Biology subjects

Oeuvray, C.

Publications and source records attributed to Oeuvray, C..

4 recordsLinked to original sources

bioRxiv2024

Insulation of ribosomal promoter activity by Fis, H-NS or a divergent promoter within the packed E. coli genome.

Gene expression in bacterial cells is dependent on a genes position along the genome, mainly because of the effects of neighbouring genes expression, but also because of the local activity of nucleoid proteins, differing levels of DNA supercoiling and changes in gene copy number with growth rate and growth phase. This genome position dependence can be a source of specific regulation, however, in some cases it is necessary to have gene expression insulated from these local effects. Escherichia coli cells express ribosomal RNA from multiple operons found at different sites along the genome. The number of ribosomal operons varies in different strains and correlates with the maximal growth rate. rRNA promoters are under the regulation of Fis, H-NS, DNA supercoiling and ppGpp. These factors are known to result in growth phase and growth rate dependent regulation of gene expression. Here we show that the combined action of Fis and H-NS also provides insulation from the activity of both local and global regulatory factors. Furthermore, our results indicate that the presence of a divergently expressed gene can also act as an insulator revealing a DNA supercoiling gradient from the origin to the terminus. The organisation of ribosomal promoters therefore has been selected to allow for gene duplication independently of the influence of local genome organisation and neighbouring genes activity.

cell biology↗

bioRxiv2023

The delayed bloodstream clearance of Plasmodium falciparum parasites after M5717 treatment is attributable to the inability to modify their red blood cell hosts.

M5717 is a promising antimalarial drug under development thatacts against multiple stages of the life cycle of Plasmodium parasites by inhibiting the translation elongation factor 2 (PfeEF2), thereby preventing protein synthesis. The parasite clearance profile after drug treatment in preclinical studies in mice, and clinical trials in humans showed a notable delayed clearance phenotype whereby parasite infected red blood cells (iRBCs) persisted in the bloodstream for a significant period before eventual clearance. In a normal P. falciparum infection iRBCs sequester in the deep circulation by cytoadherence, allowing them to avoid surveillance and clearance in the spleen. In this work we show that M5717 treatment renders iRBCs invisible to normal splenic clearance mechanisms. We found that M5717 blocks parasite modification of their host red blood cells (RBCs) by preventing synthesis of new exported proteins, rather than by directly blocking the export of these proteins into the RBC compartment. Using in vitro models, we demonstrated that M5717 treated ring/trophozoite stage iRBCs became less rigid, and cytoadhered less well compared to untreated iRBCs. This indicates that in vivo persistence of M5717 treated iRBCs in the blood stream is likely due to reduced cytoadherence and splenic clearance.

microbiology↗

bioRxiv2022

Human CD4+/CD8α+ regulatory T cells induced by Faecalibacterium prausnitzii protect against intestinal inflammation

Faecalibacterium prausnitzii (F. prausnitzii), a dominant bacterium of the human microbiota, is decreased in patients with inflammatory bowel diseases (IBD) and exhibits anti-inflammatory effects. In human, colonic lamina propria contains IL-10-positive, Foxp3-negative regulatory T cells (Treg) characterized by a double expression of CD4 and CD8 (DP8) and a specificity for F. prausnitzii. This Treg subset is decreased in IBD. The in vivo effect of DP8 cells has not been evaluated yet. Here, using a humanized model of NOD.Prkcscid IL2r{gamma}-/- (NSG) immunodeficient mouse strain that expresses human leucocyte antigen D-related 4 (HLA-DR4) but not murine class II (NSG-Ab{degrees} DR4), we demonstrated a protective effect of DP8 Tregs combined with F. prausnitzii administration in a colitis model. In a cohort of patients with IBD, we showed an independent association between the frequency of circulating DP8 cells and disease activity. Finally, we pointed out a positive correlation between F. prausnitzii-specific DP8 Tregs and the amount of F. prausnitzii in fecal microbiota in healthy individuals and patients with ileal Crohns disease.

immunology↗

bioRxiv2022

CARD9 in Neutrophils Protects from Colitis and Controls Mitochondrial Metabolism and Cell Survival

ObjectivesInflammatory bowel disease (IBD) results from a combination of genetic predisposition, dysbiosis of the gut microbiota and environmental factors, leading to alterations in the gastrointestinal immune response and chronic inflammation. Caspase recruitment domain 9 (Card9), one of the IBD susceptibility genes, has been shown to protect against intestinal inflammation and fungal infection. However, the cell types and mechanisms involved in the CARD9 protective role against inflammation remain unknown. DesignWe used dextran sulfate sodium (DSS)-induced and adoptive transfer colitis models in total and conditional CARD9 knock-out mice to uncover which cell types play a role in the CARD9 protective phenotype. The impact of Card9 deletion on neutrophil function was assessed by an in vivo model of fungal infection and various functional assays, including endpoint dilution assay, apoptosis assay by flow cytometry, proteomics and real time bioenergetic profile analysis (Seahorse). ResultsLymphocytes are not intrinsically involved in the CARD9 protective role against colitis. CARD9 expression in neutrophils, but not in epithelial or CD11c+ cells, protects against DSS-induced colitis. In the absence of CARD9, mitochondrial dysfunction in neutrophils leads to their premature death through apoptosis, especially in oxidative environment. The decrease of fonctional neutrophils in tissues could explain the impaired containment of fungi and increased susceptibility to intestinal inflammation. ConclusionThese results provide new insight into the role of CARD9 in neutrophil mitochondrial function and its involvement in intestinal inflammation, paving the way for new therapeutic strategies targeting neutrophils. Summary boxO_LIWhat is already known about this subject? O_LIInflammatory bowel disease (IBD) results from genetic predisposition, microbiota dysbiosis and environmental factors, but the alterations of the immune response leading to chronic intestinal inflammation are still not fully understood. C_LIO_LICaspase recruitment domain 9 (Card9), one of the IBD susceptibility genes, has been shown to protect against intestinal inflammation and fungal infection. C_LIO_LIHowever, the cell types and cellular mechanisms involved in the CARD9 protective role against inflammation remain unknown. C_LI C_LIO_LIWhat are the new findings? O_LICARD9 expression in neutrophils, but not in lymphocytes, epithelial cells or CD11c+ cells, protects against DSS-induced colitis. C_LIO_LIIn the absence of CARD9, mitochondrial dysfunction in neutrophils leads to their premature death through apoptosis, especially in oxidative environment. C_LIO_LIThe decrease of fonctional neutrophils in tissues could explain the impaired containment of fungi and increased susceptibility to intestinal inflammation. C_LI C_LIO_LIHow might it impact on clinical practice in the foreseeable future? O_LIThese results provide new insight into the role of CARD9 in neutrophil mitochondrial function and its involvement in intestinal inflammation. C_LIO_LIUnderstanding the role of neutrophils in chronic inflammation could lead to innovative therapeutic strategies targeting these key immune cells for various complex diseases. C_LI C_LI

immunology↗