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Berlin Brandenburg

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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 03 April 2012, Vol.109(14), pp.5388-93
    Description: In the companion article by Yang and colleagues [Yang Y, et al. (2012) Proc Natl Acad Sci USA, 109, 10.1073/pnas.1121631109], we have shown that priming with glycolipid (FtL) from Francisella tularensis live-vaccine strain (i) induces FtL-specific B-1a to produce robust primary responses (IgM 〉〉IgG); (ii) establishes persistent long-term production of serum IgM and IgG anti-FtL at natural antibody levels; and (iii) elicits FtL-specific B-1a memory cells that arise in spleen but rapidly migrate to the peritoneal cavity, where they persist indefinitely but divide only rarely. Here, we show that FtL rechallenge alone induces these PerC B-1a memory cells to divide extensively and to express a unique activation signature. However, FtL rechallenge in the context of a Toll-like receptor 4 agonist-stimulated inflammatory response readily induces these memory cells to migrate to spleen and initiate production of dominant IgM anti-FtL secondary responses. Thus, studies here reveal unique mechanisms that govern B-1a memory development and expression, and introduce B-1a memory as an active participant in immune defenses. In addition, at a practical level, these studies suggest previously unexplored vaccination strategies for pathogen-associated antigens that target the B-1a repertoire.
    Keywords: Immunity, Innate ; Immunologic Memory
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 03 April 2012, Vol.109(14), pp.5382-7
    Description: B-1a cells are primarily thought of as natural antibody-producing cells. However, we now show that appropriate antigenic stimulation induces IgM and IgG B-1a antibody responses and long-lived T-independent antigen-specific B-1a memory that differs markedly from canonical B-2 humoral immunity. Thus, we show here that in the absence of inflammation, priming with glycolipid (FtL) from Francisella tularensis live vaccine strain induces splenic FtL-specific B-1a to mount dominant IgM and activation-induced cytidine deaminase-dependent IgG anti-FtL responses that occur within 3-5 d of FtL priming and fade within 1 wk to natural antibody levels that persist indefinitely in the absence of secondary FtL immunization. Equally surprising, FtL priming elicits long-term FtL-specific B-1a memory cells (IgM〉〉IgG) that migrate rapidly to the peritoneal cavity and persist there indefinitely, ready to respond to appropriately administrated secondary antigenic stimulation. Unlike B-2 responses, primary FtL-specific B-1a responses and establishment of persistent FtL-specific B-1a memory occur readily in the absence of adjuvants, IL-7, T cells, or germinal center support. However, in another marked departure from the mechanisms controlling B-2 memory responses, rechallenge with FtL in an inflammatory context is required to induce B-1a secondary antibody responses. These findings introduce previously unexplored vaccination strategies for pathogens that target the B-1a repertoire.
    Keywords: Antibody Formation ; Immunity, Innate ; Antigens -- Immunology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 3
    Language: English
    In: Infection and immunity, April 2016, Vol.84(4), pp.1143-1149
    Description: Staphylococcus epidermidis is normally a commensal colonizer of human skin and mucus membranes, but, due to its ability to form biofilms on indwelling medical devices, it has emerged as a leading cause of nosocomial infections. Bacteremia or bloodstream infection is a frequent and costly complication resulting from biofilm fouling of medical devices. Our goal was to develop a murine model of S. epidermidis infection to identify potential vaccine targets for the prevention of S. epidermidis bacteremia. However, assessing the contribution of adaptive immunity to protection against S. epidermidis challenge was complicated by a highly efficacious innate immune response in mice. Naive mice rapidly cleared S. epidermidis infections from blood and solid organs, even when the animals were immunocompromised. Cyclophosphamide-mediated leukopenia reduced the size of the bacterial challenge dose required to cause lethality but did not impair clearance after a nonlethal challenge. Nonspecific innate immune stimulation, such as treatment with a Toll-like receptor 4 (TLR4) agonist, enhanced bacterial clearance. TLR2 signaling was confirmed to accelerate the clearance of S. epidermidis bacteremia, but TLR2(-/-)mice could still resolve a bloodstream infection. Furthermore, TLR2 signaling played no role in the clearance of bacteria from the spleen. In conclusion, these data suggest that S. epidermidis bloodstream infection is cleared in a highly efficient manner that is mediated by both TLR2-dependent and -independent innate immune mechanisms. The inability to establish a persistent infection in mice, even in immunocompromised animals, rendered these murine models unsuitable for meaningful assessment of antibody-mediated therapies or vaccine candidates.
    Keywords: Disease Models, Animal ; Antibodies, Bacterial -- Therapeutic Use ; Bacteremia -- Prevention & Control ; Staphylococcal Infections -- Prevention & Control ; Staphylococcal Vaccines -- Immunology ; Staphylococcus Epidermidis -- Immunology
    ISSN: 00199567
    E-ISSN: 1098-5522
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  • 4
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 17 March 2009, Vol.106(11), pp.4343-8
    Description: Francisella tularensis (Ft), a gram-negative intracellular bacterium, is the etiologic agent of tularemia. Infection of mice with 〈10 Ft Live Vaccine Strain (Ft LVS) organisms i.p. causes a lethal infection that resembles human tularemia. Here, we show that immunization with as little as 0.1 ng Ft LVS lipopolysaccharide (Ft-LPS), but not Ft lipid A, generates a rapid antibody response that protects wild-type (WT) mice against lethal Ft LVS challenge. Protection is not induced in Ft-LPS-immunized B cell-deficient mice (muMT or JhD), male xid mice, or Ig transgenic mice that produce a single IgH (not reactive with Ft-LPS). Focusing on the cellular mechanisms that underlie this protective response, we show that Ft-LPS specifically stimulates proliferation of B-1a lymphocytes that bind fluorochrome-labeled Ft-LPS and the differentiation of these cells to plasma cells that secrete antibodies specific for Ft-LPS. This exclusively B-1a antibody response is equivalent in WT, T-deficient (TCRalphabeta(-/-), TCRgammadelta(-/-)), and Toll-like receptor 4 (TLR4)-deficient (TLR4(-/-)) mice and thus is not dependent on T cells or typical inflammatory processes. Serum antibody levels peak approximately 5 days after Ft-LPS immunization and persist at low levels for months. Thus, immunization with Ft-LPS activates a rare population of antigen-specific B-1a cells to produce a persistent T-independent antibody response that provides long-term protection against lethal Ft LVS infection. These data support the possibility of creating effective, minimally invasive vaccines that can provide effective protection against pathogen invasion.
    Keywords: Antibody Formation ; Bacterial Vaccines -- Immunology ; Francisella Tularensis -- Immunology ; Tularemia -- Prevention & Control
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 5
    Language: English
    In: Vaccine, 2009, Vol.27(18), pp.2426-2436
    Description: , the etiologic agent of tularemia, can cause severe and fatal infection after inhalation of as few as 10–100 CFU. is a potential bioterrorism agent and, therefore, a priority for countermeasure development. Vaccination with the live vaccine strain (LVS), developed from a Type B strain, confers partial protection against aerosal exposure to the more virulent Type A strains and provides proof of principle that a live attenuated vaccine strain may be efficacious. However LVS suffers from several notable drawbacks that have prevented its licensure and widespread use. To address the specific deficiencies that render LVS a sub-optimal tularemia vaccine, we engineered LVS strains with targeted deletions in the or genes that encode critical enzymes in the guanine nucleotide biosynthetic pathway. LVSΔ and LVSΔ mutants were guanine auxotrophs and were highly attenuated in a mouse model of infection. While the mutants failed to replicate in macrophages, a robust proinflammatory cytokine response, equivalent to that of the parental LVS, was elicited. Mice vaccinated with a single dose of the LVSΔ or LVSΔ mutant were fully protected against subsequent lethal challenge with the LVS parental strain. These findings suggest the specific deletion of these target genes could generate a safe and efficacious live attenuated vaccine.
    Keywords: Francisella Tularensis ; Tularemia Vaccine ; Lvs ; Medicine ; Biology ; Veterinary Medicine ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0264-410X
    E-ISSN: 1873-2518
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  • 6
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 17 March 2009, Vol.106(11), pp.4343-4348
    Description: Francisella tularensis (Ft), a Gram-negative intracellular bacterium, is the etiologic agent of tularemia. Infection of mice with 〈10 Ft Live Vaccine Strain (Ft LVS) organisms i.p. causes a lethal infection that resembles human tularemia. Here, we show that immunization with as little as 0.1 ng Ft LVS lipopolysaccharide (Ft-LPS), but not Ft lipid A, generates a rapid antibody response that protects wild-type (WT) mice against lethal Ft LVS challenge. Protection is not induced in Ft-LPS-immunized B cell-deficient mice (μMT or JhD), male xid mice, or Ig transgenic mice that produce a single IgH (not reactive with Ft-LPS). Focusing on the cellular mechanisms that underlie this protective response, we show that Ft-LPS specifically stimulates proliferation of B-1a lymphocytes that bind fluorochrome-labeled Ft-LPS and the differentiation of these cells to plasma cells that secrete antibodies specific for Ft-LPS. This exclusively B-1a antibody response is equivalent in WT, T-deficient (${\rm{TCR\alpha \beta }}^{{\rm{ - / - }}} {\rm{, TCR\gamma \delta }}^{{\rm{ - / - }}}$), and Toll-like receptor 4 (TLR4)-deficient (${\rm{TLR4}}^{{\rm{ - / - }}}$) mice and thus is not dependent on T cells or typical inflammatory processes. Serum antibody levels peak ≈5 days after Ft-LPS immunization and persist at low levels for months. Thus, immunization with Ft-LPS activates a rare population of antigenspecific B-1a cells to produce a persistent T-independent antibody response that provides long-term protection against lethal Ft LVS infection. These data support the possibility of creating effective, minimally invasive vaccines that can provide effective protection against pathogen invasion.
    Keywords: Biological sciences -- Biology -- Physiology -- Lymphocytes ; Health sciences -- Medical sciences -- Immunology -- Lymphocytes ; Biological sciences -- Biology -- Physiology -- Lymphocytes ; Health sciences -- Medical treatment -- Biological therapy -- Lymphocytes ; Biological sciences -- Biology -- Physiology -- Lymphocytes ; Health sciences -- Medical conditions -- Infections -- Lymphocytes ; Biological sciences -- Biochemistry -- Biomolecules -- Lymphocytes ; Biological sciences -- Biology -- Microbiology -- Lymphocytes ; Health sciences -- Medical sciences -- Immunology -- Lymphocytes ; Biological sciences -- Biology -- Physiology -- Lymphocytes ; Biological sciences -- Biology -- Physiology -- Lymphocytes ; Health sciences -- Medical sciences -- Immunology -- Lymphocytes ; Biological sciences -- Biology -- Physiology -- Lymphocytes ; Health sciences -- Medical treatment -- Biological therapy -- Lymphocytes ; Biological sciences -- Biology -- Physiology -- Lymphocytes ; Health sciences -- Medical conditions -- Infections -- Lymphocytes ; Biological sciences -- Biochemistry -- Biomolecules -- Lymphocytes ; Biological sciences -- Biology -- Microbiology -- Lymphocytes ; Health sciences -- Medical sciences -- Immunology -- Lymphocytes ; Biological sciences -- Biology -- Physiology -- Lymphocytes
    ISSN: 00278424
    Source: Archival Journals (JSTOR)
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  • 7
    In: Infection and Immunity, 2002, Vol. 70(11), p.6158
    Description: Haemophilus ducreyi is the etiologic agent of the sexually transmitted genital ulcer disease chancroid. H. ducreyi serum resistance protein A (DsrA) is a member of a family of multifunctional outer membrane proteins that are involved in resistance to killing by human serum complement. The members of this family include YadA of Yersinia species, the UspA proteins of Moraxella catarrhalis, and the Eib proteins of Escherichia coli. The role of YadA, UspA1, and UspA2H as eukaryotic cell adhesins and the function of UspA2 as a vitronectin binder led to our investigation of the cell adhesion and vitronectin binding properties of DsrA. We found that DsrA was a keratinocyte- specific adhesin as it was necessary and sufficient for attachment to HaCaT cells, a keratinocyte cell line, but was not required for attachment to HS27 cells, a fibroblast cell line. We also found that DsrA was specifically responsible for the ability of H. ducreyi to bind vitronectin. We then theorized that DsrA might use vitronectin as a bridge to bind to human cells, but this hypothesis proved to be untrue as eliminating HaCaT cell binding of vitronectin with a monoclonal antibody specific to integrin [alpha] sub(v) beta sub(5) did not affect the attachment of H. ducreyi to HaCaT cells. Finally, we wanted to examine the importance of keratinocyte adhesion in chancroid pathogenesis so we tested the wild-type and dsrA mutant strains of H. ducreyi in our swine models of chancroid pathogenesis. The dsrA mutant was less virulent than the wild type in both the normal and immune cell-depleted swine models of chancroid infection.
    Keywords: Cell Cycle, Morphology and Motility ; Dsra Protein ; Hs27 Cells ; Hacat Cells ; Dsra Gene ; Vitronectin;
    ISSN: 0019-9567
    ISSN: 00199567
    E-ISSN: 10985522
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  • 8
    Language: English
    In: Journal of medical microbiology, September 2013, Vol.62(Pt 9), pp.1394-404
    Description: Clostridium difficile infection (CDI) has been identified as the leading cause of nosocomial diarrhoea and pseudomembranous colitis associated with antibiotic therapy. Recent epidemiological changes as well as increases in the number of outbreaks of strains associated with increased virulence and higher mortality rates underscore the importance of identifying alternatives to antibiotics to manage this important disease. Animal studies have clearly demonstrated the roles that toxins A and B play in gut inflammation as well as diarrhoea; therefore it is not surprising that serum anti-toxin A and B IgG are associated with protection against recurrent CDI. In humans, strong humoral toxin-specific immune responses elicited by natural C. difficile infection is associated with recovery and lack of disease recurrence, whereas insufficient humoral responses are associated with recurrent CDI. The first generation of C. difficile vaccine that contained inactivated toxin A and B was found to be completely protective against death and diarrhoea in the hamster C. difficile challenge model. When tested in young healthy volunteers in Phase I clinical trials, this investigational vaccine was shown to be safe and immunogenic. Moreover, in a separate study this vaccine was able to prevent further relapses in three out of three patients who had previously suffered from chronic relapsing C. difficile-associated diarrhoea. Herein we examined the immunogenicity and protective activity of a next-generation Sanofi Pasteur two-component highly purified toxoid vaccine in a C. difficile hamster model. This model is widely recognized as a stringent and relevant choice for the evaluation of novel treatment strategies against C. difficile and was used in preclinical testing of the first-generation vaccine candidate. Intramuscular (i.m.) immunizations with increasing doses of this adjuvanted toxoid vaccine protected hamsters from mortality and disease symptoms in a dose-dependent manner. ELISA measurements of pre-challenge sera showed that the median anti-toxin A and anti-toxin B IgG titres in the group of surviving animals were significantly higher than the median values in the group of animals that did not survive challenge. Assessment of the neutralizing activity of these sera revealed a statistically significant difference between the levels of both toxin A and toxin B neutralizing titres in protected versus unprotected animals as the median anti-toxin A and anti-toxin B neutralizing titres from surviving animals were higher than the median values from animals that succumbed to challenge. Statistically significant correlations between the toxin-specific binding titres and toxin neutralizing titres were seen for both toxin A and toxin B responses. The role of circulating anti-toxin antibodies in immunity against disease was evaluated by passive transfer of immune sera against C. difficile toxoids to naïve hamsters. Passively immunized animals were protected against morbidity and mortality associated with C. difficile challenge. Taken together, these results indicate the ability of i.m. immunization with inactivated toxins A and B to induce robust dose-dependent anti-toxin A and anti-toxin B IgG responses, the principal role of circulating anti-toxin antibody in immunity against disease and that antibody toxin binding and neutralization titres can serve as correlates of protection in the hamster challenge model of C. difficile.
    Keywords: Antibody Formation ; Immunization, Passive ; Bacterial Toxins -- Immunology ; Bacterial Vaccines -- Administration & Dosage ; Clostridium Infections -- Prevention & Control ; Clostridium Difficile -- Immunology ; Enterotoxins -- Immunology
    ISSN: 00222615
    E-ISSN: 1473-5644
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  • 9
    In: Nature Immunology, 2010, Vol.11(5), p.395
    Description: Inflammasomes regulate the activity of caspase-1 and the maturation of interleukin 1[beta] (IL-1[beta]) and IL-18. AIM2 has been shown to bind DNA and engage the caspase-1-activating adaptor protein ASC to form a caspase-1-activating inflammasome. Using Aim2-deficient mice, we identify a central role for AIM2 in regulating caspase-1-dependent maturation of IL-1[beta] and IL-18, as well as pyroptosis, in response to synthetic double-stranded DNA. AIM2 was essential for inflammasome activation in response to Francisella tularensis, vaccinia virus and mouse cytomegalovirus and had a partial role in the sensing of Listeria monocytogenes. Moreover, production of IL-18 and natural killer cell-dependent production of interferon-[gamma], events critical in the early control of virus replication, were dependent on AIM2 during mouse cytomegalovirus infection in vivo. Collectively, our observations demonstrate the importance of AIM2 in the sensing of both bacterial and viral pathogens and in triggering innate immunity.
    Keywords: Bacterial Infections -- Risk Factors ; Bacterial Infections -- Research ; Cytomegalovirus Infections -- Risk Factors ; Cytomegalovirus Infections -- Research ; Dna Viruses -- Health Aspects ; Dna Viruses -- Research ; Immune Response -- Health Aspects ; Immune Response -- Research;
    ISSN: 1529-2908
    E-ISSN: 15292916
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  • 10
    Language: English
    In: BMC Infectious Diseases, Jan 18, 2010, Vol.10, p.10
    Description: Background It has been shown previously that administration of Francisella tularensis (Ft) Live Vaccine Strain (LVS) lipopolysaccharide (LPS) protects mice against subsequent challenge with Ft LVS and blunts the pro-inflammatory cytokine response. Methods To further investigate the molecular mechanisms that underlie Ft LVS LPS-mediated protection, we profiled global hepatic gene expression following Ft LVS LPS or saline pre-treatment and subsequent Ft LVS challenge using Affymetrix arrays. Results A large number of genes (〉 3,000) were differentially expressed at 48 hours post-infection. The degree of modulation of inflammatory genes by infection was clearly attenuated by pre-treatment with Ft LVS LPS in the surviving mice. However, Ft LVS LPS alone had a subtle effect on the gene expression profile of the uninfected mice. By employing gene set enrichment analysis, we discovered significant up-regulation of the fatty acid metabolism pathway, which is regulated by peroxisome proliferator activated receptors (PPARs). Conclusions We hypothesize that the LPS-induced blunting of pro-inflammatory response in mouse is, in part, mediated by PPARs ([alpha] and [gamma]).
    Keywords: Cell Receptors -- Physiological Aspects ; Cell Receptors -- Genetic Aspects ; Cell Receptors -- Research ; Francisella Tularensis -- Physiological Aspects ; Francisella Tularensis -- Development And Progression ; Francisella Tularensis -- Genetic Aspects ; Francisella Tularensis -- Research ; Immune Response -- Physiological Aspects ; Immune Response -- Genetic Aspects ; Immune Response -- Research ; Lipopolysaccharides -- Physiological Aspects ; Lipopolysaccharides -- Genetic Aspects ; Lipopolysaccharides -- Research
    ISSN: 1471-2334
    Source: Cengage Learning, Inc.
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