New vaccine modalities need to be developed that can activate more potently the immune system, in this regard, adjuvants augment adaptive immune responses and can improve vaccine performance. Aluminium salt (alum) is the most commonly used adjuvant for human vaccination. However, it drives primarily TH2-effector responses and is not effective for vaccines that target mucosal surfaces. Thus, safe and potent adjuvants need to be developed that can increase and direct vaccine-specific immunity. Recent advances in our understanding of innate immune responses are providing opportunities to design better adjuvants. The innate immune system senses microbes through pattern-recognition receptors (PPRs), which include the Toll-like receptors (TLRs), and intracellular NOD-like receptors (NLRs) and C-type lectin-like (CTLs) receptors that are expressed by immune cells. Activation of these receptors leads to the production of cytokines that provide early defences during infection. Cytokines also regulate adaptive immunity by controlling the quantity and quality of B and T cell activation, which in turn results in protective immune responses to pathogens. Pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharides, lipopeptides, and peptidoglycan fragments can activate PPRs and are attractive compounds for the development of new adjuvant. Although during microbial infection many different PRRs are activated, almost all adjuvants that are being developed rely on the stimulation of a single PRR. In this project, we propose that compound adjuvants derived by the covalent linking of two PAMPs (fusion PAMPs), for example, TLR2 and NOD agonists, will ensure that immune cells are being exposed to both, resulting in efficient cross talk of signal transduction pathways and in synergistic immune activation. If so, chimeric immune modulators (fusion PAMPs) can be employed at lower adjuvant concentrations, thereby minimizing unwanted side effects.

The organization of nanoparticles is important for tuning material characteristics, impacting electronic and optical properties. Systems in nanotechnology are reliant upon self-assembly. Recently, liquid crystals, famous for displays, have been employed to self-assemble particles, due to the medium’s ability to form complex patterns. However, the exact interactions between nanoparticles and liquid crystals at the submicron scale remain ambiguous. EXCHANGE_inLCs seeks to elucidate particle-liquid crystal interactions at the submicron scale, by EXamining CHemistry and Nanoparticle Geometry Effects at the INterface of Liquid CrystalS through: 1) varying system GEOMETRY to elucidate the impact of confinement, particle size, and shape, and 2) varying system CHEMISTRY to clarify the activity of certain chemical species around particles. The project will be performed at Utrecht University, where the host has expertise in nanoparticle assembly and light nanoscopy. By varying system length scales and types of surface treatments, key interactions can be isolated. The project will facilitate the following two-way transfer of knowledge between the host and me: A) The host has innovated methods of functionalizing, manipulating, and imaging particle assemblies, down to the single-particle resolution. Both skills are essential for me to investigate my systems at a challenging length scale where both chemistry and geometry can be equally influential. B) The host has a history of exploring the ordering of rod-like particles (colloidal liquid crystals), and my expertise in patterning rod-like molecules (molecular liquid crystals) would complement their body of knowledge. We share a mutual interest in interparticle interactions and their effects on self-assembly. The project combines our areas of expertise to advance fundamental knowledge of nanoparticle self-assembly in anisotropic fluids, essential for developing new bottom-up approaches in nanotechnology, a European priority.

Influenza A virus has two major envelope glycoproteins: HA and neuraminidase (NA). HA binds to sialic acid moieties of glycoconjugates of the host respiratory cells to initiate infection, whereas NA facilitates the release of progeny viruses from infected cells by cleaving sialosides. It is well documented that binding preference is a major determinant of influenza virus host range and avian viruses preferentially bind Neu5Acα(2,3)Gal, whereas human viruses bind Neu5Acα(2,6)Gal. This difference in specificity represents a barrier for transmission of avian viruses into humans. Glycan arrays have been used to assess influenza A virus receptor specificity. However, the currently available glycan arrays contain only a fraction of the glycans found on human airway epithelial cells and cannot uncover glycan binding specificities. Thus, we propose to develop an array that contains glycans representative of the structures found in human airways, since it is a priority in order to understand the biology of influenza virus transmission and pathogenesis. In addition, it has been described that there are two pathways by which influenza virus enters cells. It is believed that some N-glycans serve as attachment factors for concentrating virus particles on the surface of the host cells. However, only specific cell surface proteins modified by appropriate N-glycans can facilitate cell entry. The elucidation of the influenza virus receptor structure will unveil the mechanism at molecular level by which virus enters the cell. To this end, we will develop an experiment, which allows us to identify glycoprotein receptors of flu virus using cell surface glycan editing. The full comprehension of multi-branched glycans, along with the identification of the glycoproteins receptors of influenza virus, will allow the development of new and more efficient glycan-based therapeutics.