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 Dennis L. Kasper, MDDirector William Ellery Channing Professor of Medicine Senior Physician dennis.kasper@channing.harvard.edu
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Research Interests 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. 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. On the basis of our data, we believe that antigen presentation in this instance is not accomplished by a superantigen-like mechanism. We are conducting detailed studies of the MHC class II pathway to define the mechanism of presentation. The delineation of a mechanism for carbohydrate presentation has broad relevance to the development of new immunomodulators and vaccines.
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. Selected Publications Tzianabos AO, Onderdonk AB, Rosner B, Cisneros RL, Kasper DL. Structural features of polysaccharides that induce intra-abdominal abscesses. Science 1993 Oct 15;262(5132):416-9. [abstract] Madoff LC, Paoletti LC, Tai JY, Kasper DL. Maternal immunization of mice with group B streptococcal type III polysaccharide-beta C protein conjugate elicits protective antibody to multiple serotypes. J Clin Invest 1994 Jul;94(1):286-92. [abstract] Madoff LC, Michel JL, Kling D, Gong EW, Kasper DL. Group B streptococci escape host immunity by deletion of tandem repeat elements of the alpha C protein. Proc Natl Acad Sci USA 1996 Apr 30;93(9):4131-6. [abstract] Kasper DL, Paoletti LC, Wessels MR, Guttormsen HK, Carey VJ, Jennings HJ, Baker CJ. Immune response to type III group B streptococcal polysaccharide-tetanus toxoid conjugate vaccine. J Clin Invest 1996 Nov 15;98(10):2308-14. [abstract] Li J, Kasper DL, Ausubel FM, Rosner B, Michel JL. Inactivation of the alpha C protein antigen gene, bca, by a novel shuttle/suicide vector results in attenuation of virulence and immunity in group B Streptococcus. Proc Natl Acad Sci USA 1997 Nov 25;94(24):13251-6. [abstract] Wessels MR, Paoletti LC, Guttormsen HK, Michon F, D'Ambra AJ, Kasper DL. Structural properties of group B streptococcal type III polysaccharide conjugate vaccines that influence immunogenicity and efficacy. Infect Immun 1998 May;66(5):2186-92. [abstract] Wang Y, Hollingsworth RI, Kasper DL. Ozonolysis for selectively depolymerizing polysaccharides containing ß-D-aldosidic linkages. Proc Natl Acad Sci USA 1998 Jun 9;95(12):6584-9. [abstract] Tzianabos AO, Russell PR, Onderdonk AB, Gibson III FC, Cywes C, Chan M, Finberg RW, Kasper DL. IL-2 mediates protection against abscess formation in an experimental model of sepsis. J Immunol 1999;1999 Jul 15;163(2):893-7. [abstract] Comstock LE, Coyne MJ, Tzianabos AO, Kasper DL. Interstrain variation of the polyschharide B biosynthesis locus of Bacteroides fragilis: characterization of the region from strain 638R. J Bacteriol 1999 Oct;181(19):6192-6. [abstract] Kalka-Moll WM, Tzianabos AO, Wang Y, Carey VJ, Finberg RW, Onderdonk AB, Kasper DL. Effect of molecular size on the ability of zwitterionic polysaccharides to stimulate cellular immunity. J Immunol 2000 Jan 15;164(2):719-24. [abstract] Deng L, Kasper DL, Krick TP, Wessels MR. Characterization of the linkage between the type III capsular polysaccharide and the bacterial cell wall of group B Streptococcus. J Biol Chem 2000 Mar 17;275(11):7497-504. [abstract] Tzianabos AO, Finberg RW, Wang Y, Chan M, Onderdonk AB, Jennings HJ, Kasper DL. T cells activated by zwitterionic molecules prevent abscesses induced by pathogenic bacteria. J Biol Chem 2000 Mar 10;275(10):6733-40. [abstract] Wang Y, Kalka-Moll WM, Roehrl MH, Kasper DL. Structural basis of the abscess-modulating polysaccharide A2 from Bacteroides fragilis. Proc Natl Acad Sci USA 2000 Dec 5;97(25):13478-83. [abstract] Cieslewicz MJ, Kasper DL, Wang Y, Wessels MR. Functional analysis in type Ia group B Streptococcus of a cluster of genes involved in extracellular polysaccharide production by diverse species of streptococci. J Biol Chem 2001 Jan 5;276(1):139-46. [abstract] 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 Dec 1;169(11):6149-53. [abstract] 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 Jan 1;170(1):84-90. [abstract]
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