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Research project (§ 26 & § 27)
Duration : 2020-03-01 - 2022-11-30

Plant cell walls consist of a sophisticated composite largely made of several polysaccharide networks with essential functions in the life cycle of the plant. These cell wall polysaccharides receive an enormous interest as sources of sustainable materials and for the production of biofuels. To enhance the economic viability of exploiting biomass as a renewable resource, an increasing number of plants with modified polysaccharide composition are generated. However, a prerequisite to perform targeted genetic modifications is a detailed knowledge of cell wall polysaccharide biosynthesis. We recently produced a glycan microarray equipped with synthetic cell wall oligosaccharides. This microarray provides for the first time the opportunity to develop an assay for the simultaneous screening of various plant glycosyltransferases. The microarray will be incubated with chemically synthesized azido-functionalized sugar nucleotides and putative glycosyltransferases. Any incorporated azido-functionalized monosaccharide will be visualized by subsequent labeling with a fluorescent dye using click-chemistry. Thus, the microarray format of this high-throughput assay will not only be valuable for identifying new glycosyltransferases, but will directly provide information on their substrate specificities.
Research project (§ 26 & § 27)
Duration : 2019-05-01 - 2023-04-30

Mammalian immune receptors trigger intracellular pro-inflammatory signaling cascades in response to infectious challenge, which promotes inflammation and contributes to recovery from infection. When bacteria leave the located area to invade the bloodstream (bacteremia), substantial amounts of bacterial Endotoxin is released into the circulation of the host resulting in the over-activation of inflammatory pathways and sepsis syndrome. The malfunction of the regulatory mechanisms during sepsis leads to the loss of control of inflammation and a life-threatening endotoxic shock (sepsis) with extraordinary high 50% mortality rate. Toll-like receptor 4 (TLR4) expressed by the host immune cells propagate the immediate immune response to Gram-negative bacterial infection and plays the central role in the initiation and progression of sepsis. Activation of TLR4 is interrelated with the activation of a newly discovered cytosolic Endotoxin receptor, caspase-4/11, which leads to programmed cell death and is deeply implicated in the development of sepsis. Activation of TLR4 contributes to the pathogenesis of numerous inflammatory, auto-immune and chronic diseases such as asthma, arthritis and cancer which highlights the significance of TLR4 as therapeutic target. Despite tremendous efforts of Pharma R&D to develop anti-sepsis drugs and immuno-modulators, no effective therapeutic remedy has been developed so far. Sepsis is increasingly reputed as the ultimate common pathway to death from infection and remains the leading cause of mortality in intensive care units. In a view of the globally expanding antibiotic resistance, the occurrence and frequency of sepsis is anticipated to rise emphasizing the importance of exploiting new approaches for treatment and prevention of sepsis and chronic inflammation. The objective of the Grant Proposal is to develop a new class of TLR4- and caspase-4/11 – specific sugar-based molecules having pronounced anti-inflammatory properties. Novel generation of innovative glycolipids will be designed, synthesised and biologically evaluated. Synthetic glycolipids based on the sugar scaffolds will block the binding of Endotoxin to respective receptor proteins (antagonist). Chemical modifications of the basic antagonist glycolipid structure will provide molecules with unique biological features - partial agonists at TLR4 and caspase-4/11. Partial agonist will compete with Endotoxin for binding on the receptor proteins, and thereby, block the induction of deleterious pro-inflammatory signaling. At the same time, exposure of TLR4 complex to partial agonist will ensure a constant, weak level of immune activation, preventing in this way the lethal sepsis-induced immunosuppression. This way of immunomodulation is a promising strategy for therapy of acute and chronic diseases ranging from autoimmune disorders to antibiotic-resistant infections. The project will be performed within tight cooperation between bioorganic chemists (BOKU), immunologists and molecular and structural biologists (cooperation partners in Germany, Belgium, USA and China). The research project will contribute to understanding of molecular mechanisms of inflammatory diseases and will foster the invention of novel sugar-based immunotherapeutics directed to the resolution of inflammation and treatment of sepsis.
Research project (§ 26 & § 27)
Duration : 2017-11-01 - 2022-08-31

PROJECT SUMMARY A number of Abs targeting oligomannose-type glycans on the HIV envelope spike (Env) have been described in recent years that exhibit broad neutralizing activity (bnAbs). However, eliciting such nAbs by immunization has not been very successful so far. A principal problem may be the host origin of the glycans, with immune tolerance mechanisms limiting the frequency or development of B cells capable of producing Abs with specificity for mammalian oligomannose. For example, Abs elicited by glycoconjugate immunogens presenting oligomannosides are generally unable to bind oligomannose on Env and even when Env-binding Abs have been obtained, such as with recombinant yeast, they appear to bind insufficiently avid to the virus and fail to exert meaningful neutralizing activity. Here, we propose to utilize bacterially derived oligosaccharide analogs of oligomannose to overcome these challenges. We focus in this application on a fairly conserved patch of high-mannose glycans at and surrounding Asn301 and Asn332 on HIV gp120. Prototypic for Abs targeting these oligomannose-type glycans is the PGT128 family of nAbs, which are potent and broadly active, suggesting that a vaccine component able to elicit similar nAbs could offer protection at even modest serum Ab concentrations. We not long ago discovered a bacterial oligosaccharide that closely resembles the D1 arm of mammalian oligomannose and subsequently made synthetic derivatives of it with a D3 arm-like extension. One of these derivatives, in the form of a neoglycoconjugate, is bound avidly by PGT128 family members and, notably, their predicted germline predecessor. More importantly, data from a pilot immunization with the lead conjugate in transgenic animals harboring an unarranged human Ab repertoire show elicitation of oligomannose-specific Abs with HIV cross-neutralizing activity. Here, we propose to expand on these encouraging preliminary studies. Specifically, we wish to elaborate on our conjugate design to heighten Ab responses and continue to utilize transgenic animals to identify an optimal adjuvant+conjugate combination. We also will dissect antibody responses at the serum and repertoire levels to determine similarities between the elicited responses and existing nAbs. Finally, we propose to test our strategy also in macaques to assess the extent to which it may work in outbred systems. In sum, this project will investigate whether glycan mimicry can serve to readily trigger the development of cross-reactive Abs to the highly vulnerable oligomannose patch on HIV Env. If so, this work could inform strategies for targeting other glyco-epitopes on HIV-1.

Supervised Theses and Dissertations