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Project D4 - Cryptosporidium parvum-induced modulation of host cellular metabolic signatures as a target of drug development

PI
PI
PI

 

Project description

Background: Cryptosporidiosis is an important human intestinal disease occurring worldwide, but it plays a major role in immunocompromised patients and children in developing countries, where it is linked to malnutrition, developmental deficits, and increased mortality. Currently available drugs are insufficient and, especially in the case of HIV patients, of low efficacy.

Intracellular protozoa modulate their host cells on diverse molecular levels to guarantee their development and proliferation. An important target is the metabolism of the host cell. The intracellular multiplication of parasites requires energy and cell building blocks and therefore resembles the metabolic requirements of tumor cells1.

Grafik Taubert
Fig. D4: Metabolism of C. parvum-infected host cells

The energy and cell building blocks are partially synthesized by the parasites themselves or must be provided by the host cell. In both cases, the host cell has to provide the precursors for synthetic pathways and take up most substrates of these pathways from extracellular sources. Therefore, our own investigations show that infections with another obligate intracellular parasite, Besnoitia besnoiti, significantly influence the uptake of exogenous nutrients and the release of metabolic products2. However, in contrast to other intracellular parasites such as Toxoplasma gondii, which is in principle able to synthesize most building blocks and energy by its own, C. parvum has only minimal metabolic capacities. Therefore, C. parvum is defective for de novo nucleic acid, amino acid, and cholesterol synthesis and lacks important metabolic pathways such as the tricarboxylic acid cycle, respiratory chain, and β-oxidation3,4. Due to these metabolic restrictions, C. parvumsignificantly depends on the metabolism of its host cell.

Specific goals: In this project, metabolic signatures of C. parvum-infected host cells will be analyzed based on the turnover rates of important metabolic pathways. Referring to these results, the effects of targeted inhibition of individual metabolic segments and pathways on the development of C. parvum will be examined. All analyses will be conducted under culture conditions that are physiological to the greatest possible extent. Besides the classically used HCT-8 cells, epithelial cells of non-tumorous origin shall be employed.

 

References D4: 1. Mazurek et al. (2005) Semin Cancer Biol 15:300-308 2. Taubert et al., (2016) Parasitol Res 115:2023-34. 3. Rhider & Zhu (2010) Exp. Parasitol. 124: 2-9. 4. Ramakrishnan et al. (2013) Prog Lipid Res 52: 488-512. 5. Castellanos-Gonzales et al. (2013) Infect Immun 81: 1996-2001.