A4 Metabolic stress response and growth of GI parasites Eimeria/Giardia (Lucius/Aebischer)
|Research Group:||Department of Molecular Parasitology, Humboldt Universität zu Berlin
& Robert Koch-Institute, Division 16 Mycotic and Parasitic Agents and Mycobacteria
|Address:||Humboldt-Universität zu Berlin, Department of Biology, Molecular Parasitology, Philippstr. 13, House 14, 10115 Berlin|
|Supervisors:||Prof. Dr. Richard Lucius / Dr. Anton Aebischer|
|Doctoral Researcher:||Totta Kasemo|
Parasitic protozoans such as Giardia spp. or Eimeria spp. infecting the gastrointestinal tract have evolved mechanisms to induce metabolic changes in epithelial cells to optimally support parasite growth and, possibly, compensate the parasites’ numerous auxotrophisms. We have recently shown that the Indoleamine 2,3-dioxygenase 1 (IDO) pathway impacts in vivo growth of Eimeria falciformis measured as oocyst output1. IDO can be regulated by IFN-γ and we have investigated the role of the latter during infection2,3. Giardia are tightly adhering to epithelial cells and secrete arginine-depleting enzymes of the parasites’ arginine dehydrolase pathway4. We have shown in vitro that depletion of this amino acid which is also likely to occur in vivo inhibits mTOR dependent signaling in human dendritic cells5. The mTOR and GCN2 (an eIF-2α kinase) pathways on the host cell side are key regulators of cell growth and metabolism and can be triggered by depletion of particular amino acids.
The goal of this project is to investigate the mechanism leading to the modulation of mTOR and IDO by the two GI tract parasites that display contrasting lifestyles (intracellular vs extracellularly adherent). We will use existing gene-deficient mouse and mouse-derived organoid infection models (GCN2flox IDOflox and mTORflox crossed with Crevillin mice) and pharmacological interference for analysis to address specific roles of the respective gene products in epithelial cells exploiting a range of cell, organoid and whole animal infection models that we have established. Read outs will include pathogen enumeration, histological mapping and transcriptomic analyses of colonized or infected EC.
Thus, candidates will be trained in protozoan parasite biology, use of stem cell-derived 3D organoid culture models6 and in vivo mouse models for infection research, flow cytometry, transcriptome analysis, and advanced microscopy. The project is best suited for candidates that combine their interest in parasitology with a quest for deeper understanding of the link between infection and metabolism and regulation of the latter.
(1) Schmid, M., Lehmann, M. J., Lucius, R. & Gupta, N. JBC 287, 20197-20207 (2012); (2) Rausch, S. et al. EJI 40, 2804-2815 (2010); (3) Stange, J. et al. JI 188, 2410-2418, doi:10.4049/jimmunol.1102062 (2012); (4) Stadelmann, B., Merino, M. C., Persson, L. & Svard, S. G. PloS one 7 (2012); (5) Banik, S. et al. I&I 81, 2309-2317 (2013); (6) Klotz, C., Aebischer, T. & Seeber, F. IJMM 302, 203-209 (2012).