Défense de thèse de doctorat en sciences biologiques

Study of the relationships bewteen Brucella and the mitochondrial population of infected cells, par Elodie Lobet

Jury

Bernard KNOOPS (UCL), Suzana SALCEDO (Université de Lyon 2), Anne KERIEL (UFR Médecine, Nîmes), Xavier DE BOLLE, président (UNamur), Michel JADOT (UNamur), Jean-Jacques LETESSON, co-promoteur (UNamur), Thierry ARNOULD, promoteur (UNamur)

Résumé

Mitochondria are forming a complex organelle that plays a major role in the process of host pathogen relationship. On the one hand, mitochondria fulfil many different functions in the cell including energy production, contribute to lipid and steroid synthesis, participate to redox signalling and regulate calcium homeostasis. Additionally, as this list is not exhaustive, this organelle takes part in the regulation of different cell death pathways, including apoptosis and necrosis, and represents a hub in the eukaryotic cell signalling pathways. It is also commonly recognized that those various functions make mitochondria central regulators of the immune response. On the other hand, considering the various functions fulfilled by this single organelle, mitochondria represent a target of choice for invading pathogens. It is thus not surprising that many viruses and bacteria can modulate the mitochondrial functions to their own benefit.

In this thesis, we characterised the crosstalk existing between mitochondria and Brucella, the causative agent a worldwide zoonosis named brucellosis. This intracellular bacterium invades myeloid and non-myeloid cells, where it replicates massively in a compartment derived from the endoplasmic reticulum. Despite indications suggesting that mitochondria might be affected during Brucella infection, a systematic study of the crosstalk between Brucella and the mitochondrial network of infected cells was never systematically addressed. We thus analysed the putative effect of Brucella infection on mitochondrial functions as well as the impact of mitochondrial (dys)function on Brucella replication.

First, we found that B. abortus does not rely on mitochondrial oxidative phosphorylation for its replication and that mitochondrial reactive oxygen species do not participate in the control of B. abortus infection in vitro. Secondly, we observed close appositions between Brucella-containing vacuoles and mitochondria, both in vitro and in vivo, suggesting the existence of physical contacts between those two compartments.

Finally, we demonstrated that B. abortus and B. melitensis induce a drastic mitochondrial fragmentation at 48 hours post-infection in different cell types, including myeloid and non-myeloid cells. This fragmentation is DRP1-independent and might be caused by a deficit of mitochondrial fusion as the protein abundance of the mitofusin 2, a GTPase involved in the fusion of the outer mitochondrial membrane, is decreased in Brucella-infected cells. In an attempt to determine the functional impact of mitochondrial fragmentation during Brucella infection, we showed that mitochondrial fragmentation does not change Brucella replication efficiency nor the susceptibility of infected cells to TNFa-induced apoptosis.

Even if further investigations are still needed to deeply characterize the molecular actors responsible for this fragmentation as well as the functional impact of this alteration of the mitochondrial morphology during Brucella infection, the present study highlights a new aspect of the host-pathogen relationship existing during Brucella infection that affects de powerhouse of the host cells.

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