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Dennis L Kasper

Publications and source records attributed to Dennis L Kasper.

At least 19 recordsLinked to original sources
PubMed2026

Oxygen-responsive bacterial glycosphingolipid links symbiont fitness and immune development in neonatal host.

Symbiotic gut bacteria must re-establish themselves in every host generation, yet the molecular strategies enabling this inheritance remain poorly understood. Here, we show that Bacteroides fragilis uses a membrane glycolipid, alpha-galactosylceramide (BfaGC), to colonize the neonatal gut. Genome-wide fitness profiling revealed that BfaGC biosynthesis is selectively required during early life, when transient oxygenation creates a physiological bottleneck for strict anaerobes. Mechanistically, BfaGC reduces membrane proton permeability, sustaining the proton-motive force that supports aerobic respiration. This oxygen-responsive adaptation simultaneously generates a host-facing immunomodulatory signal that calibrates neonatal natural killer T (NKT) cell development, linking bacterial fitness to immune maturation through a single metabolite. The same mechanism also enables niche expansion by enterotoxigenic strains, revealing context-dependent consequences. Notably, this strategy is distinct among gut Bacteroidales: other prominent members synthesize a different sphingolipid subclass supporting broader fitness, implying divergent evolutionary strategies. Our findings provide time-resolved insight into how bacterial metabolites shape host-microbiota symbiosis across development.

Bacteroides fragilis↗
PubMed2006

A bacterial carbohydrate links innate and adaptive responses through Toll-like receptor 2.

Commensalism is critical to a healthy Th1/Th2 cell balance. Polysaccharide A (PSA), which is produced by the intestinal commensal Bacteroides fragilis, activates CD4+ T cells, resulting in a Th1 response correcting the Th2 cell skew of germ-free mice. We identify Toll-like receptors as crucial to the convergence of innate and adaptive responses stimulated by PSA. Optimization of the Th1 cytokine interferon-gamma in PSA-stimulated dendritic cell-CD4+ T cell co-cultures depends on both Toll-like receptor (TLR) 2 and antigen presentation. Synergy between the innate and adaptive responses was also shown when TLR2-/- mice exhibited impaired intraabdominal abscess formation in response to B. fragilis. Commensal bacteria, using molecules like PSA, potentially modulate the Th1/Th2 cell balance and the response to infection by coordinating both the innate and adaptive pathways.

Animals↗
PubMed2006

The love-hate relationship between bacterial polysaccharides and the host immune system.

This article explores the fascinating relationship between the mammalian immune system and the bacteria that are present in the mammalian gut. Every human is an ecosystem that hosts 10(13)-10(14) bacteria. We review the evidence that immunomodulatory molecules produced by commensal bacteria in the gut have a beneficial influence on the development of certain immune responses, through eliciting the clonal expansion of CD4(+) T-cell populations. This process seems to contribute to the overall health of the host by offering protection against various diseases and might provide supporting evidence at a molecular level for the 'hygiene hypothesis' of allergic immune disorders.

Animals↗
PubMed2006

Bacterial glycans: key mediators of diverse host immune responses.

Recent studies have shown that the synthesis of various polysaccharides by bacteria can induce immune responses that are beneficial to the bacterium, the host, or both. Here, we discuss the diverse interactions between bacterial glycans and the host immune system.

Animals↗
PubMed2006

A mechanism for neurodegeneration induced by group B streptococci through activation of the TLR2/MyD88 pathway in microglia.

Group B Streptococcus (GBS) is a major cause of bacterial meningitis and neurological morbidity in newborn infants. The cellular and molecular mechanisms by which this common organism causes CNS injury are unknown. We show that both heat-inactivated whole GBS and a secreted proteinaceous factor from GBS (GBS-F) induce neuronal apoptosis via the activation of murine microglia through a TLR2-dependent and MyD88-dependent pathway in vitro. Microglia, astrocytes, and oligodendrocytes, but not neurons, express TLR2. GBS as well as GBS-F induce the synthesis of NO in microglia derived from wild-type but not TLR2(-/-) or MyD88(-/-) mice. Neuronal death in neuronal cultures complemented with wild-type microglia is NO-dependent. We show for the first time a TLR-mediated mechanism of neuronal injury induced by a clinically relevant bacterium. This study demonstrates a causal molecular relationship between infection with GBS, activation of the innate immune system in the CNS through TLR2, and neurodegeneration. We suggest that this process contributes substantially to the serious morbidity associated with neonatal GBS meningitis and may provide a potential therapeutic target.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Modulation of surgical fibrosis by microbial zwitterionic polysaccharides.

Bacterial carbohydrates have long been considered T cell-independent antigens that primarily induce humoral immune responses. Recently, it has been demonstrated that bacterial capsules that possess a zwitterionic charge motif can activate CD4(+) T cells after processing and presentation by antigen-presenting cells. Here we show that these zwitterionic polysaccharides can prevent T helper 1-mediated fibrosis by signaling for the release of IL-10 from CD4(+) T cells in vivo. IL-10 production by these T cells and their ability to prevent fibrosis is controlled by the inducible costimulator (ICOS)-ICOS ligand pathway. These data demonstrate that the interaction of the zwitterionic polysaccharides with T cells results in modulation of surgical fibrosis in vivo and suggest a previously undescribed approach to "harnessing" T cell function to prevent inflammatory tissue disorders in humans.

Animals↗
PubMed2005

Genome analysis of multiple pathogenic isolates of Streptococcus agalactiae: implications for the microbial "pan-genome".

The development of efficient and inexpensive genome sequencing methods has revolutionized the study of human bacterial pathogens and improved vaccine design. Unfortunately, the sequence of a single genome does not reflect how genetic variability drives pathogenesis within a bacterial species and also limits genome-wide screens for vaccine candidates or for antimicrobial targets. We have generated the genomic sequence of six strains representing the five major disease-causing serotypes of Streptococcus agalactiae, the main cause of neonatal infection in humans. Analysis of these genomes and those available in databases showed that the S. agalactiae species can be described by a pan-genome consisting of a core genome shared by all isolates, accounting for approximately 80% of any single genome, plus a dispensable genome consisting of partially shared and strain-specific genes. Mathematical extrapolation of the data suggests that the gene reservoir available for inclusion in the S. agalactiae pan-genome is vast and that unique genes will continue to be identified even after sequencing hundreds of genomes.

Amino Acid Sequence↗
PubMed2005

An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system.

The mammalian gastrointestinal tract harbors a complex ecosystem consisting of countless bacteria in homeostasis with the host immune system. Shaped by evolution, this partnership has potential for symbiotic benefit. However, the identities of bacterial molecules mediating symbiosis remain undefined. Here we show that, during colonization of animals with the ubiquitous gut microorganism Bacteroides fragilis, a bacterial polysaccharide (PSA) directs the cellular and physical maturation of the developing immune system. Comparison with germ-free animals reveals that the immunomodulatory activities of PSA during B. fragilis colonization include correcting systemic T cell deficiencies and T(H)1/T(H)2 imbalances and directing lymphoid organogenesis. A PSA mutant of B. fragilis does not restore these immunologic functions. PSA presented by intestinal dendritic cells activates CD4+ T cells and elicits appropriate cytokine production. These findings provide a molecular basis for host-bacterial symbiosis and reveal the archetypal molecule of commensal bacteria that mediates development of the host immune system.

Animals↗
PubMed2005

Identification of a universal Group B streptococcus vaccine by multiple genome screen.

Group B Streptococcus (GBS) is a multiserotype bacterial pathogen representing a major cause of life-threatening infections in newborns. To develop a broadly protective vaccine, we analyzed the genome sequences of eight GBS isolates and cloned and tested 312 surface proteins as vaccines. Four proteins elicited protection in mice, and their combination proved highly protective against a large panel of strains, including all circulating serotypes. Protection also correlated with antigen accessibility on the bacterial surface and with the induction of opsonophagocytic antibodies. Multigenome analysis and screening described here represent a powerful strategy for identifying potential vaccine candidates against highly variable pathogens.

Animals↗
PubMed2005

Role of lipoteichoic acid in the phagocyte response to group B streptococcus.

Group B Streptococcus (GBS) cell walls potently activate phagocytes by a largely TLR2-independent mechanism. In contrast, the cell wall component lipoteichoic acid (LTA) from diverse Gram-positive bacterial species has been shown to engage TLR2. In this study we examined the role of LTA from GBS in phagocyte activation and the requirements for TLR-LTA interaction. Using cells from knockout mice and genetic complementation in epithelial cells we found that highly pure LTA from both GBS and Staphylococcus aureus interact with TLR2 and TLR6, but not TLR1, in contrast to previous reports. Furthermore, NF-kappaB activation by LTA required the integrity of two putative PI3K binding domains within TLR2 and was inhibited by wortmannin, indicating an essential role for PI3K in cellular activation by LTA. However, LTA from GBS proved to be a relatively weak stimulus of phagocytes containing approximately 20% of the activity observed with LTA from Staphylococcus aureus. Structural analysis by nuclear magnetic resonance spectrometry revealed important differences between LTA from GBS and S. aureus, specifically differences in glycosyl linkage, in the glycolipid anchor and a lack of N-acetylglucosamine substituents of the glycerophosphate backbone. Furthermore, GBS expressing LTA devoid of d-alanine residues, that are essential within immune activation by LTA, exhibited similar inflammatory potency as GBS with alanylated LTA. In conclusion, LTA from GBS is a TLR2/TLR6 ligand that might contribute to secreted GBS activity, but does not contribute significantly to GBS cell wall mediated macrophage activation.

Alanine↗
PubMed2005

Coming of age: carbohydrates and immunity.

Adaptive immune responses have long been considered the "territory" of antigenic proteins, whereas carbohydrates are characterized as T-cell-independent antigens that are not typically recognized by the complete adaptive machinery. The current modus operandi when searching for dominant epitopes is the use of synthetic peptides designed from the primary structure of interesting target proteins; however, there is growing evidence that sugars can also play a critical role in immune recognition. Findings reported in this issue of the European Journal of Immunology begin to shed light on the differences in protein glycosylation that can occur in association with disorders like rheumatoid arthritis and the effect these changes have on collagen recognition by the immune system. Other recent studies have shown that immunodominant glycopeptide "remnant" epitopes as well as glycosylation changes on self-proteins can generate autoimmunity. Finally, some types of carbohydrates are now known to be processed and presented to T cells by class II MHC. Taken together, these advances illustrate a clear importance for carbohydrate recognition in foreign and self antigens by the adaptive immune system. With the common presence of carbohydrate molecules on eukaryotic, prokaryotic, and viral surfaces, the impact of carbohydrates on adaptive immunity is now indisputable.

Animals↗
PubMed2005

Zwitterionic capsular polysaccharides: the new MHCII-dependent antigens.

The immune system has evolved the ability for T cells to recognize nearly any biological polymer, including peptides, protein superantigens, and glycolipids through presentation by the major histocompatibility complex (MHC) proteins such as MHC class I (MHCI), MHC class II (MHCII), and CD1. A recent and unexpected addition to this list is the zwitterionic capsular polysaccharide (ZPS). These bacterial molecules utilize MHCII presentation to activate T cells via recognition by alphabeta T cell receptor (alphabetaTCR) proteins. In this review, we explore what is currently known about ZPS processing and presentation within antigen-presenting cells (APCs) and the immune response that follows.

Abscess↗
PubMed2005

Effect of B7-2 and CD40 signals from activated antigen-presenting cells on the ability of zwitterionic polysaccharides to induce T-Cell stimulation.

Carbohydrates have been thought to stimulate immune responses independently of T cells; however, zwitterionic polysaccharides (ZPSs) from the capsules of some bacteria elicit potent CD4+-T-cell responses in vivo and in vitro. We demonstrated that HLA-DR on professional antigen-presenting cells (APCs) is required for ZPS-induced T-cell proliferation in vitro (15). Recently, it was shown that ZPSs are processed to low-molecular-weight carbohydrates by a nitric oxide-mediated mechanism in endosomes and locate in the major histocompatibility complex class II pathway (5, 15). The effect of the ZPS-mediated expression of HLA-DR and costimulatory molecules on the APC and T-cell engagement and subsequent T-cell activation has not been elucidated. Herein, we report that ZPS-mediated induction of HLA-DR-surface expression and T-cell proliferation are maximally enhanced after incubation of APCs for 8 h with ZPS. Treatment of APCs with bafilomycin A inhibits the up-regulation of ZPS-mediated HLA-DR surface expression and leads to inhibition of T-cell proliferation. Monoclonal antibodies (MAbs) to the costimulatory molecules B7-2 and CD40L specifically block ZPS-mediated T-cell activation, while a MAb to B7-1 does not. Surface expression of B7-2 and B7-1 but not of CD40 is maximally enhanced at 8 to 16 h of treatment of APCs with ZPS. The results demonstrate that the cellular immune response to ZPS depends on the translocation of HLA-DR to the cell surface and requires costimulation via B7-2 and CD40 on activated APCs. The implication is that activation of ZPS-specific T cells requires an orchestrated arrangement of both presenting and costimulatory molecules to form an immunological synapse.

Antigen-Presenting Cells↗
PubMed2005

Regulation of virulence by a two-component system in group B streptococcus.

Group B Streptococcus (GBS) is frequently carried in the gastrointestinal or genitourinary tract as a commensal organism, yet it has the potential to cause life-threatening infection in newborn infants, pregnant women, and individuals with chronic illness. Regulation of virulence factor expression may affect whether GBS behaves as an asymptomatic colonizer or an invasive pathogen, but little is known about how such factors are controlled in GBS. We now report the characterization of a GBS locus that encodes a two-component regulatory system similar to CsrRS (or CovRS) in Streptococcus pyogenes. Inactivation of csrR, encoding the putative response regulator, in two unrelated wild-type strains of GBS resulted in a marked increase in production of beta-hemolysin/cytolysin and a striking decrease in production of CAMP factor, an unrelated cytolytic toxin. Quantitative RNA hybridization experiments revealed that these two phenotypes were associated with a marked increase and decrease in expression of the corresponding genes, cylE and cfb, respectively. The CsrR mutant strains also displayed increased expression of scpB encoding C5a peptidase. Similar, but less marked, changes in gene expression were observed in CsrS (putative sensor component) mutants, evidence that CsrR and CsrS constitute a functional two-component system. Experimental infection studies in mice demonstrated reduced virulence of both CsrR and CsrS mutant strains relative to the wild type. Together, these results indicate that CsrRS regulates expression of multiple GBS virulence determinants and is likely to play an important role in GBS pathogenesis.

Bacterial Proteins↗
PubMed2005

Anchors away: contribution of a glycolipid anchor to bacterial invasion of host cells.

Group B Streptococcus (GBS) is an important cause of infections, including meningitis. The molecular events underlying its pathogenesis are poorly understood. A study in this issue of the JCI reports that the GBS invasion-associated gene (iagA) contributes to meningeal infection and virulence by facilitating invasion of the cells that compose the blood-brain barrier and of other host cells. The mechanism involved most likely relates to the gene product's role in synthesis of a glycolipid anchor for a bacterial cell-surface entity that interacts directly with host cells.

Bacterial Adhesion↗
PubMed2004

Polysaccharide processing and presentation by the MHCII pathway.

The adaptive immune system functions through the combined action of antigen-presenting cells (APCs) and T cells. Specifically, class I major histocompatibility complex antigen presentation to CD8(+) T cells is limited to proteosome-generated peptides from intracellular pathogens while the class II (MHCII) endocytic pathway presents only proteolytic peptides from extracellular pathogens to CD4(+) T cells. Carbohydrates have been thought to stimulate immune responses independently of T cells; however, zwitterionic polysaccharides (ZPSs) from the capsules of some bacteria can activate CD4(+) T cells. Here we show that ZPSs are processed to low molecular weight carbohydrates by a nitric oxide-mediated mechanism and presented to T cells through the MHCII endocytic pathway. Furthermore, these carbohydrates bind to MHCII inside APCs for presentation to T cells. Our observations begin to elucidate the mechanisms by which some carbohydrates induce important immunologic responses through T cell activation, suggesting a fundamental shift in the MHCII presentation paradigm.

Animals↗