Modulation fonctionnelle des polynucléaires neutrophiles par les Escherichia coli d adhésion diffuse (DAEC) exprimant les adhésines Afa/Dr

Les DAEC Afa/Dr sont responsables de diarrhées et d infections urinaires. In-vitro, ils provoquent la migration des polynucléaires neutrophiles (PN) à travers l épithélium intestinal. L objectif de notre travail a été d approfondir l étude de la modulation directe des fonctions et de la mort des PN induite par les DAEC Afa/Dr, grâce à l utilisation de la lignée cellulaire PLB-985 différenciée en PN. Dans un premier temps, nous démontrons que plusieurs souches de DAEC Afa/Dr induisent une réponse pro-inflammatoire importante, en particulier en provoquant une hyperproduction d IL-8. Dans un second temps, nous montrons que l adhésine F1845 induit l externalisation de la phosphatidylsérine (PS), cet effet passant par sa fixation sur son récepteur DAF. Cette externalisation de PS n est pas liée à l apoptose mais permet la phagocytose des PLB-985 infectées, participant ainsi à la résolution de l inflammation.Afa/Dr DAEC causing childhood diarrhea can induce, in-vitro, the migration of polymorphonuclear neutrophils (PMN) through the intestinal epithelium. Using the human PLB-985 cell line differentiated into fully mature PMN, we described the coordinated response to various E. coli. We show that several strains of Afa/Dr DAEC induced a significant pro-inflammatory response, particularly by causing an overproduction of IL-8. Then we show that F1845 adhesin induced externalization of phosphatidylserine (PS). This effect was triggered in part by DAF receptor engagement. Interestingly, although apoptosis pathways were not engaged, this PS externalization displayed enhanced removal by macrophages, a phenomenon possibly participating in the resolution of inflammation.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Combinatorial Drug Therapy: Compartmentalized Encapsulation of Two Antibiotics in Porous Nanoparticles: an Efficient Strategy to Treat Intracellular Infections (Part. Part. Syst. Charact. 3/2019)

International audienceBack Cover : As demonstrated by Ruxendra Gref and co‐workers in article number 1800360, two synergic drugs, amoxicillin and potassium clavulanate, were co‐encapsulated within highly porous nanoparticles made of metal‐organic frameworks (nanoMOFs). Within the interconnected 3D structure, each drug located in a separate compartment and these findings were supported by molecular simulations. NanoMOFs were efficiently internalized in infected macrophages and contributed together with the entrapped drugs to kill intracellular bacteria

Compartmentalized Encapsulation of Two Antibiotics in Porous Nanoparticles: an Efficient Strategy to Treat Intracellular Infections

International audienceCombinatorial drug therapies emerge among the most promising strategies to treat complex pathologies such as cancer and severe infections. Biocompatible nanoparticles of mesoporous iron carboxylate metal–organic framework (nanoMOFs) are used here to address the challenging aspects related to the coincorporation of two antibiotics. Amoxicillin and potassium clavulanate, a typical example of drugs used in tandem, are efficiently coincorporated with payloads up to 36 wt%. Due to the occurrence of two distinct pore sizes/apertures within the MOF architecture, each drug is able to infiltrate the porous framework and localize within separate compartments. Molecular simulations predict drug loadings and locations consistent with experimental findings. Drug loaded nanoMOFs that are internalized by Staphylococcus aureus infected macrophages are able to colocalize with the pathogen, which in turn leads to an alleviation of bacterial infection. The data also reveal potential antibacterial properties of nanoMOFs alone as well as their ability to deliver a high payload of drugs to fight intracellular bacteria. These results pave the way toward the design of engineered “all‐in‐one” nanocarriers in which both the loaded drugs and their carrier play a role in fighting intracellular infections

Towards an Improved anti-HIV Activity of NRTI via Metal-Organic Frameworks Nanoparticles

Nanoscale mesoporous iron carboxylates metal-organic frameworks (nanoMOFs) have recently emerged as promising platforms for drug delivery, showing biodegradability, biocompatibility and important loading capability of challenging highly water-soluble drugs such as azidothymidine tryphosphate (AZT-TP). In this study, nanoMOFs made of iron trimesate (MIL-100) were able to act as efficient molecular sponges, quickly adsorbing up to 24 wt% AZT-TP with entrapment efficiencies close to 100%, without perturbation of the supramolecular crystalline organization. These data are in agreement with molecular modelling predictions, indicating maximal loadings of 33 wt% and preferential location of the drug in the large cages. Spectrophotometry, isothermal titration calorimetry, and solid state NMR investigations enable to gain insight on the mechanism of interaction of AZT and AZT-TP with the nanoMOFs, pointing out the crucial role of phosphates strongly coordinating with the unsaturated iron(III) sites. Finally, contrarily to the free AZT-TP, the loaded nanoparticles efficiently penetrate and release their cargo of active triphosphorylated AZT inside major HIV target cells, efficiently protecting against HIV infection