Excellence in Research: Biophysical mechanism by which mannose and N glycans modifies and protects biological surfaces

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The surface of pathogens is shielded by short polymers of sugars known as glycans. Glycans mask pathogens and signature molecules from host cells and confound therapeutic treatments. N-glycans are the commonly found type of glycans found on cell surfaces. Pathogens like Ebola, SARS, HIV, and COVID 19 are shielded by N-glycans having high mannose content, with the mannose content sometimes increasing during the host infection. The goal of the proposal is to investigate what biophysical properties of mannose residues present in shields of N-glycans confer protection of pathogens against the host immune system. This project will train graduate and undergraduate students and provide an annual hands-on STEM workshops to engage high school students in research and everyday science. Understanding how mannose residues presented in N-glycans protect pathogens will help us strategically disarm the glycan shield fortress, thereby making pathogens more vulnerable to detection, sanitizing, and treatment. Despite the ubiquitous presence of glycan sugars on biological surfaces, little is known currently about how glycans steer interfacial effects like aggregation, biofilm formation, charge shielding, antifouling, immune-stealth, and transport through mucus. This project will lead to a better understanding of the biophysics of mannose residues when presented in N-glycan architecture along with non-mannose sugars, and how they relate to the improved solubility and aggregation, mucous penetration, and immune evasion of glycosylated molecules. To understand the uniqueness of mannose biophysics and how it interplays with other N-glycan sugars, the cross- and self- interactions of all N-glycan sugars will be determined, and rules for integrating single-sugar biophysics to glycosylated system behavior will be evaluated. A pseudo-typed HIV virus is the controlled sugar-presentation platform. These studies will synergistically link observations from force-spectroscopy, rheology, and dynamic light scattering, along with perturbations from glycosidase and lectin addition. This project is jointly supported by the Historically Black Colleges and Universities (HBCU) Excellence in Research program and the Molecular Biophysics program in the Molecular and Cellular Biosciences Division.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.