NaxD is a deacetylase required for lipid A modification and Francisella pathogenesis

Modification of specific Gram-negative bacterial cell envelope components, such as capsule, O-antigen and lipid A, are often essential for the successful establishment of infection. Francisella species express lipid A molecules with unique characteristics involved in circumventing host defences, which significantly contribute to their virulence. In this study, we show that NaxD, a member of the highly conserved YdjC superfamily, is a deacetylase required for an important modification of the outer membrane component lipid A in Francisella. Mass spectrometry analysis revealed that NaxD is essential for the modification of a lipid A phosphate with galactosamine in Francisella novicida, a model organism for the study of highly virulent Francisella tularensis. Significantly, enzymatic assays confirmed that this protein is necessary for deacetylation of its substrate. In addition, NaxD was involved in resistance to the antimicrobial peptide polymyxin B and critical for replication in macrophages and in vivo virulence. Importantly, this protein is also required for lipid A modification in F. tularensis as well as Bordetella bronchiseptica. Since NaxD homologues are conserved among many Gram-negative pathogens, this work has broad implications for our understanding of host subversion mechanisms of other virulent bacteria

Synthetic Nanoparticles for Vaccines and Immunotherapy

The immune system plays a critical role in our health. No other component of human physiology plays a decisive role in as diverse an array of maladies, from deadly diseases with which we are all familiar to equally terrible esoteric conditions: HIV, malaria, pneumococcal and influenza infections; cancer; atherosclerosis; autoimmune diseases such as lupus, diabetes, and multiple sclerosis. The importance of understanding the function of the immune system and learning how to modulate immunity to protect against or treat disease thus cannot be overstated. Fortunately, we are entering an exciting era where the science of immunology is defining pathways for the rational manipulation of the immune system at the cellular and molecular level, and this understanding is leading to dramatic advances in the clinic that are transforming the future of medicine.1,2 These initial advances are being made primarily through biologic drugs– recombinant proteins (especially antibodies) or patient-derived cell therapies– but exciting data from preclinical studies suggest that a marriage of approaches based in biotechnology with the materials science and chemistry of nanomaterials, especially nanoparticles, could enable more effective and safer immune engineering strategies. This review will examine these nanoparticle-based strategies to immune modulation in detail, and discuss the promise and outstanding challenges facing the field of immune engineering from a chemical biology/materials engineering perspectiveNational Institutes of Health (U.S.) (Grants AI111860, CA174795, CA172164, AI091693, and AI095109)United States. Department of Defense (W911NF-13-D-0001 and Awards W911NF-07-D-0004

Synthesis of dextran-based chain transfer agent for RAFT-mediated polymerization and glyco-nanoobjects formulation

International audienceGlycopolymers based on dextran are frequently prepared via ATRP, whereas the use of RAFT polymerization is strangely limited due to the difficult synthesis of Dextran-based macromolecular chain transfer agent (DexCTA). The aim of this work is to establish a controlled and reproducible methodology for its preparation. Direct esterification of the hydroxyl dextran functions is the most common method. Our study shows that this latter leads to a very low degree of functionalization. As alternative, we report a reproductible multistep strategy consisting of oxidation, amination, and amidation reactions. Various DexCTAs with tunable degree of substitution (respectively 0.025, 0.045, and 0.06) were successfully prepared. As proof of concept, one of the DexCTAs was involved in the photo-mediated RAFT polymerization of hydroxypropyl methacrylate in DMSO to prepare amphiphilic Dex-g-PHPMA glycopolymers, which can self-assemble in water into monodisperse spherical nano-objects. MTT assays revealed the biocompatibility of all dextran derivatives