Harvard Medical School


Contact Information:

Harvard Medical School

NRB, Room 1056C

77 Avenue Louis Pasteur

Boston, MA 02115

phone: 617-432-5505

fax: 617-432-5513

 

dennis_kasper@hms.harvard.edu

 

Research Summary

An infection occurs when a potentially virulent organism comes into contact with a susceptible host. Dr. Kasper’s group is studying the molecular basis for bacterial pathogenesis from both the host’s and the organism’s perspective. Studies are aimed at the molecular, chemical, and genetic basis for the interactions of the immune system with bacteria and with important bacterial components, particularly capsular polysaccharides and surface or secreted proteins. How the immune system responds to bacterial components is a major focus of the laboratory. The overall goal is to develop an understanding of host-organism interactions that will lead to new preventive or therapeutic interventions.

Host response to infection—We have been studying why certain bacterial species, particularly Bacteroides fragilis and Staphylococcus aureus, are predisposed to induce abscesses in the host. We have found that the essential virulence factor required for abscess induction by these two pathogens is capsular polysaccharide with a unique zwitterionic charge motif. By initiating a proinflammatory Th1 cytokine response, zwitterionic polysaccharides (ZPSs) induce the host to form abscesses. In contrast to the immunologic paradigm defining polysaccharides as T cell–independent antigens, ZPSs activate T cells in vivo and in vitro [when incubated with antigen-presenting cells (APCs)]. There is currently no paradigm in immunology for how this important class of biomolecules (carbohydrates) activates the cellular immune system. Our data indicate that the polysaccharides are presented to the T cell by MHC class II molecules. We have defined novel mechanisms by which polysaccharides are processed and presented by MHCII molecules resulting in T cell activation. The delineation of a mechanism for carbohydrate presentation has broad relevance to the development of new immunomodulators and vaccines. The role of bacterial commensalism in the maturation of the immune system has been another major focus of our laboratory.

Infections due to group B Streptococcus—Group B Streptococcus (GBS) is the major pathogen of human neonates and an emerging pathogen in adults. Our studies of GBS have targeted the following interrelated areas: Molecular genetics: Basic investigations exploring the genome of this organism and the relation of specific structural and regulatory genes to virulence and immunity. Innate immunity: Studies of the innate immune system, particularly the Toll-like receptors and their activation by specific GBS molecules, including proteins and carbohydrates. Acquired immune response to glycoconjugate vaccines: Polysaccharides are poorly immunogenic when given as vaccines unless they are coupled to carrier proteins. We are studying the mechanisms of induction of enhanced immune responses as a result of the physical-chemical parameters of the vaccine. This work includes elucidation of the critical molecules on APCs and T cells that are required for this enhanced response. This work will provide crucial insights that we believe will lead to improved efficacy of future vaccines.

Kalka-Moll WM, Tzianabos AO, Bryant PW, Niemeyer M, Ploegh HL, Kasper DL. Zwitterionic polysaccharides stimulate T cells by MHC class II-dependent interactions. J Immunol 2002;169:6149-6153.

Pozdnyakova O, Guttormsen H-K, Lalani FN, Carroll MC, Kasper DL. Impaired antibody response to group B streptococcal type III capsular polysaccharide in C3- and complement receptor 2-deficient mice. J Immunol 2003;170:84-90.

Cobb BA, Wang Q, Tzianabos AO, Kasper DL. Polysaccharide processing and presentation by the MHCII pathway. Cell 2004;117:677-687.