Polymers to modulate host-microbe interactions
Author(s)Kruger, Austin Grant.
Massachusetts Institute of Technology. Department of Chemistry.
Laura L. Kiessling.
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Chemical interactions between microbes and hosts both support and destroy life. Recognition of self- and non-self, destruction of pathogens, and recruitment of symbionts are all largely mediated by multivalent interaction between macromolecules. Multivalent binding occurs when multiple receptors on one surface engage multiple ligands on another. Analogous to protein-small molecule recognition, wherein precise arrangement of atoms in ligand and receptor create complementarity, multivalent ligands and receptors gain specificity based on the three-dimensional arrangement of both targets. Cells control multivalent systems by displaying ligand-receptor pairs on polymers such as proteins. By controlling polymer properties such as size, shape, and ligand density, life utilizes multivalent chemistry to accomplish key cellular and organismal functions such as proliferation and adaptive immunity.In particular, multivalent recognition is critical to the maintenance of host-microbe symbiosis and pathogenesis. Mucins, the massive glycoprotein structural components of mucus, feature multivalent displays of oligosaccharide which specifically bind microbial adhesins recruiting them to mucosal barriers. Mucin structure has proven critical to their ability to attract symbionts, repel pathogens, and control microbial virulence. Additionally, adaptive immunity hinges on multivalent recognition of pathogenic epitopes for precise identification and elimination of harmful microbes. The structure of protein and carbohydrate antigens have profound influences on the ability of the immune system to recognize and destroy pathogens. Similar to structure-activity relationships for small molecules, synthetic polymers can be systematically tuned to perturb and enhance these systems.However, it is only with the advent of living polymerizations, such as the ring opening metathesis polymerization, that sufficient control over polymer structure has enabled precise structure-activity investigations for multivalent interactions. To better understand how chemical structure influences host-microbe relationships, I have synthesized precisely defined and highly tunable synthetic polymers to mimic the structure and anti-virulence properties of mucin and the immunogenicity of natural antigens. To assist in the transfer of this knowledge to practical applications, I have developed methodology for functionalization of degradable polymers whose structures can be readily controlled. This research has resulted in tools to better understand host-microbe symbiosis and pathogenesis. It is my sincere hope that they will contribute to a brighter future for all life.
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, September, 2020Cataloged from student-submitted PDF of thesis.Includes bibliographical references (pages 203-227).
DepartmentMassachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology