• Dennis Kasper
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What We Do

The focus of the Kasper laboratory is on the centrality of the microbiome in immune system development, maturation, and regulation. The laboratory’s research defines the phylogenetic diversity, immune mechanisms, and immunomodulatory therapeutic potential of bacteria and bacterial molecules in autoimmune and infectious diseases. We also investigate the chemistry and immunology of bacterial polysaccharides and lipids, gaining fundamental insights into their role in pathogenesis, as protective vaccine antigens, and as critical modulators of mucosal and systemic immunity.

Selected Recent Publications

Ximei Sun, Giuseppe Stefanetti, Francesco Berti, and Dennis L Kasper. 2019. “Polysaccharide structure dictates mechanism of adaptive immune response to glycoconjugate vaccines.” Proc Natl Acad Sci U S A, 116, 1, Pp. 193-198.Abstract
Glycoconjugate vaccines are among the most effective interventions for preventing several serious infectious diseases. Covalent linkage of the bacterial capsular polysaccharide to a carrier protein provides CD4 T cells with epitopes that facilitate a memory response to the polysaccharide. Classically, the mechanism responsible for antigen processing was thought to be similar to what was known for hapten-carrier conjugates: protease digestion of the carrier protein in the endosome and presentation of a resulting peptide to the T cell receptor on classical peptide-recognizing CD4 T cells. Recently, an alternative mechanism has been shown to be responsible for the memory response to some glycoconjugates. Processing of both the protein and the polysaccharide creates glycopeptides in the endosome of antigen-presenting cells. For presentation, the peptide portion of the glycopeptide is bound to MHCII, allowing the covalently linked glycan to activate carbohydrate-specific helper CD4 T cells (Tcarbs). Herein, we assessed whether this same mechanism applies to conjugates prepared from other capsular polysaccharides. All of the glycoconjugates tested induced Tcarb-dependent responses except that made with group C ; in the latter case, only peptides generated from the carrier protein were critical for helper T cell recognition. Digestion of this acid-sensitive polysaccharide, a linear homopolymer of α(2 → 9)-linked sialic acid, to the size of the monomeric unit resulted in a dominant CD4 T cell response to peptides in the context of MHCII. Our results show that different mechanisms of presentation, based on the structure of the carbohydrate, are operative in response to different glycoconjugate vaccines.
Giuseppe Stefanetti, Nihal Okan, Avner Fink, Erica Gardner, and Dennis L Kasper. 2019. “Glycoconjugate vaccine using a genetically modified O antigen induces protective antibodies to Francisella tularensis.” Proc Natl Acad Sci U S A, 2019 Mar 14, [Epub ahead of print] .Abstract
Francisella tularensis is the causative agent of tularemia, a category A bioterrorism agent. The lipopolysaccharide (LPS) O antigen (OAg) of has been considered for use in a glycoconjugate vaccine, but conjugate vaccines tested so far have failed to confer protection necessary against aerosolized pulmonary bacterial challenge. When OAg was purified under standard conditions, the antigen had a small molecular size [25 kDa, low molecular weight (LMW)]. Using milder extraction conditions, we found the native OAg had a larger molecular size [80 kDa, high molecular weight (HMW)], and in a mouse model of tularemia, a glycoconjugate vaccine made with the HMW polysaccharide coupled to tetanus toxoid (HMW-TT) conferred better protection against intranasal challenge than a conjugate made with the LMW polysaccharide (LMW-TT). To further investigate the role of OAg size in protection, we created an live vaccine strain (LVS) mutant with a significantly increased OAg size [220 kDa, very high molecular weight (VHMW)] by expressing a heterologous chain-length regulator gene () from the related species Immunization with VHMW-TT provided markedly increased protection over that obtained with TT glycoconjugates made using smaller OAgs. We found that protective antibodies recognize a length-dependent epitope better expressed on HMW and VHMW antigens, which bind with higher affinity to the organism.
Naama Geva-Zatorsky, Esen Sefik, Lindsay Kua, Lesley Pasman, Tze Guan Tan, Adriana Ortiz-Lopez, Tsering Bakto Yanortsang, Liang Yang, Ray Jupp, Diane Mathis, Christophe Benoist, and Dennis L Kasper. 2017. “Mining the Human Gut Microbiota for Immunomodulatory Organisms.” Cell, 168, 5, Pp. 928-943.e11.Abstract
Within the human gut reside diverse microbes coexisting with the host in a mutually advantageous relationship. Evidence has revealed the pivotal role of the gut microbiota in shaping the immune system. To date, only a few of these microbes have been shown to modulate specific immune parameters. Herein, we broadly identify the immunomodulatory effects of phylogenetically diverse human gut microbes. We monocolonized mice with each of 53 individual bacterial species and systematically analyzed host immunologic adaptation to colonization. Most microbes exerted several specialized, complementary, and redundant transcriptional and immunomodulatory effects. Surprisingly, these were independent of microbial phylogeny. Microbial diversity in the gut ensures robustness of the microbiota's ability to generate a consistent immunomodulatory impact, serving as a highly important epigenetic system. This study provides a foundation for investigation of gut microbiota-host mutualism, highlighting key players that could identify important therapeutics.
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