Inflammatory Properties and Adjuvant Potential of Synthetic Glycolipids Homologous to Mycolate Esters of the Cell Wall of Mycobacterium tuberculosis

&lt;p&gt;The cell wall of mycobacteria is characterised by glycolipids composed of different classes of mycolic acids (MAs; alpha-, keto-, and methoxy-) and sugars (trehalose, glucose, and arabinose). Studies using mutant Mtb strains have shown that the structure of MAs influences the inflammatory potential of these glycolipids. As mutant Mtb strains possess a complex mixture of glycolipids, we analysed the inflammatory potential of single classes of mycolate esters of the Mtb cell wall using 38 different synthetic analogues. Our results show that synthetic trehalose dimycolate (TDM) and trehalose, glucose, and arabinose monomycolates (TMM, GMM, and AraMM) activate bone marrow-derived dendritic cells in terms of the production of pro-inflammatory cytokines (IL-6 and TNF-&amp;alpha;) and reactive oxygen species, upregulation of costimulatory molecules, and activation of NLRP3 inflammasome by a mechanism dependent on Mincle. These findings demonstrate that Mincle receptor can also recognise pentose esters and seem to contradict the hypothesis that production of GMM is an escape mechanism used by pathogenic mycobacteria to avoid recognition by the innate immune system. Finally, our experiments indicate that TMM and GMM, as well as TDM, can promote Th1 and Th17 responses in mice in an OVA immunisation model, and that further analysis of their potential as novel adjuvants for subunit vaccines is warranted.&lt;/p&gt;</p

Astrotactin 1–derived peptide: A new skin-penetrating peptide against inflammatory skin diseases

International audienc

in vitro models of human mast cells: How to get more and better with induced pluripotent stem cells?

International audienceNo abstract availabl

Deletion of the ORF9p acidic cluster impairs the nuclear egress of Varicella-zoster virus capsids.

The protein encoded by the ORF9 is essential for Varicella-zoster virus (VZV) replication. Previous studies documented its presence in the trans-Golgi network and its involvement in secondary envelopment. In this work, we deleted the ORF9p acidic cluster, destroying its interaction with ORF47p and resulting in a nuclear accumulation of both proteins. This phenotype results to an accumulation of primary enveloped capsids in the perinuclear space, reflecting a capsid de-envelopment defect

Investigation of the glycolytic switch induced by saturated fatty acid in human macrophages

Obesity is a worldwide epidemic now recognized as a low-grade inflammatory disease, favoring the development of metabolic diseases and cancers. This systemic inflammation results from an accumulation of pro-inflammatory macrophages in adipose tissue. Recent work shows that these adipose tissue macrophages (ATMs) are characterized by M1/M2 and metabolic markers. Free fatty acids released in excess in obese adipose tissue could be proposed as triggers in shaping the ATM phenotype. Indeed, the treatment with saturated fatty acids (SFAs) recapitulates many features of the polarization seen in obese ATM. The goals of this research are to further characterize ATMs in obese patients and understand underlying transcriptional programs by using the model of human monocyte-derived macrophages (MDMs) treated with a common SFA. We performed the sequencing of the whole transcriptome of MDMs treated with saturated (C18:0) or unsaturated fatty acid (C18:1) complexed to BSA or with BSA alone. C18:0 treatment induces 3345 differentially expressed genes (q<0,05) while C18:1 treatment produces a weak response. As expected, gene set enrichment analysis (GSEA) demonstrates that C18:0 activates the transcription of genes involved in several M1 pathways. Interestingly, GSEA shows the enrichment of hypoxia and glycolysis gene sets, suggesting SFA-mediated aerobic glycolysis. We confirmed the glycolytic switch in C18 :0-treated MDMs by showing up-regulation of glycolysis enzymes and metabolites transporters and by measuring lactate production. We are currently investigating upstream events and have preliminary data suggesting SFAs do not induce this glycolytic switch through the TLR4 binding but has to be activated into acylCoA inside cells. This research project should lead to a better understanding of the metabolic reprogramming that occurs in ATMs during obesity and fuels an obesity-associated « sterile » inflammation

Activity differences of inflammasome NLRP3 between obese patients with and without metabolic abnormalities

peer reviewe