Probing DC-SIGN-glycan multivalent interaction and dendritic cell immune regulation using polyvalent multifunctional glycan-gold nanoparticles

Multivalent lectin-glycan interactions is central to pathogen infection and immune response regulation.

Dendritic cell (DC) surface tetrameric lectin, DC-SIGN, is particularly important in discriminating self- and foreign (pathogen) glycan patterns and regulates DC immune response. The underlying structural and immune regulation mechanisms remain poorly understood.

As various lectins have overlapping glycan specificity, this greatly limits our ability to design glycoconjugates that can specifically target DC-SIGN to block infection or exploit its powerful immune regulation to develop effective immunotherapies.Here we will address this challenge by developing polyvalent glycan-gold nanoparticles (GNPs) & multiple GNP assemblies to enhance binding affinity and specificity by exploiting multivalency.

By tuning GNP surface glycan structure, valency, inter-glycan spacing, size and shape and study their binding with DC-SIGN/R, we will reveal the optimal glycan structure for DC-SIGN binding. By exploiting GNP’s fluorescence quenching, we will develop a new lectin-glycan affinity quantifying method.

We will use glycan-GNPs to block pseudo-Ebola virus infection of DC-SIGN expressing cells and correlate the affinity and inhibition potency.

We will study how glycan-GNP binding controls DC surface DC-SIGN clustering, binding to intracellular proteins & regulating cytokine production to reveal the .

This research is extremely timely & important because it will, 1) establish a design rule for potent, highly specific DC-SIGN targeting; 2) develop a new lectin-glycan affinity quantification method; 3) reveal correlation between DC-SIGN/R binding affinity & viral inhibition potency; 4) elucidate how DC-SIGN-glycan binding signal is transduced to regulate DC immune function, paving way to develop effective immunotherapies against deadly immune-dysregulation diseases (e.g. cancer, allergy, & auto-immune diseases) by exploiting DC-SIGN’s powerful immune regulation function.