Programming innate immune responses using glycomimetic macromolecular complexes

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Non-Technical abstract: Innate immunity is a part of the immune system that recognizes specific chemical patterns used in pathogens (ex: bacteria, viruses, and fungi) but not common to our cells and mammalian cells. These patterns include double-stranded RNA, certain types of DNA and sugar-based molecules known as lipopolysaccharides (LPS). Detection of these molecular patterns is a potential sign of invasion, and trigger defensive responses. It has been discovered that certain molecules that are not supposed to be detected by the innate immune system can in fact stimulate and greatly amplify this innate immune response, by simply forming organized structures with DNA and with RNA. This is completely unexpected, and can potentially revise fundamental understanding of molecular recognition. The goal of this proposed research is to understand the rules governing these phenomena, and design and test new synthetic molecules that can mimic this immune system amplification, and to design new synthetic molecules that can turn off this process. The basic knowledge gained as a result of this research will be broadly enabling. Potential long term outcomes include biomaterials for better control of the immune system and better sensors for detection of specific chemicals. This work will broaden participation in a number of ways. The multi-disciplinary nature of the proposed work will provide ample educational opportunities in this emerging field. The research topics here are conducive to training for academic and industrial employment. Research internships will be provided through underrepresented undergraduate and veteran outreach programs. Results from this will be incorporated into the PIs' advanced undergraduate/graduate classes. Technical abstract:Innate immunity is a non-specific defense mechanism against pathogens bearing specific chemical recognition motifs not common to mammalian cells. Detection of these pathogen-associated molecular patterns (PAMPs) signals the presence of foreign cells, and trigger inflammatory responses. Toll-like receptors (TLRs) are capable of recognizing specific immune ligand classes: dsRNA is recognized by TLR3, while TLR9 recognizes pathogenic dsDNA; both activate signal transduction pathways that lead to the production of pro-inflammatory cytokines and upregulation of antimicrobial peptides (AMPs) for pathogen defense. Recent work from his research group on TLR9 and TLR3 activation reveal a new, unexpected physical basis for immunomodulation. Molecules with specific structural characteristics can co-assemble with immune ligands into nanocrystalline complexes that drastically upregulate immune responses: The spatially-periodic presentation of immune ligands by these complexes drive amplification via intercalative binding with multiple TLRs. This represents a significant generalization of the central paradigm in molecular recognition. Innate immune receptors can recognize not just PAMPs on single ligand molecules, but also recognize nanocrystalline arrangements of ligands. Here, the aim is to understand this new type of molecular recognition, and design chemically-cognate, structurally-characterized families of self-assembled dsDNA complexes and quantitatively control downstream immune stimulation. Potential long term outcomes include biomaterials for better control of the immune system and better sensors for detection of specific chemicals. The multi-disciplinary nature of the proposed work will provide ample educational opportunities in this emerging field. The research topics here are conducive to training for academic and industrial employment. Research internships will be provided through underrepresented undergraduate and veteran outreach programs. Results from this will be incorporated into the PIs' advanced undergraduate/graduate classes.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.