Silent goodbyes - the role of cell death in giardiasis

• Unité de recherche: COST
• Numéro de projet: C10.0094
• Titre du projet anglais: Silent goodbyes - the role of cell death in giardiasis

Mots-clé (Anglais)

Parasitosis; Giardia lamblia; Programmed cell death; Mitochondria; Mitosome; Inflammation; Pro-tein import; Organelle; Cell sorting; Proteomics; Evolution

Programme de recherche (Anglais)

COST-Action BM0802 - Life or death of protozoan parasites

Description succincte (Anglais)

We will use two complementary experimental approaches to test the hypothesis that mitochondrial remnant organelles (mitosomes) play a key role in a basic form of programmed cell death (PCD) in the protozoan parasite Giardia lamblia. Even severe Giardiasis of humans and animals elicits surprisingly little inflammation in the gut, suggesting active popula-tion control coupled with PCD to eliminate dying parasites and avoid immune stimulation. Since Giardia is exquisitely sen-sitive to interference with mitosome function we postulate that these minimized organelles play a key role in sensing cell health and in coordinating a basic form of PCD. We plan to combine recently developed novel technologies with large-scale approaches to provide a catalog of quantifiable changes that accompany cell death in these parasites and to define the functional range of mitosomes and their role in coordinating cell death pathways.

Partenaires et organisations internationales (Anglais)

BE, CH, DE, DK, ES, FR, GR, IL, IT, NL, PT, UK

Résumé des résultats (Abstract) (Anglais)

Programmed cell death in protozoan parasites is emerging as a target for novel therapies to treat some of the most widespread and serious infections of humans and animals. The intestinal parasite Giardia lamblia is responsible for ca. 300 million cases of water-borne diarrheal disease each year. Although infected patients harbor millions of parasitic cells attached to intestinal epithelia, inflammatory responses in the gut are surprisingly mild. We hypothesize that, despite the lack of bona fide mitochondria or conserved apoptosis pathways, Giardia lamblia possesses a molecular machinery to initiate a PCD-like form of cell death allowing damaged cells to be eliminated by the peristaltic stream and thereby avoiding a host inflammatory response. Based on preliminary data we postulate that highly degenerate mitochondria-derived organelles, mitosomes, fulfill a sentinel function in sensing cell health and are central to this hypothetical PCD pathway. Here we tested this hypothesis by defining quantitative parameters of apoptotic cell death induced in vitro by conditions that could mimic stresses encountered under physiological conditions (i.e. heat stress and glucose starvation). Once established, we used these quantifiable readouts to address a possible role of mitosomes in organizing a PCD-like response. We could show that a dramatic death phenotype induced by two different conditions which potentially interfere with mitosome function indeed displays these hallmarks of apoptosis. This is the first direct link between these highly reduced organelles and a PCD-like form of cell death. Currently, we are using the novel reporters developed in this project to perform a final experimental test to determine whether induction of the mitosome-linked death phenotype is linked to protein import into these organelles. In addition, we have now implemented a system for live cell imaging of mitosomes to determine organelle dynamics and neogenesis in real time. Most importantly, the important milestones reached in this project have allowed us to obtain competitive extramural funding to continue this work and to develop novel approaches to determine the range of functions in giardial mitosomes.

Références bases de données (Anglais)

Swiss Database: COST-DB of the State Secretariat for Education and Research Hallwylstrasse 4 CH-3003 Berne, Switzerland Tel. [phone] Swiss Project-Number: C10.0094