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Scott D Grayowen - One of the best experts on this subject based on the ideXlab platform.
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Neisserial outer membrane vesicles bind the coinhibitory receptor carcinoembryonic antigen related cellular adhesion molecule 1 and suppress cd4 t lymphocyte function
Infection and Immunity, 2007Co-Authors: Ian C Boulton, Henry K Wong, Ofer Mandelboim, Denise Halliwell, Andrew Gorringe, Karen M Reddin, Scott D GrayowenAbstract:Pathogenic Neisseria bacteria naturally liberate outer membrane “blebs,” which are presumed to contribute to pathology, and the detergent-extracted outer membrane vesicles (OMVs) from Neisseria meningitidis are currently employed as meningococcal vaccines in humans. While the composition of these vesicles reflects the bacteria from which they are derived, the functions of many of their constituent proteins remain unexplored. The Neisserial colony opacity-associated Opa proteins function as adhesins, the majority of which mediate bacterial attachment to human carcinoembryonic antigen-related cellular adhesion molecules (CEACAMs). Herein, we demonstrate that the Opa proteins within OMV preparations retain the capacity to bind the immunoreceptor tyrosine-based inhibitory motif-containing coinhibitory receptor CEACAM1. When CD4+ T lymphocytes were exposed to OMVs from Opa-expressing bacteria, their activation and proliferation in response to a variety of stimuli were effectively halted. This potent immunosuppressive effect suggests that localized infection will generate a “zone of inhibition” resulting from the diffusion of membrane blebs into the surrounding tissues. Moreover, it demonstrates that OMV-based vaccines must be developed from strains that lack CEACAM1-binding Opa variants.
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engulfment of Neisseria gonorrhoeae revealing distinct processes of bacterial entry by individual carcinoembryonic antigen related cellular adhesion molecule family receptors
Infection and Immunity, 2004Co-Authors: Shannon E. Mccaw, Edward H. Liao, Scott D GrayowenAbstract:Individual Neisseria gonorrhoeae colony opacity-associated (Opa) protein variants can bind up to four different carcinoembryonic antigen-related cellular adhesion molecule (CEACAM) receptors. Most human cells encountered by gonococci express a combination of CEACAM receptors, thereby complicating the elucidation of intracellular signaling pathways triggered by individual receptors. Here, we compare the process of bacterial engulfment by a panel of stably transfected HeLa epithelial cell lines expressing each CEACAM receptor in isolation. CEACAM1 and CEACAM3 each contain proteinaceous transmembrane and cytoplasmic domains; however, the processes of Neisserial uptake mediated by these receptors differ with respect to their susceptibilities to both tyrosine kinase inhibitors and the actin microfilament-disrupting agent cytochalasin D. Neisserial uptake mediated by glycosylphosphatidylinositol (GPI)-anchored CEACAM5 and CEACAM6 was not significantly affected by any of a broad spectrum of inhibitors tested. However, cleavage of the GPI anchor by phosphatidylinositol-specific phospholipase C reduced bacterial uptake by HeLa cells expressing CEACAM5, consistent with a single zipper-like mechanism of uptake mediated by this receptor. Regardless of the CEACAM receptor expressed, internalized gonococci were effectively killed by a microtubule-dependent process that required acidification of the bacterium-containing phagosome. Given the phase-variable nature of Neisserial Opa proteins, these results indicate that the mechanism of bacterial engulfment and the cellular response to gonococcal infection depend on both the receptor specificities of the Neisserial Opa protein variants expressed and the spectrum of CEACAM receptors present on target cells, each of which determines the combination of receptors ultimately engaged.
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pathogenic Neisseria trigger expression of their carcinoembryonic antigen related cellular adhesion molecule 1 ceacam1 previously cd66a receptor on primary endothelial cells by activating the immediate early response transcription factor nuclear fact
Journal of Biological Chemistry, 2001Co-Authors: Petra Muenzner, Thomas F Meyer, Michael Naumann, Scott D GrayowenAbstract:Abstract Neisseria gonorrhoeae express opacity-associated (Opa) protein adhesins that mediate binding to various members of the carcinoembryonic antigen-related cellular adhesion molecule (CEACAM; previously CD66) receptor family. Although human umbilical vein endothelial cells express little CEACAM receptor in vitro, we found Neisserial infection to induce expression of CEACAM1, CEACAM1-3L, and CECAM1-4L splice variants. This mediates an increased Opa52-dependent binding of gonococci by these cells. The induced receptor expression did not require bacterial Opa expression, but it was more rapid with adherent bacteria. Because the time course of induction was similar to that seen for induced proinflammatory cytokines, we tested whether CEACAM1 expression could be controlled by a similar mechanism. Gonococcal infection activated a nuclear factor-κB (NF-κB) heterodimer consisting of p50 and p65, and inhibitors that prevent the nuclear translocation of activated NF-κB complex inhibited CEACAM1 transcript expression. Each of these effects could be mimicked by using culture filtrates or purified lipopolysaccharide instead of intact bacteria. Together, our results support a model whereby the outer membrane “blebs” that are actively released by gonococci trigger a Toll-like receptor-4-dependent activation of NF-κB, which up-regulates the expression of CEACAM1 to allow Opa52-mediated Neisserial binding. The regulation of CEACAM1 expression by NF-κB also implies a broader role for this receptor in the general inflammatory response to infection.
Andrew Gorringe - One of the best experts on this subject based on the ideXlab platform.
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bexsero a multicomponent vaccine for prevention of meningococcal disease
Human Vaccines & Immunotherapeutics, 2012Co-Authors: Andrew Gorringe, Rolando PajonAbstract:Serogroup B meningococcal (MenB) disease remains a serious public health problem for which a cross-protective vaccine effective against a wide range of MenB isolates has not been available. Novartis Vaccines has developed a vaccine for the prevention of MenB disease that contains four antigenic components: factor H binding protein (fHbp), Neisserial adhesin A (NadA), Neisseria heparin binding antigen (NHBA) and outer membrane vesicles from a New Zealand epidemic strain (which provides PorA). This vaccine has been submitted for regulatory review in Europe so it is timely to review the design of the vaccine, results to date in clinical studies and the potential strain coverage provided by the vaccine. It is also critical to discuss the key issues for the long-term success of the vaccine which include strain coverage, potential persistence of protection, potential effects on carriage of MenB strains, potential for escape mutants and cost effectiveness.
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Neisserial outer membrane vesicles bind the coinhibitory receptor carcinoembryonic antigen related cellular adhesion molecule 1 and suppress cd4 t lymphocyte function
Infection and Immunity, 2007Co-Authors: Ian C Boulton, Henry K Wong, Ofer Mandelboim, Denise Halliwell, Andrew Gorringe, Karen M Reddin, Scott D GrayowenAbstract:Pathogenic Neisseria bacteria naturally liberate outer membrane “blebs,” which are presumed to contribute to pathology, and the detergent-extracted outer membrane vesicles (OMVs) from Neisseria meningitidis are currently employed as meningococcal vaccines in humans. While the composition of these vesicles reflects the bacteria from which they are derived, the functions of many of their constituent proteins remain unexplored. The Neisserial colony opacity-associated Opa proteins function as adhesins, the majority of which mediate bacterial attachment to human carcinoembryonic antigen-related cellular adhesion molecules (CEACAMs). Herein, we demonstrate that the Opa proteins within OMV preparations retain the capacity to bind the immunoreceptor tyrosine-based inhibitory motif-containing coinhibitory receptor CEACAM1. When CD4+ T lymphocytes were exposed to OMVs from Opa-expressing bacteria, their activation and proliferation in response to a variety of stimuli were effectively halted. This potent immunosuppressive effect suggests that localized infection will generate a “zone of inhibition” resulting from the diffusion of membrane blebs into the surrounding tissues. Moreover, it demonstrates that OMV-based vaccines must be developed from strains that lack CEACAM1-binding Opa variants.
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expression of heterologous antigens in commensal Neisseria spp preservation of conformational epitopes with vaccine potential
Infection and Immunity, 2004Co-Authors: Cliona A Odwyer, Andrew Gorringe, Karen M Reddin, Paul R Langford, Denis Martin, Stephen Taylor, Michael J Hudson, Bernard R Brodeur, Simon J KrollAbstract:Commensal Neisseriae share with Neisseria meningitidis (meningococcus) a tendency towards overproduction of the bacterial outer envelope, leading to the formation and release during growth of outer membrane vesicles (OMVs). OMVs from both meningococci and commensal Neisseriae have shown promise as vaccines to protect against meningococcal disease. We report here the successful expression at high levels of heterologous proteins in commensal Neisseriae and the display, in its native conformation, of one meningococcal outer membrane protein vaccine candidate, NspA, in OMVs prepared from such a recombinant Neisseria flavescens strain. These NspA-containing OMVs conferred protection against otherwise lethal intraperitoneal challenge of mice with N. meningitidis serogroup B, and sera raised against them mediated opsonophagocytosis of meningococcal strains expressing this antigen. This development promises to facilitate the design of novel vaccines containing membrane protein antigens that are otherwise difficult to present in native conformation that provide cross-protective efficacy in the prevention of meningococcal disease.
Thomas F Meyer - One of the best experts on this subject based on the ideXlab platform.
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cd46 independent binding of Neisserial type iv pili and the major pilus adhesin pilc to human epithelial cells
Infection and Immunity, 2005Co-Authors: Marieluise Kirchner, Dagmar Heuer, Thomas F MeyerAbstract:Neisseria gonorrhoeae is a gram-negative bacterial pathogen which infects the human mucosal epithelium. An early critical event in Neisserial infection is the type IV pilus-mediated adherence to the host cell. The PilC protein, located on the pilus tip, has earlier been identified as the major pilus adhesin. Previous studies suggested that the cell surface protein CD46 is a pilus receptor for Neisseria. We investigated the role of CD46 in pilus-mediated gonococcal infection of epithelial cells. Differences in binding efficiencies of piliated gonococci as well as purified pilus adhesin PilC2 on human epithelial cell lines did not correlate to the level of surface-expressed CD46. Additionally, no binding of piliated gonococci or PilC2 protein was observed on CD46-transfected CHO and MDCK cells. Furthermore, specific down-regulation of CD46 expression in human epithelial cell lines by RNA interference did not alter the binding efficiency of piliated gonococci or purified PilC2 protein, although other CD46-dependent processes, such as measles virus infection and C3b cleavage, were significantly reduced. These data support the notion that pilus-mediated gonococcal infection of epithelial cells can occur in a CD46-independent manner, thus questioning the function of CD46 as an essential pilus receptor for pathogenic Neisseriae.
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pathogenic Neisseria trigger expression of their carcinoembryonic antigen related cellular adhesion molecule 1 ceacam1 previously cd66a receptor on primary endothelial cells by activating the immediate early response transcription factor nuclear fact
Journal of Biological Chemistry, 2001Co-Authors: Petra Muenzner, Thomas F Meyer, Michael Naumann, Scott D GrayowenAbstract:Abstract Neisseria gonorrhoeae express opacity-associated (Opa) protein adhesins that mediate binding to various members of the carcinoembryonic antigen-related cellular adhesion molecule (CEACAM; previously CD66) receptor family. Although human umbilical vein endothelial cells express little CEACAM receptor in vitro, we found Neisserial infection to induce expression of CEACAM1, CEACAM1-3L, and CECAM1-4L splice variants. This mediates an increased Opa52-dependent binding of gonococci by these cells. The induced receptor expression did not require bacterial Opa expression, but it was more rapid with adherent bacteria. Because the time course of induction was similar to that seen for induced proinflammatory cytokines, we tested whether CEACAM1 expression could be controlled by a similar mechanism. Gonococcal infection activated a nuclear factor-κB (NF-κB) heterodimer consisting of p50 and p65, and inhibitors that prevent the nuclear translocation of activated NF-κB complex inhibited CEACAM1 transcript expression. Each of these effects could be mimicked by using culture filtrates or purified lipopolysaccharide instead of intact bacteria. Together, our results support a model whereby the outer membrane “blebs” that are actively released by gonococci trigger a Toll-like receptor-4-dependent activation of NF-κB, which up-regulates the expression of CEACAM1 to allow Opa52-mediated Neisserial binding. The regulation of CEACAM1 expression by NF-κB also implies a broader role for this receptor in the general inflammatory response to infection.
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Neisserial porin porb causes rapid calcium influx in target cells and induces apoptosis by the activation of cysteine proteases
The EMBO Journal, 1999Co-Authors: Anne Muller, Dirk Günther, Thomas F Meyer, Michael Naumann, Frank Dux, Thomas RudelAbstract:The porin (PorB) of Neisseria gonorrhoeae is an intriguing bacterial factor owing to its ability to translocate from the outer bacterial membrane into host cell membranes where it modulates the infection process. Here we report on the induction of programmed cell death after prolonged infection of epithelial cells with pathogenic Neisseria species. The underlying mechanism we propose includes translocation of the porin, a transient increase in cytosolic Ca2+ and subsequent activation of the Ca2+ dependent protease calpain as well as proteases of the caspase family. Blocking the porin channel by ATP eliminates the Ca2+ signal and also abolishes its pro-apoptotic function. The Neisserial porins share structural and functional homologies with the mitochondrial voltage-dependent anion channels (VDAC). The Neisserial porin may be an analogue or precursor of the ancient permeability transition pore, the putative central regulator of apoptosis.
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modulation of Neisseria porin porb by cytosolic atp gtp of target cells parallels between pathogen accommodation and mitochondrial endosymbiosis
Cell, 1996Co-Authors: Thomas Rudel, Roland Benz, Angela Schmid, Hans Albert Kolb, Florian Lang, Thomas F MeyerAbstract:PorB of the pathogenic Neisseria species belongs to the large family of pore-forming proteins (porins) produced by gram-negative bacteria. PorB is exceptional in that it is capable of translocating vectorially into membranes of infected target cells and functions in the infection process. Here we report on an unexpected similarity between Neisserial PorB and mitochondrial porins. Both porin classes interact with purine nucleoside triphosphates, which down-regulate pore size and cause a shift in voltage dependence and ion selectivity. Patch-clamp analyses indicate that PorB channel activity is tightly regulated in intact epithelial cells. In light of recent findings on the pivotal role of PorB in virulence and the prevention of phagosome lysosome fusion, these data provide important mechanistic clues on the intracellular pathogen accommodation reminiscent of mitochondrial endosymbiosis.
Lee M Wetzler - One of the best experts on this subject based on the ideXlab platform.
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innate immune function of the Neisserial porins and the relationship to vaccine adjuvant activity
Future Microbiology, 2010Co-Authors: Lee M WetzlerAbstract:Neisseria meningitidis is a Gram-negative pathogenic bacteria responsible for bacterial meningitis and septicemia. Porins are the most represented outer membrane proteins in the pathogenic Neisseria species, functioning as pores for the exchange of ions, and are characterized by a trimeric beta-barrel structure. Neisserial porins have been shown to act as adjuvants in the immune response via activation of B cells and other antigen-presenting cells. Their effect on the immune response is mediated by upregulation of the costimulatory molecule B7-2 (CD86) on the surface of antigen-presenting cells, an effect that is dependent on Toll-like receptor (TLR)2 and MyD88, through a cascade of signal transduction events mediated by direct binding of the porin to the TLR2-TLR1 heterodimer. This article summarizes work carried out investigating the mechanisms of the immune stimulating capacity of the Neisserial porins (specifically meningococcal PorB), emphasizing cellular events involved in antigen-presenting cell activation and induction of expression of cell surface molecules involved in the immune response.
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the porb porin from commensal Neisseria lactamica induces th1 and th2 immune responses to ovalbumin in mice and is a potential immune adjuvant
Vaccine, 2008Co-Authors: Xiuping Liu, Lee M Wetzler, Paola MassariAbstract:Porins from pathogenic Neisseriae are among several bacterial products with immune adjuvant activity. Neisseria meningitidis (Nme) PorB, has been shown to induce immune cells activation in a TLR2-dependent manner and acts as a vaccine immune adjuvant. The PorB porin from Neisseria lactamica (Nlac), a common nasopharyngeal commensal, shares significant structural and functional similarities with Nme PorB. In this work we ask whether the immune adjuvant ability of porins from pathogenic Neisserial strains is a characteristic shared with porins from non-pathogenic Neisserial species or whether it is unique for bacterial products derived from microorganisms capable of inducing inflammation and disease. We evaluated the potential immune adjuvant effect of Nlac PorB in mice using ovalbumin (OVA) as a prototype antigen. Immunization with Nlac PorB/OVA induced high OVA-specific IgG and IgM titers compared to OVA alone, similar to other adjuvants such as Nme PorB and alum. High titers of IgG1 and IgG2b were detected as well as production of IL-4, IL-10, IL-12 and INF-γ in response to Nlac PorB, consistent with induction of both a Th1-type and a Th2-type immune response. OVA-specific proliferation was also determined in splenocytes from Nlac PorB/OVA-immunized mice. In addition, B cell activation in vitro and cytokine production in response to Nlac PorB was found to be mediated by TLR2, in a similar manner to Nme PorB.
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The role of porins in Neisserial pathogenesis and immunity.
Trends in microbiology, 2003Co-Authors: Paola Massari, Sanjay Ram, Heather Macleod, Lee M WetzlerAbstract:Neisseria meningitidis and Neisseria gonorrhoeae are Gram-negative pathogenic bacteria responsible for bacterial meningitis and septicemia, and the sexually transmitted disease gonorrhea, respectively. Porins are the most represented outer membrane proteins in the pathogenic Neisseria species, functioning as pores for the exchange of ions, and are characterized by a trimeric beta-barrel structure. Neisserial porins have been shown to act as adjuvants in the immune response via activation of B cells and other antigen-presenting cells (APCs). Their effect on the immune response is mediated by upregulation of the costimulatory molecule B7-2 (CD86) on the surface of APCs, an effect that is Toll-like receptor 2- and MyD88-dependent. The effect of Neisserial porins on the immune system also involves interaction with components of the complement cascade. Furthermore, Neisserial porins co-localize with mitochondria of target cells, where they appear to modulate apoptosis.
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cutting edge immune stimulation by Neisserial porins is toll like receptor 2 and myd88 dependent
Journal of Immunology, 2002Co-Authors: Paola Massari, Philipp Henneke, Eicke Latz, Douglas T Golenbock, Lee M WetzlerAbstract:The immunopotentiating activity of Neisserial porins, the major outer membrane protein of the pathogenic Neisseria, is mediated by its ability to stimulate B cells and up-regulate the surface expression of B7-2. This ability is dependent on MyD88 and Toll-like receptor (TLR)2 expression, as demonstrated by a lack of a response by B cells from MyD88 or TLR2 knockout mice to the porins. Using previously described TLR2-dependent reporter constructs, these results were confirmed and were shown to be due to induction of NF-κB nuclear translocation. This is the first demonstration of known vaccine adjuvant to stimulate immune cells via TLR2.
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Neisseria meningitidis porin porb interacts with mitochondria and protects cells from apoptosis
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Paola Massari, Lee M WetzlerAbstract:Abstract Neisserial porins are strong immune adjuvants and B cell activators. The effect of Neisserial porin PorB on activation-induced cell death was investigated, as a potential additional mechanism of the porin's immunopotentiating ability. Neisserial porins interact with target cells to localize intracellularly in the mitochondrial compartment without negatively affecting cellular survival. Pretreatment with Neisseria meningitidis PorB porin decreased or abrogated the mitochondrial damage induced by apoptotic stimuli. In addition, end stage determinants of apoptosis, including DNA breakdown, were diminished by PorB. Immunoprecipitation experiments revealed that PorB interacts with the mitochondrial porin VDAC (voltage-dependent anion channel). The mechanism of the antiapoptotic effect of Neisserial porins could be explained by the protein–protein interaction of PorB with VDAC, similar to the interaction of VDAC with antiapoptotic Bcl-2 proteins, resulting in an enhancement of cell survival and continued activation of B cells.
Karen M Reddin - One of the best experts on this subject based on the ideXlab platform.
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Neisserial outer membrane vesicles bind the coinhibitory receptor carcinoembryonic antigen related cellular adhesion molecule 1 and suppress cd4 t lymphocyte function
Infection and Immunity, 2007Co-Authors: Ian C Boulton, Henry K Wong, Ofer Mandelboim, Denise Halliwell, Andrew Gorringe, Karen M Reddin, Scott D GrayowenAbstract:Pathogenic Neisseria bacteria naturally liberate outer membrane “blebs,” which are presumed to contribute to pathology, and the detergent-extracted outer membrane vesicles (OMVs) from Neisseria meningitidis are currently employed as meningococcal vaccines in humans. While the composition of these vesicles reflects the bacteria from which they are derived, the functions of many of their constituent proteins remain unexplored. The Neisserial colony opacity-associated Opa proteins function as adhesins, the majority of which mediate bacterial attachment to human carcinoembryonic antigen-related cellular adhesion molecules (CEACAMs). Herein, we demonstrate that the Opa proteins within OMV preparations retain the capacity to bind the immunoreceptor tyrosine-based inhibitory motif-containing coinhibitory receptor CEACAM1. When CD4+ T lymphocytes were exposed to OMVs from Opa-expressing bacteria, their activation and proliferation in response to a variety of stimuli were effectively halted. This potent immunosuppressive effect suggests that localized infection will generate a “zone of inhibition” resulting from the diffusion of membrane blebs into the surrounding tissues. Moreover, it demonstrates that OMV-based vaccines must be developed from strains that lack CEACAM1-binding Opa variants.
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expression of heterologous antigens in commensal Neisseria spp preservation of conformational epitopes with vaccine potential
Infection and Immunity, 2004Co-Authors: Cliona A Odwyer, Andrew Gorringe, Karen M Reddin, Paul R Langford, Denis Martin, Stephen Taylor, Michael J Hudson, Bernard R Brodeur, Simon J KrollAbstract:Commensal Neisseriae share with Neisseria meningitidis (meningococcus) a tendency towards overproduction of the bacterial outer envelope, leading to the formation and release during growth of outer membrane vesicles (OMVs). OMVs from both meningococci and commensal Neisseriae have shown promise as vaccines to protect against meningococcal disease. We report here the successful expression at high levels of heterologous proteins in commensal Neisseriae and the display, in its native conformation, of one meningococcal outer membrane protein vaccine candidate, NspA, in OMVs prepared from such a recombinant Neisseria flavescens strain. These NspA-containing OMVs conferred protection against otherwise lethal intraperitoneal challenge of mice with N. meningitidis serogroup B, and sera raised against them mediated opsonophagocytosis of meningococcal strains expressing this antigen. This development promises to facilitate the design of novel vaccines containing membrane protein antigens that are otherwise difficult to present in native conformation that provide cross-protective efficacy in the prevention of meningococcal disease.
