Dennis L. Kasper

Channing Laboratory, Harvard Medical School, Boston, MA, USA

Title: Bacterial carbohydrates of the intestinal microbiota in health and disease

Abstract:

Adaptive immune responses had long been considered the “territory” of antigenic proteins, whereas carbohydrates are characterized as T-cell-independent antigens that are not typically recognized by the full array of immune cells- specifically T cells. However, studies published over the past few have shown that polysaccharides with zwitterionic charge motifs are processed and presented by the MHC class II pathway and activate T cells.

No place are these concepts better illustrated than the interactions of commensal bacteria in the intestine with the host immune system. A zwitterionic polysaccharide (PSA) from the commensal Bacteroides fragilis has been shown to be the archetypal molecule of commensal bacteria that mediates development of the host immune system. PSA stimulates the normal balance of Th1 and Th2 CD4+ T cells and can complement defects seen in the histology of the spleen and thymus of germ-free mice. This molecule stimulates the innate immune system as a ligand for Toll-like receptor 2 and as such promotes interactions with the adaptive immune system that are required for T cell activation. PSA protects animals from experimental colitis induced by Helicobacter hepaticus, a commensal with pathogenic potential. In animals harboring B. fragilis not expressing PSA, H. hepaticus colonization leads to disease and pro-inflammatory cytokine production in colonic tissues. Purified PSA administered to animals is required to suppress pro-inflammatory interleukin-17 production by intestinal immune cells, as well as inhibition of in vitro reactions in cell cultures. Furthermore, PSA protects from inflammatory disease through a functional requirement for interleukin 10–producing CD4+ T cells. These results reveal that polysaccharides of the bacterial microbiota can mediate the critical balance between health and disease.  These concepts might have been considered heretical only a few years ago, yet they are slowly being accepted as an important part of the immune repertoire.

Biography:

For more than three decades, Dennis Kasper has conducted research in microbiology, infectious diseases and public health while discharging a broad range of administrative and educational responsibilities. Dr. Kasper is the William Ellery Channing Professor of Medicine and a Professor of Microbiology and Molecular Genetics at Harvard Medical School. As Director of the Channing Laboratory, a research facility with a high international profile, he plays a powerful role in shaping cutting-edge research programs in infectious diseases and epidemiology.

Dr. Kasper has studied the carbohydrates of group B Streptococcus, the foremost cause of serious neonatal bacterial infections and Bacteroides fragilis, an important intestinal commensal and cause of intraabdominal infections and abscesses. His studies innovatively integrate structural carbohydrate chemistry, microbiology, immunology, biochemistry, and genetics. He elucidated the structure of all nine capsular polysaccharides and important surface proteins of group B Streptococcus and their role in pathogenesis and derived a highly immunogenic glycoconjugate vaccine, now in clinical trials. Studying B. fragilis, he discovered capsular polysaccharides on the organism's surface, which are essential for virulence. Remarkably, Dr. Kasper found that single strains produce eight phase-varying polysaccharides; at least two have a zwitterionic charge motif. Overturning immunologic paradigms, he discovered how one zwitterionic polysaccharide, PSA, is processed via the endosomal MIIC pathway in antigen-presenting cells, depolymerized by NO-dependent deamination, and presented to CD4+ T-cells by MHCII. He then found an essential role for PSA in shaping mammalian immune development by stimulating normal splenic CD4+ T cell numbers, TH1/TH2 balance and thereby directing splenic organogenesis. PSA has potent immunomodulatory and anti-inflammatory activity stimulating CD4+ T-cell production of IL-10, which protects against inflammatory bowel disease.  Dr. Kasper’s investigations have opened new fields of research on the role of carbohydrates in shaping immune development balance.

Dr. Kasper also directs the New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research and is the Chairman of the National Science Advisory Board on Biosecurity. He has served as Executive Dean for Academic Programs at Harvard Medical School,  Chair of the NIAID's Board of Scientific Counselors and as President of the International Society for Infectious Diseases. Dr. Kasper is also a member of the Institute of Medicine of the National Academy of Science.

Since 1990, Dr. Kasper has served as the Infectious Disease Editor for Harrison’s Principles of Internal Medicine (HPIM). He was Editor-in-Chief of the 16th edition of HPIM. He is the author of more than 350 research and clinical publications encompassing an array of topics in infectious diseases and microbiology.