Coxiella burnetii, the Agent of Q Fever, Replicates within Trophoblasts and Induces a Unique Transcriptional Response

Q fever is a zoonosis caused by Coxiella burnetii, an obligate intracellular bacterium typically found in myeloid cells. The infection is a source of severe obstetrical complications in humans and cattle and can undergo chronic evolution in a minority of pregnant women. Because C. burnetii is found in the placentas of aborted fetuses, we investigated the possibility that it could infect trophoblasts. Here, we show that C. burnetii infected and replicated in BeWo trophoblasts within phagolysosomes. Using pangenomic microarrays, we found that C. burnetii induced a specific transcriptomic program. This program was associated with the modulation of inflammatory responses that were shared with inflammatory agonists, such as TNF, and more specific responses involving genes related to pregnancy development, including EGR-1 and NDGR1. In addition, C. burnetii stimulated gene networks organized around the IL-6 and IL-13 pathways, which both modulate STAT3. Taken together, these results revealed that trophoblasts represent a protective niche for C. burnetii. The activation program induced by C. burnetii in trophoblasts may allow bacterial replication but seems unable to interfere with the development of normal pregnancy. Such pathophysiologocal processes should require the activation of immune placental cells associated with trophoblasts

Peptidoglycan detection and regulation during the antibacterial response in Drosophila

Les interactions cellules épithéliales-bactéries peuvent conduire à l'établissement d'une tolérance vis-à-vis des bactéries commensales ou à l’élimination des bactéries pathogènes par le système immunitaire. La détection des bactéries est une étape indispensable à l’orientation de cette réponse. Contrairement aux mammifères, la reconnaissance des bactéries chez la drosophile repose principalement sur la détection d’un composant de la paroi bactérienne, le peptidoglycane (PG), par une famille de récepteurs, les "PeptidoGlycan Recognition Receptors" (PGRPs). Chez la drosophile, le PG des bactéries intestinales extracellulaires peut pénétrer dans les entérocytes et aussi traverser l’épithélium intestinal. Dans l’intestin la détection du PG est régionalisée, elle implique en fonction des domaines deux récepteurs PGRPs distincts (PGRP-LC et PGRP-LE). L'activation de ces PGRPs déclenche une même voie de signalisation NF-kB et conduit à la production de peptides antimicrobiens. La sur-activation de cette voie peut être néfaste pour l'hôte, son intensité est notamment contrôlée par des PGRPs à activité enzymatique qui clivent le PG pour le rendre non immunogène.Au cours de ma thèse, j’ai développé des outils visant à étudier le double mode de détection du PG dans l’intestin. J’ai également testé si les transporteurs de la famille SLC15 étaient impliqués dans le trafic cellulaire du PG. Une partie de ma thèse a aussi été consacrée à préciser le rôle des PGRPs catalytiques dans la réponse immunitaire.Bacterial interactions with the host epithelium can lead to the establishment of a tolerance regarding commensal bacteria or to the triggering of an immune response to eliminate pathogenic bacteria. The detection of bacteria is an essential step in the orientation of this response. In contrast to mammals, the bacteria recognition in Drosophila is mainly based on the detection of a bacterial wall component, peptidoglycan (PG), by a family of receptors, the PeptidoGlycan Recognition Receptors (PGRP). In Drosophila, the PG of extracellular intestinal bacteria can enter the enterocytes and also cross the intestinal epithelium. In the intestine, the detection of PG is regionalized and involves, depending on the domains, two distinct PGRP receptors (PGRP-LC and PGRP-LE). The activation of these PGRPs leads to the activation of the same NF-kB signaling pathway and triggers the production of antimicrobial peptides. The over-activation of this pathway can be harmful to the host, and therefore its intensity is controlled by PGRP proteins which have an enzymatic activity that degrades the elicitor activity of PG.During my thesis, I have generated tools to study the dual mode of PG detection in the intestine. I also tested whether the carriers of the SLC15 family were involved in PG cell trafficking. Part of my thesis was also devoted to clarify the role of catalytic PGRPs in the immune response

Caractéristiques et limites du leadership en management de l'expérience client cross-canal : le cas des groupements d'adhérents

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Gamma Emission Tomography of LOCA-transient test rods

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The Intestine of Drosophila melanogaster: An Emerging Versatile Model System to Study Intestinal Epithelial Homeostasis and Host-Microbial Interactions in Humans

In all metazoans, the intestinal tract is an essential organ to integrate nutritional signaling, hormonal cues and immunometabolic networks. The dysregulation of intestinal epithelium functions can impact organism physiology and, in humans, leads to devastating and complex diseases, such as inflammatory bowel diseases, intestinal cancers, and obesity. Two decades ago, the discovery of an immune response in the intestine of the genetic model system, Drosophila melanogaster, sparked interest in using this model organism to dissect the mechanisms that govern gut (patho) physiology in humans. In 2007, the finding of the intestinal stem cell lineage, followed by the development of tools available for its manipulation in vivo, helped to elucidate the structural organization and functions of the fly intestine and its similarity with mammalian gastrointestinal systems. To date, studies of the Drosophila gut have already helped to shed light on a broad range of biological questions regarding stem cells and their niches, interorgan communication, immunity and immunometabolism, making the Drosophila a promising model organism for human enteric studies. This review summarizes our current knowledge of the structure and functions of the Drosophila melanogaster intestine, asserting its validity as an emerging model system to study gut physiology, regeneration, immune defenses and host-microbiota interactions

Oligopeptide Transporters of the SLC15 Family Are Dispensable for Peptidoglycan Sensing and Transport in <b><i>Drosophila</i></b>

International audiencePeptidoglycan (PGN) detection by PGN recognition proteins (PGRP) is the main trigger of the antibacterial immune response in Drosophila. Depending on the type of immune cell, PGN can be sensed either at the cell membrane by PGRP-LC or inside the cell by PGRP-LE, which plays a role similar to that of Nod2 in mammals. Previous work, mainly in cell cultures, has shown that oligopeptide transporters of the SLC15 family are essential for the delivery of PGN for Nod2 detection inside of the cells, and that this function might be conserved in flies. By generating and analyzing the immune phenotypes of loss-of-function mutations in 3 SLC15 Drosophila family members, we tested their role in mediating PGRP-LE-dependent PGN activation. Our results show that Yin, CG2930, and CG9444 are required neither for PGRP-LE activation by PGN nor for PGN transport from the gut lumen to the insect blood. These data show that, while intracellular PGN detection is an essential step of the antibacterial response in both insects and mammals, the types of PGN transporters and sensors are different in these animals

Cytosolic and Secreted Peptidoglycan-Degrading Enzymes in Drosophila Respectively Control Local and Systemic Immune Responses to Microbiota

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Defects in mitophagy promote redox-driven metabolic syndrome in the absence of TP53INP1

International audienceThe metabolic syndrome covers metabolic abnormalities including obesity and type 2 diabetes (T2D). T2D is characterized by insulin resistance resulting from both environmental and genetic factors. A genome-wide association study (GWAS) published in 2010 identified TP53INP1 as a new T2D susceptibility locus, but a pathological mechanism was not identified. In this work, we show that mice lacking TP53INP1 are prone to redox-driven obesity and insulin resistance. Furthermore, we demonstrate that the reactive oxygen species increase in TP53INP1-deficient cells results from accumulation of defective mitochondria associated with impaired PINK/ PARKIN mitophagy. This chronic oxidative stress also favors accumulation of lipid droplets. Taken together, our data provide evidence that the GWAS-identified TP53INP1 gene prevents metabolic syndrome, through a mechanism involving prevention of oxidative stress by mitochondrial homeostasis regulation. In conclusion, this study highlights TP53INP1 as a molecular regulator of redox-driven metabolic syndrome and provides a new preclinical mouse model for metabolic syndrome clinical research