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New approaches to the therapy and diagnosis of toxoplasmosis

Principle investigator: Frank Seeber

Approximately one-third of the worldwide population is infected with the unicellular parasite Toxoplasma gondii, without this leading necessarily to serious symptoms. However, humans with a strongly suppressed immune system (e.g. AIDS patients; transplant recipients) and also unborn children during pregnancy are at risk of contracting a new or resurging acute infection with a serious outcome (acute toxoplasmosis).

Phase contrast and fluorescence microscopy. Quelle: Frank Seeber/ RKIIndividual tachyzoites of T. gondii in a fibroblast cell. Left: the microscopic image as seen by differential interference contrast microscopy (with the fibroblast nucleus on the bottom right). Right: the same under fluorescence light illumination whereby the green structures are mitochondria of the fibroblasts; the yellow/red structures are those of the parasite and the light blue stained “dots” represent an organelle (called apicoplast) related to plant plastids. Source: Frank Seeber, RKI (Crawford et al. 2006 EMBO J.)

Although there are effective medicines available against the acute infection stage (referred to as tachyzoites), the persistent chronic form of the pathogen (referred to as bradyzoites) remains in the body of the host throughout its life and can lead repeatedly to the transformation to tachyzoites and hence to a re-infection in the event of a strongly weakened immune system. Effective drugs against this form of Toxoplasma gondii are not available so far. Moreover, direct proof of live tachyzoites continues to be unsatisfying, although this is important in several clinical situations. Standard diagnostic tests through the detection of antibodies in blood do not differentiate in general as to whether those were formed by live, dying or dead pathogens. These two fields are, therefore, one of the main research foci of the working group.

Moreover, we are also interested in more general issues of cell biology, biochemistry and molecular biology of the parasite, which are dealt within co-operation with national and international colleagues. Due to the biological relationship of Toxoplasma gondii with the malaria pathogen Plasmodium falciparum several questions (e.g. with regard to metabolism, targets for new drugs, etc.) are relevant for both pathogens, but due to the easier handling in the laboratory those can often be studied better initially with Toxoplasma gondii.

Co-workers:

  • Sandra Klein
  • Nora Frohnecke

Generation of recombinant camelid antibodies for diagnostic and cell biological purposes

The goal of this project is to use the many positive properties of antibodies initially generated in camelids now in their recombinant form for both, diagnostic purposes (e.g. for concentrating of minimal quantities of circulating Toxoplasma antigens in blood or urine and their subsequent mass spectrometric detection), and for their use for cell biological questions in cell culture (e.g. to “capture” the respective parasite antigen through intracellular expression of the recombinant antibody directed against it).

The ferredoxin redox system of Toxoplasma as "drug target"

In this PhD project short cyclic peptides are to be identified by means of a genetic screen in E. coli which prevent and/or dissociate the physical interaction of two important proteins in the cellular metabolism of the parasite (ferredoxin and its reductase, cf. Seeber et al. 2005) and hence disturb the essential function of this protein pair for the parasite. Substances derived from these peptides could then form the basis for new drugs.

Metabolism of Toxoplasma and its corresponding dependency on the host cell

Toxoplasma depends on its surrounding host cell for a number of biochemical substances (e.g. amino acids, vitamins and co-factors, lipids; see e.g. Crawford et al. 2006). These dependencies and the resulting questions (e.g. how do these substances reach the parasite; can these paths be used to control the growth of the pathogen; etc.) constitute a further focus of our interest.

Date: 07.03.2017

Publications

  • Delgado Betancourt E, Hamid B, Fabian BT, Klotz C, Hartmann S, Seeber F (2019): From entry to early dissemination—Toxoplasma gondii's initial encounter with its host.
    Front. Cell. Infect. Microbiol. 9: 46. Epub Mar 5. doi: 10.3389/fcimb.2019.00046. more

  • Ferreira SCM, Torelli F, Klein S, Fyumagwa R, Karesh WB, Hofer H, Seeber F et al. (2019): Evidence of high exposure to Toxoplasma gondii in free-ranging and captive African carnivores.
    Int. J. Parasitol. Parasites Wildl. 8 (April): 111–117. Epub 2018 Dec 24. doi: 10.1016/j.ijppaw.2018.12.007. more

  • Blume M, Seeber F (2018): Metabolic interactions between Toxoplasma gondii and its host.
    F1000Res 7 (F1000 Faculty Rev): 1719. Epub Oct 30. doi: 10.12688/f1000research.16021.1. more

  • Torelli F, Zander S, Ellerbrok H, Kochs G, Ulrich RG, Klotz C, Seeber F (2018): Recombinant IFN-γ from the bank vole Myodes glareolus: a novel tool for research on rodent reservoirs of zoonotic pathogens.
    Sci. Rep. 8 (1): 2797. Epub Feb 12. doi: 10.1038/s41598-018-21143-0. more

  • Ehret T, Torelli F, Klotz C, Pedersen AB, Seeber F (2017): Translational rodent models for research on parasitic protozoa – a review of confounders and possibilities.
    Front. Cell. Infect. Microbiol. 7: 238. Epub Jun 7. doi: 10.3389/fcimb.2017.00238. more

  • Ufermann CM, Müller F, Frohnecke N, Laue M, Seeber F (2017): Toxoplasma gondii plaque assays revisited: improvements for ultrastructural and quantitative evaluation of lytic parasite growth.
    Exp. Parasitol. 180: 19-26. Epub 2016 Dec 21. doi: 10.1016/j.exppara.2016.12.015. more

  • Seeber F, Steinfelder S (2016): Recent advances in understanding apicomplexan parasites.
    F1000Res 5 (F1000 Faculty Rev): 1369. Epub Jun 14. doi: 10.12688/f1000research.7924.1. more

  • Wilking H, Thamm M, Stark K, Aebischer T, Seeber F (2016): Prevalence, incidence estimations, and risk factors of Toxoplasma gondii infection in Germany: a representative, cross-sectional, serological study.
    Sci. Rep. 6: 22551. Epub Mar 3. doi: 10.1038/srep22551. more

  • Frohnecke N, Klein S, Seeber F (2015): Protein–protein interaction studies provide evidence for electron transfer from ferredoxin to lipoic acid synthase in Toxoplasma gondii.
    FEBS Lett. 589 (1): 31–36. Epub 2014 Nov 27. doi: 10.1016/j.febslet.2014.11.020. more

  • Oppenheim RD, Creek DJ, Macrae JI, Modrzynska KK, Pino P, Limenitakis J, Polonais V, Seeber F et al. (2014): BCKDH: The missing link in apicomplexan mitochondrial metabolism is required for full virulence of Toxoplasma gondii and Plasmodium berghei.
    PLoS Pathog. 10 (7): e1004263. doi: 10.1371/journal.ppat.1004263. more

  • Klotz C, Aebischer T, Seeber F (2012): Stem cell-derived cell cultures and organoids for protozoan parasite propagation and studying host–parasite interaction.
    Int. J. Med. Microbiol. 302 (4-5): 203-209. Epub Aug 13. DOI: 10.1016/j.ijmm.2012.07.010. more

  • Deschermeier C, Hecht LS, Bach F, Rützel K, Stanway RR, Nagel A, Seeber F, Heussler VT (2012): Mitochondrial lipoic acid scavenging is essential for Plasmodium berghei liver stage development.
    Cell. Microbiol. 14 (3): 416–430. more

  • Baumeister S, Wiesner J, Reichenberg A, Hintz M, Bietz S, Harb OS, Roos DS, Kordes M, Friesen J, Matuschewski K, Lingelbach K, Jomaa H, Seeber F (2011): Fosmidomycin Uptake into Plasmodium and Babesia-Infected Erythrocytes Is Facilitated by Parasite-Induced New Permeability Pathways.
    PLoS ONE 6 (5): e19334. doi:10.1371/journal.pone.0019334. more

  • Seeber F, Soldati-Favre D (2010): Metabolic pathways in the apicoplast of apicomplexa.
    Int. Rev. Cell Mol. Biol. 281: 161-228. doi:10.1016/S1937-6448(10)81005-6 . more

  • Seeber F, Limenitakis J, Soldati-Favre D (2008): Apicomplexan mitochondrial metabolism: a story of gains, losses and retentions.
    Trends Parasitol. 24 (10): 468-478. Epub 2008 Sep 3. more

  • Milani M, Balconi E, Aliverti A, Mastrangelo E, Seeber F, Bolognesi M, Zanetti G (2007): Ferredoxin-NADP+ reductase from Plasmodium falciparum undergoes NADP+-dependent dimerization and inactivation: functional and crystallographic analysis.
    J. Mol. Biol. 367 (2): 501-513. Epub 2007 Jan 9. more

  • Crawford MJ, Thomsen-Zieger N, Ray M, Schachtner J, Roos DS, Seeber F (2006): Toxoplasma gondii scavenges host-derived lipoic acid despite its de novo synthesis in the apicoplast.
    EMBO J. 25 (13): 3214-3222. Epub 2006 Jun 15. more

  • Röhrich RC, Englert N, Troschke K, Reichenberg A, Hintz M, Seeber F, Balconi E, Aliverti A, Zanetti G, Köhler U, Pfeiffer M, Beck E, Jomaa H, Wiesner J (2005): Reconstitution of an apicoplast-localised electron transfer pathway involved in the isoprenoid biosynthesis of Plasmodium falciparum.
    FEBS Lett. 579 (28): 6433-6438. Epub 2005 Nov 2. more

  • Seeber F, Aliverti A, Zanetti G (2005): The plant-type ferredoxin-NADP+ reductase/ferredoxin redox system as a possible drug target against apicomplexan human parasites.
    Curr. Pharm. Des. 11 (24): 3159-3172. more

  • Wiesner J, Seeber F (2005): The plastid-derived organelle of protozoan human parasites as a target of established and emerging drugs.
    Expert Opin. Ther. Targets 9 (1): 23-44. more