Research Profile Prof. Dr. Carsten Lüder
The main focus of the work of the Lüder group is on the interaction of Toxoplasma gondii and its hosts, in particular immunity and immune evasion, host cell type-specific responses during infection, and the differentiation of different parasite stages. Our work will help to elucidate cellular and molecular mechanisms that, on the one hand, contribute to infection defense and prevent severe disease progression, and, on the other hand, allow the parasite to establish infections that persist for years. Recently, we have also become interested in how chronic infection affects immune reactivity in humans.
T. gondii is a worldwide intracellular parasite of humans and animals; it is estimated that about 25-30% of the world's population is infected with the parasite. Infections are mostly subclinical, however, the parasite persists in its hosts for life, mainly in the brain and muscles.
In contrast, persons with immunodeficiency or after infection in utero are at risk of severe disease progression. Due to its high prevalence, T. gondii is one of the most important foodborne diseases in humans. The ability of infected individuals to mostly control the parasite, as well as the ability of parasites to persist throughout life, requires a well-regulated balance between pathogen virulence and host defenses. The study of these interactions is not only a fascinating chapter in infection biology, but is also important for the development of new intervention strategies against toxoplasmosis.
Current projects
Inhibition of STAT-dependent immune responses.
Interferon (IFN)-γ is essential for effective immune defense against T. gondii. It activates 'signal transducer and activator of transcription' (STAT)-1, which regulates the expression of approximately 1000 different genes in macrophages, including those encoding molecules involved in infection defense, antigen presentation, and immune regulation. In previous work, we have shown that T. gondii largely inhibits the expression of STAT-1-dependent genes in monocytes/macrophages and that the parasite thereby ensures its survival in IFN-γ-activated cells.
Recent work by us and other research groups shows that the parasite inhibits euchromatin formation by inhibiting histone acetylation and partial methylation, thereby preventing gene expression after IFN-γ activation. It also leads to the sequestration of STAT1 at functionally irrelevant DNA by binding of the virulence factor TgIST primarily to STAT1 tetramers. Pharmacologically, using the histone deacetylase inhibitor MS-275, we were able to partially increase IFN-γ-regulated gene expression in the presence of the parasite, but this did not result in improved parasite defense.
Metabolic regulation of infection defense in monocytes/macrophages.
Monocytes and macrophages, as host cells, contribute significantly to the dissemination of the parasite in the host during acute toxoplasmosis. As defense cells of the innate immune system, they also play a central role in the defense against infection by T. gondii. Subpopulations of monocytes and macrophages differ markedly functionally, including in the defense against infection by intracellular pathogens such as T. gondii. Different metabolic properties have been identified as important regulators of infection defense ('immunometabolism'). Our previous work shows that glycolysis of macrophages controls intracellular development of T. gondii. In this project, we will investigate the influence of host cell metabolism on the infection defense of T. gondii, and identify underlying molecular mechanisms.
Influence of the host cell on the parasite-host interaction.
T. gondii can infect all nucleated cells of its hosts during acute infection by active, parasite-driven invasion. The course of infection in vivo is therefore largely determined by the interactions of the parasite with different host cell types. We would like to understand the influence of the cellular microenvironment on parasite-host cell interactions.
Using dual 'next generation' RNA sequencing, we have compared the transcriptomes of different host cell types before and after infection as well as those of T. gondii within these cell types in a pilot project. Our results show that different cell types respond extremely heterogeneously to infection with the parasite through up- and down-regulation of genes. T. gondii also regulates the expression of different genes in response to different cell environments. Different host cell characteristics and the molecular flexibility of T. gondii to respond differently to cellular niches are the subject of further work.
Stage conversion of T. gondii in skeletal muscle cells and neurons.
After initial infection, T. gondii disseminates in the form of rapidly replicating tachyzoites. Within 1 to 2 weeks, tachyzoites differentiate into slowly replicating, largely metabolically inactive bradyzoites that persist mainly in neurons and muscle cells and characterize the chronic infection phase. In this project, we are investigating the hypothesis that host cell-specific factors of muscle cells and neurons promote stage conversion of T. gondii. Indeed, our previous work in an in vitro model using skeletal muscle cells shows that terminally differentiated, cell cycle arrested myotubes, but not their proliferating precursors called myoblasts, promote bradyzoite formation. By siRNA, we identified the cell cycle inhibitor Tspyl-2 as an important host cell regulator of stage conversion of T. gondii. In addition, metabolic properties of myotubes, such as low activity of the pentose phosphate pathway, low NADPH/NADP quotients, and increased levels of reactive oxygen species (ROS), appear to play an important role. Currently, we are also establishing a neuron infection model to identify molecular host factors that regulate stage conversion of T. gondii in neurons in a complementary research approach.
Influence of chronic infections on immune reactivity.
T. gondii leads to persistent infections for years in immunocompromised individuals. In mice, persistent toxoplasmosis leads to enhanced innate immune responses, including against heterologous pathogens ('trained immunity'). We investigate whether humans chronically infected with T. gondii also show phenotypically and functionally altered immune responses.
Our work shows that monocytes from healthy blood donors chronically infected with T. gondii express less CD16 and CD62L but more CD64 on their surface than monocytes from uninfected control subjects. In addition, after stimulation with T. gondii in vitro, they respond with greater expression of MHC class II and the cytokine IL-12. We are currently investigating whether other phenotypic characteristics of monocytes are altered by chronic toxoplasmosis, and whether they also respond differently to heterologous antigens than monocytes from naïve controls. This would also have practical implications, e.g. for vaccination and co-infection.
Employees & Alumni (last 5 years)
Prof. Dr. Carsten Lüder (Project Manager)
Cand. Vincent Buschatzky, MD
Hauke Ehmen, MD
Melanie Eisele, MD
MSc (Microbiology, Biotechnology & Biochemistry) Hannah Fuchs
Cand. Hyeon-June Kim, M.D.
Dr. rer. nat. Roswitha Nast
Dr. rer. nat. Md. Taibur Rahman
Cand. Noémie Thieffenat, M.D.
Cooperations
Dr. Martin Blume, Junior Research Group 2, Robert Koch Institute, Berlin
Prof. Dr. mult. Thomas Meyer, Molecular Psychocardiology, University Medical Center Göttingen
Selected publications
Rahman T, Swierzy IJ, Downie B, Salinas G, Blume M, McConville MJ, Lueder CGK. 2021. the redox homeostasis of skeletal muscle cells regulates stage differentiation of Toxoplasma gondii. Front. Cell. Infect. Microbiol, 11:798549. doi:10.3389/fcimb.2021.798549.[pubmed.]
Nast R, Choepak T, Lüder CGK. 2020. epigenetic control of IFN-γ host responses during infection with Toxoplasma gondii. Front. Immunol., 11:581241. doi: 10.3389/fimmu.2020.581241.[pubmed]
Ehmen HG, Lüder CGK. 2019. long-term impact of Toxoplasma gondii infection on human monocytes. Front. Cell. Infect. Microbiol, 9:235. doi: 10.3389/fcimb.2019.000235.[pubmed]
Swierzy IJ, Händel U, Kaever A, Jarek M, Scharfe M, Schlüter D, Lüder CGK. 2017. divergent co-transcriptomes of different host cells infected with Toxoplasma gondii reveal cell type-specific host-parasite interactions. Scientific Reports 7: 7229. doi:101038/s41598-017-07838-w.[pubmed]
Lüder CGK, Seeber F. 2016. toxoplasma. In: Walochnik, J. & Duchene, M. (Eds.). Molecular Parasitology: Protozoan Parasites and their molecules. p. 217-239. Springer-Verlag, Vienna, Austria.
Swierzy IJ, Lüder CGK. 2015. withdrawal of skeletal muscle cells from cell cycle progression triggers differentiation of Toxoplasma gondii toward the bradyzoite stage. Cell. Microbiol.17, 2-17. doi: 10.1111/cmi.12342 Epub 2014 Sep 17[pubmed].
Lang C, Hildebrandt A, Brand F, Opitz L, Dihazi H, Lüder CGK. 2012. Impaired chromatin remodeling at STAT1-regulated promoters leads to global unresponsiveness of Toxoplasma gondii-infected macrophages to IFN-g. PLoS Pathog. 8(1), e10002483. doi:101371/journal.ppat.1002483.[pubmed.]
Hippe D, Weber A, Zhou L, Chang DC, Häcker G, Lüder CGK. 2009. toxoplasma gondii infection confers resistance against BimS-induced apoptosis by preventing the activation and mitochondrial targeting of pro-apoptotic Bax. J. Cell Sci. 122, 3511-3521.[pubmed]
Lueder CGK, Stanway R, Chaussepied M, Langsley G, Heussler VT. 2009. intracellular survival of apicomplexan parasites and host cell modification. Int. J. Parasitol. 39, 163-173.[pubmed.]
Vutova P, Wirth M, Hippe D, Gross U, Schulze-Osthoff K, Schmitz I, Lüder CGK. 2007. toxoplasma gondii inhibits Fas/CD95-triggered cell death by inducing aberrant processing and degradation of caspase 8. Cell. Microbiol. 9, 1556-1570.[pubmed]
Lüder CGK. 2007. survival strategies of Toxoplasma gondii: interference with regulatory and effector functions of macrophages. In: Denkers, E.Y.. & Gazzinelli R.T. (Eds.). Protozoans in macrophages. p. 130-138. Landes Bioscience, Austin, TX, USA. ISBN: 978-1-58706-150-9.
Lüder CGK, Walter W, Beuerle B, Maeurer MJ, Gross U. 2001. Toxoplasma gondii down-regulates MHC class II gene expression and antigen presentation by murine macrophages via interference with nuclear translocation of STAT1a. Eur. J. Immunol. 31, 1475-1484.[pubmed].
Contact
Prof. Dr. rer. nat. Carsten Lüder, Tel. 0551-39 65869, Email: clueder(at)gwdg.de