New approaches to the therapy and diagnosis of toxoplasmosis
Date: 16/04/2021
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).
Individual 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.
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.