Carbohydrate epitope discovery via chemical synthesis

Abstract The human immune system is capable of eliminating nearly any type of infectious agent; however, in many cases it must be "instructed" how to recognize specific pathogens. Bacteria have evolved means of evading aspects of immunity by cloaking themselves in polymeric sugars (glycans), and the first interactions between bacteria and the immune system involve these glycans. While this cloaking mechanism can protect bacteria from potent immune responses, it can also be an exploitable weakness. Our collaborative group, borrowing on work from many pioneering scientists, has developed means of using this cloaking mechanism to "instruct" the immune system to selectively target specific types of bacteria. In this Project, we are preparing the specific instructions for adaptive immunity, which will result in production of highly specific antibodies for the targeted bacteria. The targeted bacteria include some of the most prevalent and dangerous human pathogens, including drug-resistant Staphylococcus aureus, Klebsiella pneumoniae and Neisseria gonorrhoeae. In this project, we are investigating how antibodies recognize specific sections of the polymeric glycans produced by bacteria. This investigation involves preparation of individual sections of the glycans, comprised of two, three or four sugars. From these sections, vaccines will be generated that will trigger production of high-affinity antibodies for each individual section. These antibodies will be evaluated for how well they bind to the polymeric glycan and to intact bacteria and how well these antibodies function in promoting elimination the targeted bacteria by the immune system. From information generated by the study of the performance of antibodies generated to specific sections of the polymeric glycan, we will learn which portions of the glycan can be bound by antibodies and how large of section provides the strongest and most selective binding. Outcomes of this research include an understanding the size and nature of bacterial glycans that can be used for vaccine generation and for the development of high-affinity antibodies that will provide a means of treating bacterial infections.