Pharma (TRIP)
(II) Principles in Evolutionary Design of Proteins: Residue networks are powerful tools to analyze multiple sequence and protein structure data. Here we apply bioinformatics algorithms to understand statistical properties of viral proteins related to the dynamics of selection between specific conformational states on an RNA virus evolutionary time scale. Our aim is to understand the physical basis and underlying molecular principles that are known to be captured as an evolutionary fingerprint in the sequence information of a respective protein and are likely relate to changing conditions in fitness.
Welsch et al., AAC 2012;56(4):1907-15 Welsch et al., Gastroenterology 2012;142(3):654-63
Liver Immunology: Using our bioinformatics and structure biology tools we work in close collaboration with AG Lange on molecular structural aspects of the immune system of the liver in health and disease. A special emphasis is made on the resolution of liver inflammation.
Funding: Landes-Offensive zur Entwicklung Wissenschaftlich-ökonomischer Exzellenz (LOEWE) - Research Center for Translational Medicine and Pharmacology TMP.
PD Dr. med. Christoph Welsch, Group Leader (firstname.lastname@example.org)
Phone: +49 69 6301 4840
University Hospital Frankfurt Max Planck Institute for Informatics
Goethe University Computational Biology & Applied Algorithmics
Department of Internal Medicine I Campus E1 4
Theodor-Stern-Kai 7 66123 Saarbrücken
Dr. rer. nat. Claudia Stross, PostDoc (Claudia.Stross @gmx.de)
Dr. rer. nat. Katrin Bäumer, PostDoc (Haselow@med.uni-frankfurt.de)
Dr. med. Georg Dultz, PostDoc (Georg.Dultz@kgu.de)
Christian Grimm, PhD student (Grimm@em.uni-frankfurt.de)
Michael Konetschnik, MD student (Michael.Konetschnik@web.de)
Bioinformatics, Biochemistry, Molecular Virology, Structure Biology
Mario Albrecht, Bio MedTech-Graz, University of Technology, Austria
Iris Antes, Protein Modelling, Technical University Munich
Francisco S. Domingues, EURAC Research Bozen, Italy
Stanley M. Lemon, University of North Carolina at Chapel Hill (USA)
Thomas Lengauer, Max Planck Institute for Informatics, Saarbrücken
Tetsuro Shimakami, Gastroenterology Department, Kanazawa University, Japan
Robert Tampé, Institute of Biochemistry, Goethe University-Frankfurt
Our research projects are supported by the Deutsche Forschungsgemeinschaft (DFG), the Else Kröner-Fresenius-Stiftung (EKFS), the Landes-Offensive zur Entwicklung Wissenschaftlich-ökonomischer Exzellenz (LOEWE), Deutscher Akademische Austauschdienst (DAAD) and by the Goethe-University Frankfurt.
Stross C, Shimakami T, Haselow K, Ahmad MQ, Zeuzem S, Lange CM, Welsch C. Natural HCV variants with increased replicative fitness due to NS3 helicase mutations in the C-terminal helix α18. Sci Rep. 2016 Jan 20;6:19526.
Welsch C, Haselow K, Gouttenoire J, Schneider M, Morikawa K, Martinez Y, Susser S, Sarrazin C, Zeuzem S, Antes I, Moradpour D, Lange CM. Hepatitis C virus variants resistant to macrocyclic NS3-4A inhibitors subvert IFN-β induction by efficient MAVS cleavage. J Hepatol. 2015 Apr;62(4):779-84.
Yamane D, McGivern DR, Wauthier E, Yi M, Madden VJ, Welsch C, Antes I, Wen Y, Chugh PE, McGee CE, Widman DG, Misumi I, Bandyopadhyay S, Kim S, Shimakami T, Oikawa T, Whitmire JK, Heise MT, Dittmer DP, Kao CC, Pitson SM, Merrill AH Jr, Reid LM, Lemon SM. Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation. Nat Med. 2014 Aug;20(8):927-35.
Grammatikos G, Jabara CB, Ahmad MQ, Herrmann E, Zeuzem S, Welsch C. Genetic background for development of resistance mutations within the HCV NS3 protease-helicase in direct acting antiviral naive patients. Antivir Ther. 2014;19(5):455-61.
Yi M, Hu F, Joyce M, Saxena V, Welsch C, Chavez D, Guerra B, Yamane D, Veselenak R, Pyles R, Walker CM, Tyrrell L, Bourne N, Lanford RE, Lemon SM. Evolution of a cell culture-derived genotype 1a hepatitis C virus (H77S.2) during persistent infection with chronic hepatitis in a chimpanzee. J Virol. 2014 Apr;88(7):3678-94.
Dansako H, Yamane D, Welsch C, McGivern DR, Hu F, Kato N, Lemon SM. Class A scavenger receptor 1 (MSR1) restricts hepatitis C virus replication by mediating toll-like receptor 3 recognition of viral RNAs produced in neighboring cells. PLoS Pathog. 2013;9(5):e1003345.
Welsch C, Schweizer S, Shimakami T, Domingues FS, Kim S, Lemon SM, Antes I. Ketoamide resistance and hepatitis C virus fitness in val55 variants of the NS3 serine protease. Antimicrob Agents Chemother. 2012 Apr;56(4):1907-15.
Welsch C, Shimakami T, Hartmann C, Yang Y, Domingues FS, Lengauer T, Zeuzem S, Lemon SM. Peptidomimetic escape mechanisms arise via genetic diversity in the ligand-binding site of the hepatitis C virus NS3/4A serine protease. Gastroenterology. 2012 Mar;142(3):654-63.
Kim S, Welsch C, Yi M, Lemon SM. Regulation of the production of infectious genotype 1a hepatitis C virus by NS5A domain III. J Virol. 2011 Jul;85(13):6645-56.
Shimakami T, Welsch C, Yamane D, McGivern DR, Yi M, Zeuzem S, Lemon SM. Protease inhibitor-resistant hepatitis C virus mutants with reduced fitness from impaired production of infectious virus. Gastroenterology. 2011 Feb;140(2):667-75.
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