@article {1502656, title = {Targeting PD-L2-RGMG overcomes microbiome-related immunotherapy resistance.}, journal = {Nature}, volume = {617}, year = {2023}, pages = {377-385}, abstract = {
\ }, url = {https://doi.org/10.1038/s41586-023-06026-3}, author = {Joon Seok Park, Francesca Gazzaniga, Meng Wu, Amalia Luthens, Jacob Gillis, Wen Zheng, Martin LaFleur, Sarah Johnson, Golnaz Morad, Elizabeth Park, Yifan Zhou, Stephanie S. Watowich, Jennifer A. Wargo, Gordan J. Freeman, Dennis L. Kasper, Arlene H. Sharpe} } @article {1364627, title = {Microbiota-targeted maternal antibodies protect neonates from enteric infection}, journal = {Nature}, volume = {577}, year = {2020}, pages = {543-548.}, abstract = {Although maternal antibodies protect newborn babies from infection1,2, little is known about how protective antibodies are induced without prior pathogen exposure. Here we show that neonatal mice that lack the capacity to produce IgG are protected from infection with the enteric pathogen enterotoxigenic Escherichia coli by maternal natural IgG antibodies against enterotoxigenic E. coli when antibodies are delivered either across the placenta or through breast milk. By challenging pups that were fostered by either maternal antibody-sufficient or antibody-deficient dams, we found that breast-milk-derived IgG was critical for protection against mucosal disease induced by enterotoxigenic E. coli. IgG also provides protection against systemic infection by E. coli. Pups used the neonatal Fc receptor (FcRn) to transfer IgG from milk into serum. The maternal commensal microbiota can induce antibodies that recognize antigens expressed by enterotoxigenic E. coli and other Enterobacteriaceae species. Induction of maternal antibodies against a commensal Pantoea species confers protection against enterotoxigenic E. coli in pups. This role of the microbiota in eliciting protective antibodies to a specific neonatal pathogen represents an important host defence mechanism against infection in neonates.}, author = {Zheng, Wen and Zhao, Wenjing and Wu, Meng and Song, Xinyang and Caro, Florence and Sun, Ximei and Gazzaniga, Francesca and Stefanetti, Giuseppe and Oh, Sungwhan and Mekalanos, John J and Kasper, Dennis L} } @article {1364630, title = {When lab mice go wild, fungi are in play}, journal = {Cell Host Microbe}, volume = {27}, year = {2020}, pages = {687-688.}, abstract = {In this issue of Cell Host \& Microbe, Yeung et al. (2020) and Lin et al. (2020) expose laboratory mice to a natural environment and use immune and microbiota characterization to show that fungi promote more human-like immunity. These studies will help develop animal models to more accurately resemble human immune responses.}, author = {Wu, Meng and Kasper, Dennis L} } @article {1364629, title = {An immunologic mode of multigenerational transmission governs a gut Treg setpoint}, journal = {Cell}, volume = {181}, year = {2020}, pages = {1276-1290.}, abstract = {

At the species level, immunity depends on the selection and transmission of protective components of the\ immune system. A microbe-induced population of RORg -expressing regulatory T cells (Tregs) is essential\ in controlling gut inflammation. We uncovered a non-genetic, non-epigenetic, non-microbial mode of transmission\ of their homeostatic setpoint. RORg+\ Treg proportions varied between inbred mouse strains, a trait\ transmitted by the mother during a tight age window after birth but stable for life, resistant to many microbial\ or cellular perturbations, then further transferred by females for multiple generations. RORg+\ Treg proportions\ negatively correlated with IgA production and coating of gut commensals, traits also subject to\ maternal transmission, in an immunoglobulin- and RORg+\ Treg-dependent manner. We propose a model\ based on a double-negative feedback loop, vertically transmitted via the entero-mammary axis. This immunologicmode\ of multi-generational transmission may provide adaptability and modulate the genetic tuning of\ gut immune responses and inflammatory disease susceptibility.

}, author = {Ramanan, Deepshika and Sefik, Esen and Galvin-Pena, Silvia and Wu, Meng and Yang, Liang and Yang, Zhen and Kostic, Aleksandar and Golovkina, Tatyana and Kasper, Dennis L and Mathis, Diane and Benoist, Christophe} } @article {1364625, title = {Microbial bile acid metabolites modulate gut RORγ +Regulatory T cellhomeostasis.}, journal = {Nature}, volume = {577}, year = {2020}, pages = {410-415.}, abstract = {

The metabolic pathways encoded by the human gut microbiome constantly interact with host gene products through numerous bioactive molecules1. Primary bile acids (BAs) are synthesized within hepatocytes and released into the duodenum to facilitate absorption of lipids or fat-soluble vitamins2. Some BAs (~5\%) escape into the colon, where gut commensal bacteria convert them into a variety of intestinal BAs2 that are important hormones regulating host cholesterol metabolism and energy balance via several nuclear receptors and/or G protein{\textendash}coupled receptors3,4. These receptors play pivotal roles in shaping host innate immune responses1,5. However, the impact of this host{\textendash}microbe biliary network on the adaptive immune system remains poorly characterized. Here we report that both dietary and microbial factors influence the composition of the gut BA pool and modulate an important population of colonic Foxp3+ regulatory T cells (Tregs) expressing the transcriptional factor RORγ. Genetic abolition of BA metabolic pathways in individual gut symbionts significantly decreases this Treg population. Restoration of the intestinal BA pool increases colonic RORγ+ Treg levels and ameliorates host susceptibility to inflammatory colitis via BA nuclear receptors. Thus, a pan-genomic biliary network interaction between hosts and their bacterial symbionts can control host immunologic homeostasis via the resulting metabolites.

}, author = {Song, Xinyang and Sun, Ximei and Oh, Sungwang and Zhang, Yanbo and Zheng, Wen and Geva-Zatorsky, Naama and Jupp, Ray and Mathis, Diane and Benoist, Christophe and Kasper, Dennis L.} } @article {1162172, title = {Polysaccharide structure dictates mechanism of adaptive immune response to glycoconjugate vaccines}, journal = {Proc Natl Acad Sci U S A}, volume = {116}, year = {2019}, month = {2019 01 02}, pages = {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 {\textrightarrow} 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.}, keywords = {Adaptive Immunity, Animals, Antibody Formation, Antigens, Epitopes, Female, Flow Cytometry, Glycoconjugates, Meningococcal Vaccines, Mice, Mice, Inbred BALB C, N-Acetylneuraminic Acid, Neisseria meningitidis, Polysaccharides, Bacterial, T-Lymphocytes, Helper-Inducer, Vaccines, Conjugate}, issn = {1091-6490}, doi = {10.1073/pnas.1816401115}, author = {Sun, Ximei and Stefanetti, Giuseppe and Berti, Francesco and Kasper, Dennis L} } @article {1162171, title = {Glycoconjugate vaccine using a genetically modified O antigen induces protective antibodies to Francisella tularensis}, journal = {Proc Natl Acad Sci U S A}, volume = {2019 Mar 14}, year = {2019}, month = {2019 Mar 14}, 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.}, issn = {1091-6490}, doi = {10.1073/pnas.1900144116}, author = {Stefanetti, Giuseppe and Okan, Nihal and Fink, Avner and Gardner, Erica and Kasper, Dennis L} } @article {1155042, title = {Illuminating vital surface molecules of symbionts in health and disease}, journal = {Nat Microbiol}, volume = {2}, year = {2017}, month = {2017 Jun 26}, pages = {17099}, abstract = {The immunomodulatory surface molecules of commensal and pathogenic bacteria are critical to microorganisms{\textquoteright} survival and the host{\textquoteright}s response1,2. Recent studies have highlighted the unique and important responses elicited by commensal-derived surface macromolecules3-5. However, the technology available to track these molecules in host cells and tissues remains primitive. We report, here, an interdisciplinary approach that uses metabolic labelling combined with bioorthogonal click chemistry (that is, reactions performed in living organisms)6 to specifically tag up to three prominent surface immunomodulatory macromolecules-peptidoglycan, lipopolysaccharide and capsular polysaccharide-either simultaneously or individually in live anaerobic commensal bacteria. Importantly, the peptidoglycan labelling enables, for the first time, the specific labelling of live endogenous, anaerobic bacteria within the mammalian host. This approach has allowed us to image and track the path of labelled surface molecules from live, luminal bacteria into specific intestinal immune cells in the living murine host during health and disease. The chemical labelling of three specific macromolecules within a live organism offers the potential for in-depth visualization of host-pathogen interactions.}, author = {Hudak, Jason E and Alvarez, David and Skelly, Ashwin and von Andrian, Ulrich H and Kasper, Dennis L} } @article {1155043, title = {Mining the Human Gut Microbiota for Immunomodulatory Organisms}, journal = {Cell}, volume = {168}, year = {2017}, month = {2017 Feb 23}, pages = {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{\textquoteright}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.}, keywords = {Adaptive Immunity, Animals, Bacteria, Bacterial Physiological Phenomena, Gastrointestinal Microbiome, Gastrointestinal Tract, Germ-Free Life, Humans, Immunity, Innate, Mice, Mice, Inbred C57BL, symbiosis}, author = {Geva-Zatorsky, Naama and Sefik, Esen and Kua, Lindsay and Pasman, Lesley and Tan, Tze Guan and Ortiz-Lopez, Adriana and Yanortsang, Tsering Bakto and Yang, Liang and Jupp, Ray and Mathis, Diane and Benoist, Christophe and Kasper, Dennis L} } @article {1155044, title = {Moving beyond microbiome-wide associations to causal microbe identification}, journal = {Nature}, volume = {552}, year = {2017}, month = {2017 Dec 14}, pages = {244-247}, abstract = {Microbiome-wide association studies have established that numerous diseases are associated with changes in the microbiota. These studies typically generate a long list of commensals implicated as biomarkers of disease, with no clear relevance to disease pathogenesis. If the field is to move beyond correlations and begin to address causation, an effective system is needed for refining this catalogue of differentially abundant microbes and to allow subsequent mechanistic studies. Here we demonstrate that triangulation of microbe-phenotype relationships is an effective method for reducing the noise inherent in microbiota studies and enabling identification of causal microbes. We found that gnotobiotic mice harbouring different microbial communities exhibited differential survival in a colitis model. Co-housing of these mice generated animals that had hybrid microbiotas and displayed intermediate susceptibility to colitis. Mapping of microbe-phenotype relationships in parental mouse strains and in mice with hybrid microbiotas identified the bacterial family Lachnospiraceae as a correlate for protection from disease. Using directed microbial culture techniques, we discovered Clostridium immunis, a previously unknown bacterial species from this family, that-when administered to colitis-prone mice-protected them against colitis-associated death. To demonstrate the generalizability of our approach, we used it to identify several commensal organisms that induce intestinal expression of an antimicrobial peptide. Thus, we have used microbe-phenotype triangulation to move beyond the standard correlative microbiome study and identify causal microbes for two completely distinct phenotypes. Identification of disease-modulating commensals by microbe-phenotype triangulation may be more broadly applicable to human microbiome studies.}, author = {Surana, Neeraj K and Kasper, Dennis L} } @article {1155045, title = {How colonization by microbiota in early life shapes the immune system}, journal = {Science}, volume = {352}, year = {2016}, month = {2016 Apr 29}, pages = {539-44}, abstract = {Microbial colonization of mucosal tissues during infancy plays an instrumental role in the development and education of the host mammalian immune system. These early-life events can have long-standing consequences: facilitating tolerance to environmental exposures or contributing to the development of disease in later life, including inflammatory bowel disease, allergy, and asthma. Recent studies have begun to define a critical period during early development in which disruption of optimal host-commensal interactions can lead to persistent and in some cases irreversible defects in the development and training of specific immune subsets. Here, we discuss the role of early-life education of the immune system during this "window of opportunity," when microbial colonization has a potentially critical impact on human health and disease.}, keywords = {Age Factors, Asthma, Humans, Hypersensitivity, Immune System, Immune Tolerance, Infant, Newborn, Inflammatory Bowel Diseases, Intestinal Mucosa, microbiota, Natural Killer T-Cells, symbiosis, T-Lymphocyte Subsets}, author = {Gensollen, Thomas and Iyer, Shankar S and Kasper, Dennis L and Blumberg, Richard S} } @article {1155046, title = {Veggies and Intact Grains a Day Keep the Pathogens Away}, journal = {Cell}, volume = {167}, year = {2016}, month = {2016 11 17}, pages = {1161-1162}, abstract = {In this issue of Cell, Desai et~al. compare how dietary fiber affects the gut microbiota and susceptibility to disease. They find that a fiber-free diet promotes mucus-degrading bacteria and susceptibility to Citrobacter rodentium infection.}, keywords = {Bacteria, Citrobacter rodentium, Diet, Disease Susceptibility, Enterobacteriaceae Infections, Humans}, author = {Gazzaniga, Francesca S and Kasper, Dennis L} } @article {1155047, title = {In vivo imaging and tracking of host-microbiota interactions via metabolic labeling of gut anaerobic bacteria}, journal = {Nat Med}, volume = {21}, year = {2015}, month = {2015 Sep}, pages = {1091-100}, abstract = {The intestine is densely populated by anaerobic commensal bacteria. These microorganisms shape immune system development, but understanding of host-commensal interactions is hampered by a lack of tools for studying the anaerobic intestinal environment. We applied metabolic oligosaccharide engineering and bioorthogonal click chemistry to label various commensal anaerobes, including Bacteroides fragilis, a common and immunologically important commensal. We studied the dissemination of B. fragilis after acute peritonitis and characterized the interactions of the intact microbe and its polysaccharide components in myeloid and B cell lineages. We were able to assess the distribution and colonization of labeled B. fragilis along the intestine, as well as niche competition after coadministration of multiple species of the microbiota. We also fluorescently labeled nine additional commensals (eight anaerobic and one microaerophilic) from three phyla common in the gut--Bacteroidetes, Firmicutes and Proteobacteria--as well as one aerobic pathogen (Staphylococcus aureus). This strategy permits visualization of the anaerobic microbial niche by various methods, including intravital two-photon microscopy and non-invasive whole-body imaging, and can be used to study microbial colonization and host-microbe interactions in real time.}, keywords = {Animals, Bacteria, Anaerobic, Bacteroides fragilis, Female, Fluorescent Dyes, Glycocalyx, Intestines, Male, Mice, Mice, Inbred C57BL, microbiota, Peritonitis}, author = {Geva-Zatorsky, Naama and Alvarez, David and Hudak, Jason E and Reading, Nicola C and Erturk-Hasdemir, Deniz and Dasgupta, Suryasarathi and von Andrian, Ulrich H and Kasper, Dennis L} } @article {1155048, title = {Deciphering the t{\^e}te-{\`a}-t{\^e}te between the microbiota and the immune system}, journal = {J Clin Invest}, volume = {124}, year = {2014}, month = {2014 Oct}, pages = {4197-203}, abstract = {The past decade has witnessed an explosion in studies--both clinical and basic science--examining the relationship between the microbiota and human health, and it is now clear that the effects of commensal organisms are much broader than previously believed. Among the microbiota{\textquoteright}s major contributions to host physiology is regulation of the development and maintenance of the immune system. There are now a handful of examples of intestinal commensal bacteria with defined immunomodulatory properties, but our mechanistic understanding of how microbes influence the immune system is still in its infancy. Nevertheless, several themes have emerged that provide a framework for appreciating microbe-induced immunoregulation. In this Review, we discuss the current state of knowledge regarding the role of the intestinal microbiota in immunologic development, highlighting mechanistic principles that can guide future work.}, keywords = {Animals, Bacteria, Humans, Immune System, Intestines, Mice, microbiota}, author = {Surana, Neeraj K and Kasper, Dennis L} } @article {1155049, title = {An intestinal commensal symbiosis factor controls neuroinflammation via TLR2-mediated CD39 signalling}, journal = {Nat Commun}, volume = {5}, year = {2014}, month = {2014 Jul 21}, pages = {4432}, abstract = {The mammalian immune system constitutively senses vast quantities of commensal bacteria and their products through pattern recognition receptors, yet excessive immune reactivity is prevented under homeostasis. The intestinal microbiome can influence host susceptibility to extra-intestinal autoimmune disorders. Here we report that polysaccharide A (PSA), a symbiosis factor for the human intestinal commensal Bacteroides fragilis, protects against central nervous system demyelination and inflammation during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, through Toll-like receptor 2 (TLR2). TLR2 mediates tissue-specific expansion of a critical regulatory CD39(+) CD4 T-cell subset by PSA. Ablation of CD39 signalling abrogates PSA control of EAE manifestations and inflammatory cytokine responses. Further, CD39 confers immune-regulatory phenotypes to total CD4 T cells and Foxp3(+) CD4 Tregs. Importantly, CD39-deficient CD4 T cells show an enhanced capability to drive EAE progression. Our results demonstrate the therapeutic potential and underlying mechanism by which an intestinal symbiont product modulates CNS-targeted demyelination.}, keywords = {Animals, Antigens, CD, Apyrase, Bacteroides fragilis, CD4-Positive T-Lymphocytes, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Female, Forkhead Transcription Factors, Humans, Inflammation, Intestines, Mice, Inbred C57BL, Mice, Knockout, Multiple Sclerosis, Polysaccharides, Bacterial, Signal Transduction, symbiosis, Toll-Like Receptor 2}, author = {Wang, Yan and Telesford, Kiel M and Ochoa-Rep{\'a}raz, Javier and Haque-Begum, Sakhina and Christy, Marc and Kasper, Eli J and Wang, Li and Wu, Yan and Robson, Simon C and Kasper, Dennis L and Kasper, Lloyd H} } @article {1155050, title = {Plasmacytoid dendritic cells mediate anti-inflammatory responses to a gut commensal molecule via both innate and adaptive mechanisms}, journal = {Cell Host Microbe}, volume = {15}, year = {2014}, month = {2014 Apr 09}, pages = {413-23}, abstract = {Polysaccharide A (PSA), the archetypical immunomodulatory molecule of the gut commensal Bacteroides fragilis, induces regulatory T~cells to secrete the anti-inflammatory cytokine interleukin-10 (IL-10). The cellular mediators of PSA{\textquoteright}s immunomodulatory properties are incompletely understood. In a mouse model of colitis, we find that PSA requires both innate and adaptive immune mechanisms to generate protection. Plasmacytoid DCs (PDCs) exposed to PSA do not produce proinflammatory cytokines, but instead they specifically stimulate IL-10 secretion by CD4+ T~cells and efficiently mediate PSA-afforded immunoprotection. PSA induces and preferentially ligates Toll-like receptor 2 on PDCs but not on conventional DCs. Compared with other TLR2 ligands, PSA is better at enhancing PDC expression of costimulatory molecules required for protection against colitis. PDCs can thus orchestrate the beneficial immunoregulatory interaction of commensal microbial molecules, such as PSA, through both innate and adaptive immune mechanisms.}, keywords = {Adaptive Immunity, Adoptive Transfer, Animals, B7-1 Antigen, B7-2 Antigen, Bacteroides fragilis, Bone Marrow Cells, CD28 Antigens, CD4-Positive T-Lymphocytes, Cells, Cultured, Dendritic Cells, Encephalomyelitis, Autoimmune, Experimental, Female, Gastrointestinal Tract, Immunity, Innate, Inducible T-Cell Co-Stimulator Ligand, Inflammation, Interleukin-10, Lymphocyte Depletion, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Animal, Polysaccharides, Bacterial, Toll-Like Receptor 2}, author = {Dasgupta, Suryasarathi and Erturk-Hasdemir, Deniz and Ochoa-Reparaz, Javier and Reinecker, Hans-Christian and Kasper, Dennis L} } @article {1155051, title = {Sphingolipids from a symbiotic microbe regulate homeostasis of host intestinal natural killer T cells}, journal = {Cell}, volume = {156}, year = {2014}, month = {2014 Jan 16}, pages = {123-33}, abstract = {Coevolution of beneficial microorganisms with the mammalian intestine fundamentally shapes mammalian physiology. Here, we report that the intestinal microbe Bacteroides fragilis modifies the homeostasis of host invariant natural killer T (iNKT) cells by supplementing the host{\textquoteright}s endogenous lipid antigen milieu with unique inhibitory sphingolipids. The process occurs early in life and effectively impedes iNKT cell proliferation during neonatal development. Consequently, total colonic iNKT cell numbers are restricted into adulthood, and hosts are protected against experimental iNKT cell-mediated, oxazolone-induced colitis. In studies with neonatal mice lacking access to bacterial sphingolipids, we found that treatment with B. fragilis glycosphingolipids-exemplified by an isolated peak (MW = 717.6) called GSL-Bf717-reduces colonic iNKT cell numbers and confers protection against oxazolone-induced colitis in adulthood. Our results suggest that the distinctive inhibitory capacity of GSL-Bf717 and similar molecules may prove useful in the treatment of autoimmune and allergic disorders in which iNKT cell activation is destructive.}, keywords = {Animals, Animals, Newborn, Bacteroides fragilis, Cell Proliferation, Colitis, Colon, Glycosphingolipids, Mice, Mice, Inbred C57BL, Natural Killer T-Cells, Oxazolone}, author = {An, Dingding and Oh, Sungwhan F and Olszak, Torsten and Neves, Joana F and Avci, Fikri Y and Erturk-Hasdemir, Deniz and Lu, Xi and Zeissig, Sebastian and Blumberg, Richard S and Kasper, Dennis L} } @article {1155052, title = {The atypical lipopolysaccharide of Francisella}, journal = {Carbohydr Res}, volume = {378}, year = {2013}, month = {2013 Aug 30}, pages = {79-83}, abstract = {Bacterial lipopolysaccharides (LPSs) are ubiquitous molecules that are prominent components of the outer membranes of most gram-negative bacteria. Genetic and structural characterizations of Francisella LPS have revealed substantial differences when compared to more commonly studied LPSs of the Enterobacteriaceae. This review discusses both the general characteristics and the unusual features of Francisella LPS.}, keywords = {Francisella, Lipid A, Lipopolysaccharides, O Antigens}, author = {Okan, Nihal A and Kasper, Dennis L} } @article {1155053, title = {Resident commensals shaping immunity}, journal = {Curr Opin Immunol}, volume = {25}, year = {2013}, month = {2013 Aug}, pages = {450-5}, abstract = {All animals coexist with myriad commensal microorganisms in a symbiotic relationship that plays a key role in health and disease. Continuous commensal-host interactions profoundly affect the development and regulation of the host{\textquoteright}s immune system. The complex interaction of the commensal microbiota with the immune system is a topic of substantial interest. An understanding of these interactions and the mechanisms through which commensal microbes actively shape host immunity may yield new insights into the pathogenesis of many immune-mediated diseases and lead to new prophylactic and therapeutic interventions. This review examines recent advances in this field and their potential implications not just for the colonized tissues but also for the entire immune system.}, keywords = {Animals, Dendritic Cells, Epithelial Cells, Humans, Immune System, Immunoglobulin A, Microbial Interactions, T-Lymphocytes}, author = {Erturk-Hasdemir, Deniz and Kasper, Dennis L} } @article {1155054, title = {Testosterone: more than having the guts to win the Tour de France}, journal = {Immunity}, volume = {39}, year = {2013}, month = {2013 Aug 22}, pages = {208-10}, abstract = {Sex bias in susceptibility to autoimmune diseases is evident but poorly characterized. Yurkovetskiy et~al. (2013) report that host testosterone mediates changes in the microbiome to confer protection to adult male NOD mice from type 1 diabetes.}, keywords = {Androgens, Animals, Autoimmune Diseases, Autoimmunity, Bacterial Infections, Diabetes Mellitus, Type 1, Female, Male}, author = {An, Dingding and Kasper, Dennis L} } @article {1155055, title = {Gut immune maturation depends on colonization with a host-specific microbiota}, journal = {Cell}, volume = {149}, year = {2012}, month = {2012 Jun 22}, pages = {1578-93}, abstract = {Gut microbial induction of host immune maturation exemplifies host-microbe mutualism. We colonized germ-free (GF) mice with mouse microbiota (MMb) or human microbiota (HMb) to determine whether small intestinal immune maturation depends on a coevolved host-specific microbiota. Gut bacterial numbers and phylum abundance were similar in MMb and HMb mice, but bacterial species differed, especially the Firmicutes. HMb mouse intestines had low levels of CD4(+) and CD8(+) T cells, few proliferating T cells, few dendritic cells, and low antimicrobial peptide expression--all characteristics of GF mice. Rat microbiota also failed to fully expand intestinal T cell numbers in mice. Colonizing GF or HMb mice with mouse-segmented filamentous bacteria (SFB) partially restored T cell numbers, suggesting that SFB and other MMb organisms are required for full immune maturation in mice. Importantly, MMb conferred better protection against Salmonella infection than HMb. A host-specific microbiota appears to be critical for a healthy immune system.}, keywords = {Animals, Bacteria, Cell Proliferation, Female, Germ-Free Life, Humans, Immunity, Innate, Intestines, Male, Metagenome, Mice, Rats, Rats, Sprague-Dawley, Salmonella Infections, Species Specificity, Specific Pathogen-Free Organisms, symbiosis, T-Lymphocytes}, author = {Chung, Hachung and Pamp, S{\"u}nje J and Hill, Jonathan A and Surana, Neeraj K and Edelman, Sanna M and Troy, Erin B and Reading, Nicola C and Villablanca, Eduardo J and Wang, Sen and Mora, Jorge R and Umesaki, Yoshinori and Mathis, Diane and Benoist, Christophe and Relman, David A and Kasper, Dennis L} } @article {1155056, title = {Microbial exposure during early life has persistent effects on natural killer T cell function}, journal = {Science}, volume = {336}, year = {2012}, month = {2012 Apr 27}, pages = {489-93}, abstract = {Exposure to microbes during early childhood is associated with protection from immune-mediated diseases such as inflammatory bowel disease (IBD) and asthma. Here, we show that in germ-free (GF) mice, invariant natural killer T (iNKT) cells accumulate in the colonic lamina propria and lung, resulting in increased morbidity in models of IBD and allergic asthma as compared with that of specific pathogen-free mice. This was associated with increased intestinal and pulmonary expression of the chemokine ligand CXCL16, which was associated with increased mucosal iNKT cells. Colonization of neonatal-but not adult-GF mice with a conventional microbiota protected the animals from mucosal iNKT accumulation and related pathology. These results indicate that age-sensitive contact with commensal microbes is critical for establishing mucosal iNKT cell tolerance to later environmental exposures.}, keywords = {Aging, Animals, Animals, Newborn, Antigens, CD1d, Asthma, Bacteria, Chemokine CXCL16, Chemokine CXCL6, Colitis, Ulcerative, Colon, Disease Models, Animal, Disease Susceptibility, DNA Methylation, Germ-Free Life, Intestinal Mucosa, Intestines, Lung, Mice, Mice, Inbred C57BL, Natural Killer T-Cells, Oxazolone, Receptors, CXCR, Receptors, CXCR6, Specific Pathogen-Free Organisms}, author = {Olszak, Torsten and An, Dingding and Zeissig, Sebastian and Vera, Miguel Pinilla and Richter, Julia and Franke, Andre and Glickman, Jonathan N and Siebert, Reiner and Baron, Rebecca M and Kasper, Dennis L and Blumberg, Richard S} } @article {1155057, title = {A mechanism for glycoconjugate vaccine activation of the adaptive immune system and its implications for vaccine design}, journal = {Nat Med}, volume = {17}, year = {2011}, month = {2011 Nov 20}, pages = {1602-9}, abstract = {Glycoconjugate vaccines have provided enormous health benefits globally, but they have been less successful in some populations at high risk for developing disease. To identify new approaches to enhancing glycoconjugate effectiveness, we investigated molecular and cellular mechanisms governing the immune response to a prototypical glycoconjugate vaccine. We found that in antigen-presenting cells a carbohydrate epitope is generated upon endolysosomal processing of group B streptococcal type III polysaccharide coupled to a carrier protein. In conjunction with a carrier protein-derived peptide, this carbohydrate epitope binds major histocompatibility class II (MHCII) and stimulates carbohydrate-specific CD4(+) T cell clones to produce interleukins 2 and 4-cytokines essential for providing T cell help to antibody-producing B cells. An archetypical glycoconjugate vaccine that we constructed to maximize the presentation of carbohydrate-specific T cell epitopes is 50-100 times more potent and substantially more protective in a neonatal mouse model of group B Streptococcus infection than a vaccine constructed by methods currently used by the vaccine industry. Our discovery of how glycoconjugates are processed resulting in presentation of carbohydrate epitopes that stimulate CD4(+) T cells has key implications for glycoconjugate vaccine design that could result in greatly enhanced vaccine efficacy.}, keywords = {Adaptive Immunity, Animals, Antigen-Presenting Cells, CD4-Positive T-Lymphocytes, Cell Line, Cell Proliferation, Epitopes, T-Lymphocyte, Female, Glycoconjugates, Histocompatibility Antigens Class II, Humans, Immunization, Immunoglobulin G, Interleukin-2, Interleukin-4, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Polysaccharides, Bacterial, Vaccines}, author = {Avci, Fikri Y and Li, Xiangming and Tsuji, Moriya and Kasper, Dennis L} } @article {1155058, title = {3-Deoxy-D-manno-octulosonic acid (Kdo) hydrolase identified in Francisella tularensis, Helicobacter pylori, and Legionella pneumophila}, journal = {J Biol Chem}, volume = {285}, year = {2010}, month = {2010 Nov 05}, pages = {34330-6}, abstract = {3-Deoxy-D-manno-octulosonic acid (Kdo) is an eight-carbon sugar ubiquitous in Gram-negative bacterial lipopolysaccharides (LPS). Although its biosynthesis is well described, no protein has yet been identified as a Kdo hydrolase. However, Kdo hydrolase enzymatic activity has been detected in membranes of Helicobacter pylori and Francisella tularensis and may be responsible for the removal of side-chain Kdo from the LPS core saccharides. We now report the identification of genes encoding a Kdo hydrolase in F. tularensis Schu S4 and live vaccine strain strains, in H. pylori 26695 strain and in Legionella pneumophila Philadelphia 1 strain. We have renamed the genes kdhA for keto-deoxyoctulosonate hydrolase A. Deletion of kdhA abolished Kdo hydrolase activity in membranes of F. tularensis live vaccine strain. The F. tularensis kdhA mutant synthesized a core oligosaccharide containing a Kdo disaccharide with one of the Kdo residues being a terminal side chain. This side-chain Kdo monosaccharide was absent in the wild-type core oligosaccharide. Expression in Escherichia coli of recombinant KdhA from F. tularensis, H. pylori, and L. pneumophila resulted in a reduction of membrane-associated side-chain Kdo. The identification of this previously faceless enzyme will accelerate study of the biosynthetic basis and biologic impact for postbiosynthetic LPS structural modification.}, keywords = {Bacterial Proteins, Bacterial Vaccines, Cell Membrane, Francisella tularensis, Gene Deletion, Glycoside Hydrolases, Helicobacter pylori, Legionella pneumophila, Lipopolysaccharides, Oligosaccharides, Sugar Acids, Vaccines, Attenuated}, author = {Chalabaev, Sabina and Kim, Tae-Hyun and Ross, Robin and Derian, Alec and Kasper, Dennis L} } @article {1155059, title = {Microbiota-stimulated immune mechanisms to maintain gut homeostasis}, journal = {Curr Opin Immunol}, volume = {22}, year = {2010}, month = {2010 Aug}, pages = {455-60}, abstract = {In recent years there has been an explosion of interest to identify microbial inhabitants of human and understand their beneficial role in health. In the gut, a symbiotic host-microbial interaction has coevolved as bacteria make essential contributions to human metabolism and bacteria in turn benefits from the nutrient-rich niche in the intestine. To maintain host-microbe coexistence, the host must protect itself against microbial invasion, injury, and overreactions to foreign food antigens, and gut microbes need protection against competing microbes and the host immune system. Perturbation of this homeostatic coexistence has been strongly associated with human disease. This review discusses how gut bacteria regulate host innate and adaptive immunity, with emphasis on how this regulation contributes to host-microbe homeostasis in the gut.}, keywords = {Gastrointestinal Tract, Homeostasis, Humans, Immune System, Immunity, Mucosal, Intestinal Mucosa, Metagenome}, author = {Chung, Hachung and Kasper, Dennis Lee} } @article {1155060, title = {Microbial carbohydrate depolymerization by antigen-presenting cells: deamination prior to presentation by the MHCII pathway}, journal = {Proc Natl Acad Sci U S A}, volume = {105}, year = {2008}, month = {2008 Apr 01}, pages = {5183-8}, abstract = {After uptake by the endosome of an antigen-presenting cell (APC), exogenous proteins are known to be degraded into peptides by protease digestion. Here, we report the mechanism by which pure carbohydrates can be depolymerized within APC endosomes/lysosomes by nitric oxide (NO)-derived reactive nitrogen species (RNSs) and/or superoxide-derived reactive oxygen species (ROSs). Earlier studies showed that depolymerization of polysaccharide A (PSA) from Bacteroides fragilis in the endosome depends on the APC{\textquoteright}s having an intact inducible nitric oxide synthase (iNOS) gene; the chemical mechanism underlying depolymerization of a carbohydrate within the endosome/lysosome is described here. Examining the ability of the major RNSs to degrade PSA, we determined that deamination is the predominant mechanism for PSA processing in APCs and is a required step in PSA presentation to CD4(+) T cells by MHCII molecules. Structural characterization of the NO-derived product PSA-NO indicates that partial deaminative depolymerization does not alter the zwitterionic nature of PSA. Unlike native PSA, PSA-NO is presented by iNOS-deficient APCs to induce CD4(+) T cell proliferation. Furthermore, metabolically active APCs are required for PSA-NO presentation. In contrast to PSA degradation by RNSs, dextran depolymerization in the endosome depends on ROSs, including hydrogen peroxide- and superoxide-derived ROSs. This study provides evidence that MHCII pathway-mediated carbohydrate antigen processing in APCs is achieved by chemical reactions. RNSs and ROSs may be involved in the presentation of glycopeptides by MHC molecules via the processing of other carbohydrate-containing antigens, such as bacterial or viral glycoproteins or glycoconjugate vaccines.}, keywords = {Animals, Antigen Presentation, Antigen-Presenting Cells, Chromatography, Gel, Endosomes, Histocompatibility Antigens Class II, Magnetic Resonance Spectroscopy, Mice, Mice, Knockout, Nitric Oxide Synthase Type II, Polysaccharides, Bacterial, Reactive Nitrogen Species, Reactive Oxygen Species, T-Lymphocytes}, author = {Duan, Jinyou and Avci, Fikri Y and Kasper, Dennis L} } @article {1155061, title = {A microbial symbiosis factor prevents intestinal inflammatory disease}, journal = {Nature}, volume = {453}, year = {2008}, month = {2008 May 29}, pages = {620-5}, abstract = {Humans are colonized by multitudes of commensal organisms representing members of five of the six kingdoms of life; however, our gastrointestinal tract provides residence to both beneficial and potentially pathogenic microorganisms. Imbalances in the composition of the bacterial microbiota, known as dysbiosis, are postulated to be a major factor in human disorders such as inflammatory bowel disease. We report here that the prominent human symbiont Bacteroides fragilis protects animals from experimental colitis induced by Helicobacter hepaticus, a commensal bacterium with pathogenic potential. This beneficial activity requires a single microbial molecule (polysaccharide A, PSA). In animals harbouring 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 and also inhibits 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 show that molecules of the bacterial microbiota can mediate the critical balance between health and disease. Harnessing the immunomodulatory capacity of symbiosis factors such as PSA might potentially provide therapeutics for human inflammatory disorders on the basis of entirely novel biological principles.}, keywords = {Animals, Bacteroides fragilis, CD4-Positive T-Lymphocytes, Colitis, Disease Models, Animal, Germ-Free Life, Helicobacter hepaticus, Inflammation, Inflammatory Bowel Diseases, Interleukin-10, Interleukin-17, Intestines, Mice, Polysaccharides, Bacterial, symbiosis, Tumor Necrosis Factor-alpha}, author = {Mazmanian, Sarkis K and Round, June L and Kasper, Dennis L} } @article {1155062, title = {A bacterial carbohydrate links innate and adaptive responses through Toll-like receptor 2}, journal = {J Exp Med}, volume = {203}, year = {2006}, month = {2006 Dec 25}, pages = {2853-63}, abstract = {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.}, keywords = {Animals, B7-2 Antigen, CD4-Positive T-Lymphocytes, Cell Line, Cytokines, Dendritic Cells, Gene Expression, Histocompatibility Antigens Class II, Humans, Immunity, Cellular, Immunity, Innate, Macrophages, Male, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Knockout, Models, Immunological, Myeloid Differentiation Factor 88, Nitric Oxide, Nitric Oxide Synthase Type II, Polysaccharides, Bacterial, Toll-Like Receptor 2, Toll-Like Receptor 4, Transcription Factor RelA}, author = {Wang, Qun and McLoughlin, Rachel M and Cobb, Brian A and Charrel-Dennis, Marie and Zaleski, Kathleen J and Golenbock, Douglas and Tzianabos, Arthur O and Kasper, Dennis L} } @article {1155063, title = {Bacterial glycans: key mediators of diverse host immune responses}, journal = {Cell}, volume = {126}, year = {2006}, month = {2006 Sep 08}, pages = {847-50}, abstract = {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.}, keywords = {Animals, Bacterial Capsules, Bacterial Infections, Bacteroides fragilis, Bacteroides Infections, Humans, Immunologic Surveillance, Molecular Mimicry, O Antigens}, author = {Comstock, Laurie E and Kasper, Dennis L} } @article {1155064, title = {The love-hate relationship between bacterial polysaccharides and the host immune system}, journal = {Nat Rev Immunol}, volume = {6}, year = {2006}, month = {2006 Nov}, pages = {849-58}, abstract = {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 {\textquoteright}hygiene hypothesis{\textquoteright} of allergic immune disorders.}, keywords = {Animals, Antigens, health, Humans, Immune System, Lymphocyte Activation, Polysaccharides, Bacterial, T-Lymphocytes}, author = {Mazmanian, Sarkis K and Kasper, Dennis L} } @article {1155065, title = {An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system}, journal = {Cell}, volume = {122}, year = {2005}, month = {2005 Jul 15}, pages = {107-18}, abstract = {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.}, keywords = {Animals, Bacteroides fragilis, CD4-Positive T-Lymphocytes, Cell Proliferation, Cytokines, Dendritic Cells, Immune System, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Polysaccharides, Bacterial, symbiosis}, author = {Mazmanian, Sarkis K and Liu, Cui Hua and Tzianabos, Arthur O and Kasper, Dennis L} } @article {1155066, title = {Polysaccharide processing and presentation by the MHCII pathway}, journal = {Cell}, volume = {117}, year = {2004}, month = {2004 May 28}, pages = {677-87}, abstract = {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.}, keywords = {Animals, Antigen Presentation, Antigen-Presenting Cells, Endocytosis, Histocompatibility Antigens Class II, Mice, Polysaccharides, Receptors, Antigen, T-Cell, T-Lymphocytes}, author = {Cobb, Brian A and Wang, Qun and Tzianabos, Arthur O and Kasper, Dennis L} } @article {1155067, title = {Zwitterionic polysaccharides stimulate T cells by MHC class II-dependent interactions}, journal = {J Immunol}, volume = {169}, year = {2002}, month = {2002 Dec 01}, pages = {6149-53}, abstract = {Polysaccharides of pathogenic extracellular bacteria commonly have negatively charged groups or no charged groups at all. These molecules have been considered classic T cell-independent Ags that do not elicit cell-mediated immune responses in mice. However, bacterial polysaccharides with a zwitterionic charge motif (ZPSs), such as the capsular polysaccharides of many strains of Bacteroides fragilis, Staphylococcus aureus, and Streptococcus pneumoniae type 1 elicit potent CD4(+) T cell responses in vivo and in vitro. The cell-mediated response to ZPS depends on the presence of both positively charged and negatively charged groups on each repeating unit of the polysaccharide. In this study, we define some of the requirements for the presentation of ZPS to CD4(+) T cells. We provide evidence that direct interactions of T cells with APCs are essential for T cell activation by ZPS. Monocytes, dendritic cells, and B cells are all able to serve as APCs for ZPS-mediated T cell activation. APCs lacking MHC class II molecules do not support this activity. Furthermore, mAb to HLA-DR specifically blocks ZPS-mediated T cell activation, while mAbs to other MHC class II and class I molecules do not. Immunoprecipitation of lysates of MHC class II-expressing cells following incubation with ZPS shows binding of ZPS and HLA-DR. Electron microscopy reveals colocalization of ZPS with HLA-DR on the cell surface and in compartments of the endocytic pathway. These results indicate that MHC class II molecules expressing HLA-DR on professional APCs are required for ZPS-induced T cell activation. The implication is that binding of ZPS to HLA-DR may be required for T cell activation.}, keywords = {Animals, Antigen Presentation, Antigen-Presenting Cells, CD4-Positive T-Lymphocytes, Cell Compartmentation, Cell Membrane, Endosomes, HLA-DR Antigens, Humans, In Vitro Techniques, Ions, Lymphocyte Activation, Lysosomes, Mice, Polysaccharides, Bacterial, T-Lymphocytes}, author = {Kalka-Moll, Wiltrud M and Tzianabos, Arthur O and Bryant, Paula W and Niemeyer, Marcus and Ploegh, Hidde L and Kasper, Dennis L} } @article {1155068, title = {Extensive surface diversity of a commensal microorganism by multiple DNA inversions}, journal = {Nature}, volume = {414}, year = {2001}, month = {2001 Nov 29}, pages = {555-8}, abstract = {The dynamic interactions between a host and its intestinal microflora that lead to commensalism are unclear. Bacteria that colonize the intestinal tract do so despite the development of a specific immune response by the host. The mechanisms used by commensal organisms to circumvent this immune response have yet to be established. Here we demonstrate that the human colonic microorganism, Bacteroides fragilis, is able to modulate its surface antigenicity by producing at least eight distinct capsular polysaccharides-a number greater than any previously reported for a bacterium-and is able to regulate their expression in an on-off manner by the reversible inversion of DNA segments containing the promoters for their expression. This means of generating surface diversity allows the organism to exhibit a wide array of distinct surface polysaccharide combinations, and may have broad implications for how the predominant human colonic microorganisms, the Bacteroides species, maintain an ecological niche in the intestinal tract.}, keywords = {Antigenic Variation, Antigens, Surface, Bacterial Capsules, Bacteroides fragilis, Chromosome Inversion, Colon, DNA, Bacterial, Gene Expression Regulation, Bacterial, Humans, Polysaccharides, Bacterial, Promoter Regions, Genetic, symbiosis}, author = {Krinos, C M and Coyne, M J and Weinacht, K G and Tzianabos, A O and Kasper, D L and Comstock, L E} } @article {1155069, title = {Structural basis of the abscess-modulating polysaccharide A2 from Bacteroides fragilis}, journal = {Proc Natl Acad Sci U S A}, volume = {97}, year = {2000}, month = {2000 Dec 05}, pages = {13478-83}, abstract = {Zwitterionic capsular polysaccharides from pathogenic bacteria have peculiar immunological properties. They are capable of eliciting T-cell proliferation and modulating the course of abscess formation. To understand the molecular basis of this characteristic immune response, we are conducting detailed structure-function studies on these polysaccharides. We have identified, purified, and characterized an abscess-modulating polysaccharide, PS A2, from the clinical strain Bacteroides fragilis 638R. Here, we report the elucidation of both the chemical and three-dimensional structures of PS A2 by NMR spectroscopy, chemical methods, gas chromatography-mass spectrometry, and restrained molecular dynamics calculations. PS A2 consists of a pentasaccharide repeating unit containing mannoheptose, N-acetylmannosamine, 3-acetamido-3,6-dideoxyglucose, 2-amino-4-acetamido-2,4,6-trideoxygalactose, fucose, and 3-hydroxybutanoic acid. PS A2 is zwitterionic and carries one cationic free amine and one anionic carboxylate in each repeating unit. It forms an extended right-handed helix with two repeating units per turn and a pitch of 20 A. Positive and negative charges are exposed on the outer surface of the polymer in a regularly spaced pattern, which renders them easily accessible to other molecules. The helix is characterized by repeated large grooves whose lateral boundaries are occupied by the charges. The three-dimensional structure of PS A2 explicitly suggests mechanisms of interaction between zwitterionic polysaccharides and proteins.}, keywords = {Abscess, Bacteroides fragilis, Carbohydrate Conformation, Carbohydrate Sequence, Molecular Sequence Data, Polysaccharides, Bacterial}, author = {Wang, Y. and Kalka-Moll, W M and Roehrl, M H and Kasper, D L} } @article {1155070, title = {Group B streptococci escape host immunity by deletion of tandem repeat elements of the alpha C protein}, journal = {Proc Natl Acad Sci U S A}, volume = {93}, year = {1996}, month = {1996 Apr 30}, pages = {4131-6}, abstract = {Group B streptococci (GBS) are the most common cause of neonatal sepsis, pneumonia, and meningitis. The alpha C protein is a surface-associated antigen; the gene (bca) for this protein contains a series of tandem repeats (each encoding 82 aa) that are identical at the nucleotide level and express a protective epitope. We previously reported that GBS isolates from two of 14 human maternal and neonatal pairs differed in the number of repeats contained in their alpha C protein; in both pairs, the alpha C protein of the neonatal isolate was smaller in molecular size. We now demonstrate by PCR that the neonatal isolates contain fewer tandem repeats. Maternal isolates were susceptible to opsonophagocytic killing in the presence of alpha C protein-specific antiserum, whereas the discrepant neonatal isolates proliferated. An animal model was developed to further study this phenomenon. Adult mice passively immunized with antiserum to the alpha C protein were challenged with an alpha C protein-expressing strain of GBS. Splenic isolates of GBS from these mice showed a high frequency of mutation in bca--most commonly a decrease in repeat number. Isolates from non-immune mice were not altered. Spontaneous deletions in the repeat region were observed at a much lower frequency (6 x 10(-4)); thus, deletions in that region are selected for under specific antibody pressure and appear to lower the organism{\textquoteright}s susceptibility to killing by antibody specific to the alpha C protein. This mechanism of antigenic variation may provide a means whereby GBS evade host immunity.}, keywords = {Animals, Antigens, Surface, Bacterial Proteins, Base Sequence, DNA Primers, Female, Humans, Immune Sera, Immunization, Passive, Infant, Newborn, Infectious Disease Transmission, Vertical, Mice, Molecular Sequence Data, Phagocytosis, Polymerase Chain Reaction, Pregnancy, Repetitive Sequences, Nucleic Acid, Sequence Deletion, Spleen, Streptococcal Infections, Streptococcus agalactiae}, author = {Madoff, L C and Michel, J L and Gong, E W and Kling, D E and Kasper, D L} } @article {1155071, title = {Immune response to type III group B streptococcal polysaccharide-tetanus toxoid conjugate vaccine}, journal = {J Clin Invest}, volume = {98}, year = {1996}, month = {1996 Nov 15}, pages = {2308-14}, abstract = {Group B Streptococcus (GBS) is an important perinatal pathogen. Because transplacentally acquired maternal antibodies to the GBS capsular polysaccharides (CPS) confer protection, prevention of infant disease may be possible after immunization of women. Unfortunately, the purified CPS of GBS are only variably immunogenic in adults; therefore to enhance immunogenicity we have designed and developed a CPS-protein conjugate vaccine. The lability of a conformationally dependent epitope on the III CPS containing a critical sialic acid residue was important to consider in vaccine design. 100 women were randomized to receive GBS type III CPS-tetanus toxoid conjugate (III-TT) vaccine at one of three doses; unconjugated GBS type III CPS; or saline. Serum samples were obtained before immunization and 2, 4, 8, and 26 wk thereafter, and specific antibody to type III CPS was measured. Vaccines were well tolerated. In sera from recipients of the highest dose of III-TT, CPS-specific IgG levels rose from a geometric mean of 0.09 microg/ml before immunization to 4.53 microg/ml 8 wk later, whereas levels in recipients of unconjugated type III CPS rose from 0.21 microg/ml to 1.41 microg/ml. Lower doses resulted in lower antibody levels. A > or = 4-fold rise in antibody concentration was achieved in 90\% of recipients of III-TT compared with 50\% of those that received III CPS (P = 0.0015). Antibodies evoked by the conjugate vaccine recognized a conformationally dependent epitope of the III-CPS, promoted opsonophagocytosis and killing of GBS, and, after maternal immunization, protected neonatal mice from lethal challenge with type III GBS. We conclude that directed coupling of type III GBS polysaccharide to a carrier protein yielded a conjugate vaccine with preserved expression of a highly labile conformational epitope involving sialic acid and enhanced immunogenicity compared with uncoupled CPS.}, keywords = {Adolescent, Adult, Animals, Antibodies, Bacterial, Antibody Affinity, Antibody Specificity, Cytotoxicity, Immunologic, Epitopes, Female, Humans, Immunoglobulin A, Immunoglobulin G, Immunoglobulin M, Mice, N-Acetylneuraminic Acid, Opsonin Proteins, Phagocytosis, Polysaccharides, Bacterial, Streptococcal Infections, Streptococcus agalactiae, Vaccines, Vaccines, Conjugate}, author = {Kasper, D L and Paoletti, L C and Wessels, M R and Guttormsen, H K and Carey, V J and Jennings, H J and Baker, C J} } @article {1155072, title = {Maternal immunization of mice with group B streptococcal type III polysaccharide-beta C protein conjugate elicits protective antibody to multiple serotypes}, journal = {J Clin Invest}, volume = {94}, year = {1994}, month = {1994 Jul}, pages = {286-92}, abstract = {Group B streptococcal infection is a major cause of neonatal mortality. Antibody to the capsular polysaccharide protects against invasive neonatal disease, but immunization with capsular polysaccharides fails to elicit protective antibody in many recipients. Conjugation of the polysaccharide to tetanus toxoid has been shown to increase immune response to the polysaccharide. In animal models, C proteins of group B streptococci are also protective determinants. We examined the ability of the beta C protein to serve in the dual role of carrier for the polysaccharide and protective immunogen. Type III polysaccharide was covalently coupled to beta C protein by reductive amination. Immunization of rabbits with the polysaccharide-protein conjugate elicited high titers of antibody to both components, and the serum induced opsonophagocytic killing of type III, Ia/C, and Ib/C strains of group B streptococci. Female mice were immunized with the conjugate vaccine and then bred; 93\% of neonatal pups born to these dams vaccinated with conjugate survived type III group B streptococcal challenge and 76\% survived type Ia/C challenge, compared with 3\% and 8\% survival, respectively, in controls (P < 0.001). The beta C protein acted as an effective carrier for the type III polysaccharide while simultaneously induced protective immunity against beta C protein--containing strains of group B streptococci.}, keywords = {Animals, Animals, Newborn, Antibodies, Bacterial, Antigens, Bacterial, Bacterial Vaccines, Epitopes, Female, Immunity, Maternally-Acquired, Immunization, Mice, Phagocytosis, Polysaccharides, Bacterial, Rabbits, Streptococcus agalactiae, Vaccines, Conjugate}, author = {Madoff, L C and Paoletti, L C and Tai, J Y and Kasper, D L} } @article {1155073, title = {The changing spectrum of group B streptococcal disease}, journal = {N Engl J Med}, volume = {328}, year = {1993}, month = {1993 Jun 24}, pages = {1843-4}, keywords = {Adult, Bacterial Vaccines, Disease Susceptibility, Humans, Infant, Serotyping, Streptococcal Infections, Streptococcus agalactiae}, author = {Wessels, M R and Kasper, D L} } @article {1155074, title = {Structural features of polysaccharides that induce intra-abdominal abscesses}, journal = {Science}, volume = {262}, year = {1993}, month = {1993 Oct 15}, pages = {416-9}, abstract = {The capsular polysaccharide complex from Bacteroides fragilis promotes the formation of intra-abdominal abscesses--a pathologic host response to infecting microorganisms. This complex consists of two distinct polysaccharides, each with repeating units that have positively charged amino groups and negatively charged carboxyl or phosphate groups. Analysis of these polysaccharides as well as other charged carbohydrates before and after chemical modification revealed that these oppositely charged groups are required for the induction of intra-abdominal abscesses in a rat model.}, keywords = {Abdomen, Abscess, Animals, Bacterial Capsules, Bacteroides fragilis, Bacteroides Infections, Carbohydrate Sequence, Male, Molecular Sequence Data, Neisseria meningitidis, Polysaccharides, Bacterial, Rats, Rats, Wistar, Salmonella typhi, Streptococcus pneumoniae, Structure-Activity Relationship}, author = {Tzianabos, A O and Onderdonk, A B and Rosner, B and Cisneros, R L and Kasper, D L} } @article {1155075, title = {The capsular polysaccharide of Bacteroides fragilis comprises two ionically linked polysaccharides}, journal = {J Biol Chem}, volume = {267}, year = {1992}, month = {1992 Sep 05}, pages = {18230-5}, abstract = {Recently, we have shown that the capsular polysaccharide of Bacteroides fragilis NCTC 9343 is composed of an aggregate of two discrete large molecular weight polysaccharides (designated polysaccharides A and B). Following disaggregation of this capsular complex by very mild acid treatment, high resolution NMR spectroscopy demonstrated that polysaccharides A and B consist of highly charged repeating unit structures with unusual substituent groups (Baumann, H., Tzianabos, A. O., Brisson, J.-R., Kasper, D.L., and Jennings, H.J. (1992) Biochemistry 31, 4081-4089). Presently, we report that the capsular polysaccharide of B. fragilis represents a complex structure that is formed as a result of ionic interactions between polysaccharides A and B. Electron microscopy of immunogold-labeled organisms (with monoclonal antibodies specific for polysaccharides A and B) demonstrated that the two polysaccharides are co-expressed on the cell surface of B. fragilis. We have shown that the purified capsule complex is made up exclusively of polysaccharide A and polysaccharide B (no other macromolecular structure was detected) in a 1:3.3 ratio and that disaggregation of this complex into the native forms of the constituent polysaccharides could be accomplished by preparative isoelectric focusing. Structural analyses of the native polysaccharides A and B showed that they possessed the same repeating unit structures as the respective acid-derived polysaccharides. The ionic nature of the linkage between polysaccharides A and B was demonstrated by reassociation of the native polysaccharides to form an aggregated polymer comparable to the original complex. The distinctive composition of this macromolecule may provide a rationale for the unusual biologic properties associated with the B. fragilis capsular polysaccharide.}, keywords = {Bacteroides fragilis, Carbohydrate Conformation, Carbohydrate Sequence, Immunoelectrophoresis, Isoelectric Focusing, Magnetic Resonance Spectroscopy, Microscopy, Immunoelectron, Molecular Sequence Data, Molecular Structure, Polysaccharides, Bacterial}, author = {Tzianabos, A O and Pantosti, A and Baumann, H and Brisson, J R and Jennings, H J and Kasper, D L} } @article {1155076, title = {Response to type III polysaccharide in women whose infants have had invasive group B streptococcal infection}, journal = {N Engl J Med}, volume = {322}, year = {1990}, month = {1990 Jun 28}, pages = {1857-60}, keywords = {Antibodies, Bacterial, Antibody Formation, Antigens, Bacterial, Bacterial Vaccines, Female, Humans, Infant, Newborn, Polysaccharides, Bacterial, Pregnancy, Pregnancy Complications, Infectious, Streptococcal Infections, Streptococcus agalactiae, Vaccination}, author = {Baker, C J and Rench, M A and Kasper, D L} } @article {1155077, title = {Antibody recognition of the type 14 pneumococcal capsule. Evidence for a conformational epitope in a neutral polysaccharide}, journal = {J Exp Med}, volume = {169}, year = {1989}, month = {1989 Jun 01}, pages = {2121-31}, abstract = {Oligosaccharides consisting of one or more tetrasaccharide repeating units were derived from the capsular polysaccharide of type 14 pneumococcus (Pn14) by endo-beta-galactosidase digestion. The relative affinity of anticapsular antibody binding to derivative oligosaccharides of different chain lengths was measured in a Pn 14 ELISA inhibition assay. The concentration of inhibiting antigen required to achieve 50\% inhibition of IgG binding increased progressively from 5.6 x 10(-4) M to 7.0 x 10(-11) M as the inhibiting saccharide chain length increased from 1 tetrasaccharide repeating unit to 2,500 repeating units. These data indicate that antibodies directed against the Pn14 polysaccharide recognize a conformational epitope fully expressed only in high molecular weight forms of the antigen. Similar results were found for inhibition of Fab fragment binding, suggesting that recognition of the conformational epitope is largely dependent on the intrinsic affinity of the Fab combining region. Unlike previously reported polysaccharides for which conformational epitopes have been described, the Pn14 polysaccharide does not contain negatively charged residues, indicating that expression of conformational determinants is not limited to acidic polysaccharides. Antibody recognition of conformational epitopes may be a common mechanism by which the host immune response discriminates between bacterial polysaccharides and host oligosaccharides of similar structure.}, keywords = {Animals, Antibodies, Bacterial, Antigens, Bacterial, Bacterial Capsules, Binding Sites, Antibody, Binding, Competitive, Carbohydrate Conformation, Epitopes, Immune Sera, Immunoglobulin Fab Fragments, Immunoglobulin G, Oligosaccharides, Polysaccharides, Bacterial, Rabbits, Streptococcus pneumoniae}, author = {Wessels, M R and Kasper, D L} } @article {1155078, title = {Definition of a bacterial virulence factor: sialylation of the group B streptococcal capsule}, journal = {Proc Natl Acad Sci U S A}, volume = {86}, year = {1989}, month = {1989 Nov}, pages = {8983-7}, abstract = {Sialylation of bacterial capsules has been proposed as an important virulence factor for several species of encapsulated pathogens, including group B Streptococcus. We have constructed a transposon mutant strain of type III group B Streptococcus that expresses a capsular polysaccharide differing from the wild type only in that the mutant strain{\textquoteright}s capsule lacks sialic acid. The mutant polysaccharide is antigenically identical to the capsular polysaccharide of type 14 Streptococcus pneumoniae, as predicted by the structures of the type III group B Streptococcus and S. pneumoniae polysaccharides. Loss of capsular sialic acid was associated with loss of virulence in the mutant strain in a neonatal rat model of lethal group B Streptococcus infection. These studies demonstrate directly that capsular sialic acid is a critical virulence determinant for type III group B Streptococcus and support the general hypothesis that surface sialylation aids pathogenic microorganisms in evading host defenses.}, keywords = {Bacterial Toxins, DNA Transposable Elements, Enzyme-Linked Immunosorbent Assay, Fluorescent Antibody Technique, Immunoblotting, Immunodiffusion, Microscopy, Electron, Mutation, Nucleic Acid Hybridization, Plasmids, Polysaccharides, Bacterial, Sialic Acids, Streptococcus agalactiae, Virulence}, author = {Wessels, M R and Rubens, C E and Bened{\'\i}, V J and Kasper, D L} } @article {1155079, title = {Immunization of pregnant women with a polysaccharide vaccine of group B streptococcus}, journal = {N Engl J Med}, volume = {319}, year = {1988}, month = {1988 Nov 03}, pages = {1180-5}, abstract = {Immunization of pregnant women with a polysaccharide vaccine of group B streptococcus is a promising strategy for the prevention of perinatal infections caused by group B streptococci. To explore the feasibility of this strategy, we vaccinated 40 pregnant women at a mean gestation of 31 weeks with a single 50-microgram dose of the Type III capsular polysaccharide of group B streptococcus. The only adverse effect detected was a mild local reaction in nine women (22 percent). Of the 35 women with low or unprotective antibody levels before immunization (less than 2 micrograms per milliliter), 20 (57 percent) responded to the vaccine. The geometric mean antibody level rose from 1.3 to 7.1 micrograms per milliliter four weeks after vaccination (P less than 0.02), and these levels persisted at delivery and three months post partum. Sixty-two percent of the vaccine-induced immunoglobulin in the mothers was IgG, which readily crosses the placenta. Infant antibody levels in cord serum correlated directly with maternal antibody levels at delivery (r = 0.913, P less than 0.001). Of the 25 infants born to women who responded to the vaccine, 80 percent continued to have protective levels of antibody at one month of age and 64 percent had protective levels at three months. Serum samples from infants with greater than or equal to 2 micrograms of antibody to Type III group B streptococcus per milliliter uniformly promoted efficient opsonization, phagocytosis, and bacterial killing in vitro of Type III strains. This effect could be mediated exclusively by the alternative complement pathway. Although this vaccine with an overall response rate of 63 percent is not optimally immunogenic, we conclude that maternal immunization is feasible and can provide passive immunity against systemic infection with Type III group B streptococcus in the majority of newborns. Larger trials with better vaccines will be required to evaluate the safety and clinical effectiveness of this strategy.}, keywords = {Adult, Antibodies, Bacterial, Bacterial Vaccines, Female, Humans, Immunity, Maternally-Acquired, Immunization, Immunoglobulin G, Infant, Newborn, Polysaccharides, Bacterial, Pregnancy, Pregnancy Trimester, Third, Streptococcal Infections, Streptococcus agalactiae}, author = {Baker, C J and Rench, M A and Edwards, M S and Carpenter, R J and Hays, B M and Kasper, D L} } @article {1155080, title = {Demonstration of a saturable binding site for thyrotropin in Yersinia enterocolitica}, journal = {Science}, volume = {219}, year = {1983}, month = {1983 Mar 18}, pages = {1331-3}, abstract = {Several lines of evidence suggest that there might be immunologic cross-reactivity between the thyroid plasma membrane in humans and antigenic determinants in the enteric pathogen Yersinia enterocolitica. Studies were therefore performed to determine whether Y. enterocolitica, like the thyroid membrane, contains a thyrotropin binding site. A saturable binding site for bovine thyrotropin was indeed demonstrable, particularly in preparations of the organism that have been treated with ethylenediaminetetraacetate and lysozyme. Hormonal specificity of the binding site, as judged from the inhibition of binding of 125I-labeled bovine thyrotropin, was similar to that of the thyrotropin receptor in human thyroid tissue.}, keywords = {Binding Sites, Binding, Competitive, Kinetics, Receptors, Cell Surface, Receptors, Thyrotropin, Thyrotropin, Yersinia enterocolitica}, author = {M. Weiss and Ingbar, S H and Winblad, S and Kasper, D L} } @article {1155081, title = {Structural determination of the capsular polysaccharide antigen of type II group B Streptococcus}, journal = {J Biol Chem}, volume = {258}, year = {1983}, month = {1983 Feb 10}, pages = {1793-8}, keywords = {Antigens, Bacterial, Antigens, Surface, Carbohydrate Conformation, Carbohydrate Sequence, Methylation, Neuraminidase, Polysaccharides, Bacterial, Streptococcus agalactiae}, author = {Jennings, H J and Rosell, K G and Katzenellenbogen, E and Kasper, D L} } @article {1155082, title = {Conformational aspects critical to the immunospecificity of the type III group B streptococcal polysaccharide}, journal = {Biochemistry}, volume = {20}, year = {1981}, month = {1981 Aug 04}, pages = {4511-8}, abstract = {Immunization of rabbits with group B type III streptococcus organisms induces two distinct populations of antibodies with a specificity for determinants on the native capsular polysaccharide antigen of these organisms. Some of the structural and conformational features of the two determinants responsible for the formation of these antibodies were elucidated by (13)C NMR and serological studies on the native type III polysaccharide and some of its structurally modified analogues. The specificity of the determinant corresponding to the major population of antibodies is dependent of the presence of sialic acid residues on the native type III antigen, and although these residues are not an integral part of the determinant, they exert conformational control over it. The carboxylate groups of the sialic acid residues are an important factor in this control mechanism which could possibly involve intramolecular hydrogen bonding. The terminal sialic acid residues control the orientation of the penultimate beta-d-galactopyranose residues with respect to the backbone of the native antigen. The orientation of these residues is critical to the determinant because the determinant is probably small and is located precisely at the junction of the same beta-d-galactopyranose residues with the backbone of the native type III antigen. The determinant corresponding to the other population of antibodies is not sialic acid dependent. This determinant is located on the backbone of the native antigen in the vicinity of the other determinant but on the opposite side to the oligosaccharide branches. In this position, its conformation is unaffected even by the removal of the oligosaccharide branches from the native antigen.}, keywords = {Antibodies, Antigen-Antibody Complex, Carbohydrate Conformation, Epitopes, Immunoassay, Immunodiffusion, Magnetic Resonance Spectroscopy, Models, Molecular, Oxidation-Reduction, Polysaccharides, Bacterial, Sialic Acids, Streptococcus agalactiae}, author = {Jennings, H J and Lugowski, C and Kasper, D L} } @article {1155083, title = {Immunogenicity of polysaccharides from type III, group B Streptococcus}, journal = {J Clin Invest}, volume = {61}, year = {1978}, month = {1978 Apr}, pages = {1107-10}, abstract = {The immunogenicity and safety of two polysaccharides isolated from type III, group B Streptococcus, were tested in adults selected for existing low concentrations of natural antibody to the capsular polysaccharide of this organism. Both vaccine preparations (trichloroacetic acid and EDTA) were found to lack pyrogenicity and toxicity for experimental animals. A single 50-microgram subcutaneous injection of either polysaccharide in human subjects elicited significant increase in antibody concentration in immunized compared with control individuals receiving phosphate-buffered saline. Antibody responses were maximal by 2 wk and remained at 21 wk after immunization. Vaccine-induced antibody was primarily of the IgG class. Of the two vaccines, the larger molecular size polysaccharide was significantly more immunogenic. Although no systemic reactions were recorded, mild transient local reactions occurred in 45\% of vaccinees.}, keywords = {Animals, Antibodies, Bacterial, Bacterial Vaccines, Guinea Pigs, Haplorhini, Immunoglobulin G, Mice, Molecular Weight, Polysaccharides, Bacterial, Rabbits, Streptococcus agalactiae, Time Factors}, author = {Baker, C J and Edwards, M S and Kasper, D L} } @article {1155084, title = {Correlation of maternal antibody deficiency with susceptibility to neonatal group B streptococcal infection}, journal = {N Engl J Med}, volume = {294}, year = {1976}, month = {1976 Apr 01}, pages = {753-6}, abstract = {We investigated the role of maternal antibody in neonatal Group B streptococcal infection with a radioactive antigen-binding assay employing a purified polysaccharide antigen with both Type III and Group B determinants. Serums from seven women who gave birth to infants who had invasive Group B streptococcal infection with Type III strains were all deficient in antibody. In contrast, serums from 22 of 29 pregnant Type III vaginal carriers whose infants were healthy contained antibody with a prevalence significantly different from that in women delivering infants with Type III disease (P less than 0.01). Three healthy neonates born to women with antibody in serums had demonstrable antibody in umbilical-cord serum. These data suggest that transplacental transfer of maternal antibody protects infants from invasive Group B streptococcal infection with Type III strains.}, keywords = {Animals, Antibodies, Bacterial, Antigens, Bacterial, Carrier State, Female, Humans, Immune Sera, Infant, Newborn, Infant, Newborn, Diseases, Maternal-Fetal Exchange, Polysaccharides, Bacterial, Pregnancy, Rabbits, Streptococcal Infections, Streptococcus agalactiae, Vagina}, author = {Baker, C J and Kasper, D L} }