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Johansson, Linda. "Host responses and bacterial virulence factors in Neisseria infections /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-017-6/.
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Leyral, Jérôme. "Endocardites à Neisseria Mucosa à propos d'un cas : revue de la littérature." Bordeaux 2, 1997. http://www.theses.fr/1997BOR2M060.
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Levy, Michael. "Impact de la corticothérapie dans les infections invasives à Neisseria meningitidis." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC323.
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L’évolution fatale des infections invasives à méningocoque (IIM) est souvent associée à une réaction inflammatoire systémique exacerbée déclenchée par des souches de Neisseria meningitidis (Nm) hyper-virulente. L’ajout de glucocorticoïdes, puissants anti-inflammatoires, à l’antibiothérapie adaptée pourrait dans ce cas améliorer le pronostic des patients bien que cela reste difficile à évaluer dans les études cliniques. L’objectif de notre travail était d’évaluer l’impact de ce traitement sur l’infection expérimentale par une souche hyper-invasive de Nm de complexe clonal ST-11 dans le modèle de souris transgénique exprimant la transferrine humaine. Dans notre modèle expérimental, l’infection par voie intrapéritonéale des souris transgéniques avec la souche hyper-invasive Nm C LNP24198 de complexe clonal ST-11 était effectivement associée à une réponse inflammatoire intense et provoquait une atteinte multi-organes avec dissémination des bactéries au niveau méningé, cardiaque, hépatique, splénique et rénal.Les traitements par amoxicilline ou amoxicilline et dexaméthasone à partir de trois heures d’infection puis toutes les six heures pendant 48 heures, ont permis une amélioration clinique et biologique nette en comparaison aux souris traitées par sérum physiologique. Une amélioration clinique nette était notée chez les souris traitées par l’association amoxicilline et dexaméthasone au niveau de la survie et de l’état général par rapport au souris traitées par amoxicilline seule. De plus, on notait une diminution significative de la réaction inflammatoire évaluée par le taux de CRP et de Lipocaline 2 ainsi qu’une augmentation précoce et significative du taux sanguin d’IL-10 après six heures d’infection. Il y avait également une tendance à une diminution de la charge bactérienne évaluée par hémoculture et bioluminescence in-vivo.En réalisant une analyse transcriptomique approfondie, l’adjonction de dexaméthasone à l’amoxicilline a entrainé des différences significatives dans l’expression de gènes et ce, particulièrement concernant les voies de signalisation des monocytes-macrophages. La déplétion des monocytes-macrophages par anticorps monoclonal anti-CSF1R chez des souris infectées par la souche de Nm C LNP24198 a par la suite montré que les souris déplétées (que ce soit au préalable de l’infection ou pendant l’infection) présentaient des infections plus sévères avec sécrétion exacerbée de cytokines pro et anti-inflammatoires. En accord avec ces résultats, les enfants hospitalisés pour IIM sévères de type Purpura fulminans avaient des taux significativement plus bas de monocytes à l’admission.En conclusion, nos travaux suggèrent que les corticoïdes pourraient avoir un effet bénéfique dans les IIM et ce, en modulant la réponse inflammatoire avec notamment une régulation des monocytes-macrophages en favorisant un phénotype de type anti-inflammatoire (M2) plutôt qu’un phénotype pro-inflammatoire (M1)The fatal course of invasive meningococcal disease (IMD) is often associated with an exacerbated systemic inflammatory response triggered by hyper virulent strains of Neisseria meningitidis (Nm). In view of this, the addition of glucocorticoids, strong anti-inflammatory drugs, to the appropriate antibiotherapy could improve the prognosis of patients but remains difficult to evaluate in clinical studies.The objective of our work was to evaluate the impact of this treatment on experimental infection by a hyper-invasive strain of Nm that belongs to the ST-11 clonal complex in transgenic mice expressing human transferrin.In our experimental model, the intraperitoneal infection of transgenic mice with the hyper-invasive strain Nm C LNP24198 belonging to the ST-11 clonal complex was indeed associated with an intense inflammatory response and caused multi-organ invasion with bacteria spreading to the meninges, the heart, the liver, the spleen and the kidneys.Treatments with amoxicillin or amoxicillin and dexamethasone from three hours of infection and then every six hours for 48 hours, allowed a clear clinical and biological improvement compared to mice treated with physiological saline. A clear clinical improvement (better survival and general condition) was noted in mice treated with amoxicillin and dexamethasone compared to mice treated with amoxicillin alone. In addition, there was a significant decrease in the inflammatory response evaluated by CRP and Lipocalin 2 levels as well as an early and significant increase in the blood level of IL-10 after six hours of infection. There was also a decreasing trend in the bacterial load assessed by blood cultures and in-vivo bioluminescence.By performing a thorough transcriptomic analysis, the addition of dexamethasone to amoxicillin resulted in significant differences in gene expression, particularly regarding the monocyte-macrophage signaling pathways.Monocyte-macrophage depletion using monoclonal antibody anti-CSF1R in mice infected with the strain Nm C LNP24198 subsequently showed that depleted mice (whether prior to infection or during infection) had more severe infections with exacerbated secretion of pro and anti-inflammatory cytokines. In accordance with these results, children hospitalized for severe IMD with purpura fulminans had significantly lower rates of monocytes on admission compared with children with meningitis.In conclusion, our work suggests that corticosteroids may have a beneficial effect on IMD by modulating the inflammatory response, including the regulation of monocytes-macrophages by favoring an anti-inflammatory (M2) phenotype rather than a pro-inflammatory phenotype (M1)
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Rytkönen, Anne. "Molecular studies of Neisseria - host cell interactions /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-018-4/.
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Makepeace, Benjamin Lawrence. "The aetiology and cell biology of inflammation in sexually transmitted bacterial infections." Thesis, University of Southampton, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.327260.
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Quinternet, Marc Cung Manh Thông. "Analyse structurale et dynamique par RMN des domaines N-terminaux des protéines DsbD et PilB de Neisseria meningitidis et de leur interaction." S. l. : S. n, 2008. http://www.scd.inpl-nancy.fr/theses/2008_QUINTERNET_M.pdf.
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PENARD, MARIE-CHRISTINE. "Prevention des infections a neisseria meningitidis et haemophilus influenzae : connaissances actuelles sur les vaccins polysaccharidiques." Nantes, 1989. http://www.theses.fr/1989NANT151M.
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Bergman, Peter. "Antimicrobial peptides and pathogenic Neisseria : experimental studies in mouse, man and rat /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-428-7/.
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Folger, Alonzo T. V. "Maternal Chlamydia trachomatis and Neisseria gonorrhoeae Infections and the Outcome of Preterm Birth: The Impact of Early Detection." University of Cincinnati / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1353098416.
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Maurakis, Stavros. "Characterization of the Novel Interaction Between Neisseria gonorrhoeae TdfJ and its Human Ligand S100A7." VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/5710.
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Neisseria gonorrhoeae is an obligate human pathogen that causes the common STI gonorrhea, which presents a growing threat to global health. The WHO estimated 78 million new cases of gonorrhea worldwide in 2017, with estimates of 820,000 new cases in the United States alone according to the CDC. High-frequency phase and antigenic variation inherent in N. gonorrhoeae, coupled with its natural ability to rapidly acquire and stably integrate antimicrobial resistance factors into its genome, have culminated in an infection against which there is no effective vaccine, and for which the list of viable therapeutic options is quickly shrinking. Moreover, no protective immunity against subsequent infections is elicited upon exposure to N. gonorrhoeae, which highlights the need for research of novel antimicrobial and vaccination strategies. Within the human host, N. gonorrhoeae utilizes a unique strategy to overcome host sequestration of essential nutrients – termed nutritional immunity (NI) – such as ions of trace metals. The pathogen produces a family of outer membrane proteins called TonB-dependent transporters (TdTs) capable of binding to host NI factors and stripping them of their nutritional cargo for use by the pathogen. Importantly, these TdTs are very highly conserved and expressed among Neisseria species. TbpA is a well-characterized TdT that allows N. gonorrhoeae to acquire iron from human transferrin, and recent studies from our lab have shown that TdfH is capable of binding to a zinc-sequestering S100 protein called calprotectin and stripping it of its zinc ion. The S100 proteins are EF-hand calcium-binding proteins that naturally play an integral role in Ca2+ homeostasis, but due to their ability to bind transition metals, they have also demonstrated an innate immunity role by participating in nutrient sequestration.
The S100 proteins are expressed in all human cells, and all are capable of binding transition metals including zinc, manganese, and cobalt. Calprotectin, S100A7, and S100A12 have demonstrated an ability to hinder the infection potential of pathogenic E. coli, S. aureus, C. albicans, and various other pathogens via zinc sequestration. Herein, we demonstrate that N. gonorrhoeae is able to overcome this phenomenon and actually utilize these proteins as a zinc source in vitro. Furthermore, we identify S100A7 as the specific ligand for TdfJ, which utilizes this ligand to internalize zinc during infection. S100A7 growth support in vitro is dependent upon a functional TonB, TdfJ, and the cognate ABC transport system ZnuABC, and isogenic mutants incapable of producing znuA or tdfJ recover S100A7 utilization by complementation. Whole-cell binding assays and affinity pulldowns show that S100A7 binds specifically to both gonococcal and recombinant TdfJ, and growth and binding experiments show that these described phenomena are specific to human and not mouse S100A7. Finally, we show that a His-Asn double mutant S100A7 that is incapable of binding zinc cannot be utilized for growth by gonococci. These data illustrate the unique nature of the gonococcus’ ability to co-opt host defense strategies for its own purposes, and further identify the TdTs as promising targets for strategies to combat and prevent gonococcal infection.
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Henson, Camille Jeanette. "Risk Factors Contributing to Transmission Rates of Chlamydia trachomatis and Neisseria gonorrhoeae Among Women in Veron, Dominican Republic." Diss., Virginia Tech, 2011. http://hdl.handle.net/10919/26241.
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Background
Selected factors place Dominican female adolescent and adults at risk for sexually transmitted infections (STIs) such as Chlamydia, causative organism Chlamydia trachomatis, and Gonorrhea, causative organism Neisseria gonorrhoeae. The purpose of this study was to determine the prevalence of Chlamydia and Gonorrhea among adolescent and adult females that utilize the clinic in Veron, Dominican Republic. Clinical standards of care for these STIs and educational programs for prevention were developed from the data gathered from this study. Significance at 0.05 ά of the relationship of educational level, management of risk factors and other selected independent variables on prevalence rate of Chlamydia and Gonorrhea in the clinic population of Veron, Dominican Republic were determined. The objectives of the study were to 1) determine the prevalence of adolescent and young adult females diagnosed with Gonorrhea and Chlamydia who visit the clinic for prenatal visits, annual pap smear exams and gynecological complaints; 2) determine the extent to which educational level is a predictor of positive diagnosis or risk for infection of Chlamydia and Gonorrhea and; 3) determine which selected demographic and risk factors are associated with positive test results for Gonorrhea and Chlamydia.
Methods
All adolescent and adult females ages 15 years and older visiting the clinic in Veron for prenatal exams, pap smear exams and gynecological complaints between January 28, 2008 â March 3, 2008 were invited to participate in this prevalence study. Of the 90 invited, the accepting sample was 90 who signed an informed consent form. Prior to STI testing each patient completed a verbal interview and questionnaire on sociodemographic characteristics as well as knowledge, attitudes, and beliefs related to Chlamydia and gonorrhea, sexual experiences and behaviors and illicit drugs use. Specimens collected from the endocervical canal of each female were tested and results provided within two hours, followed by immediate treatment by a licensed Dominican physician and follow-up care based on the guidelines and standards of care. The data were analyzed using descriptive statistics, chi square, t-test and logistic regression.
Results
A total of ninety women participated in the study. Chlamydia was detected in 6.7% of the patient population and Gonorrhea was detected in 22.2% of the patient population. Co-infection of both Chlamydia and Gonorrhea was present in 2 cases. Among the positive Chlamydia tests results, 50% had less than a six-year education and 50% had more then six years of education. In addition, 83.3% of the patients with positive Chlamydia results answered â yesâ , they could read and 16.6% stated they could not read, while 83.3% of the patients with positive Chlamydia results stated they could write and 16.6% stated they could not write (P>0.05). Among the patients that tested positive for Gonorrhea, 55% stated they had less than six years of formal education and 45% had more than six years of formal education (P>0.05). There were 75% of the patients that tested positive for Gonorrhea that stated they could read and 25% who stated they could not read (P>0.05); while 85% of the patients with positive Gonorrhea results stated they could write and 15% stated they could not write (P> 0.05).
Conclusion
Educational level and other selected demographic characteristics and risk factors in this study are not a significant predictor of positive diagnosis or risk of infection for Chlamydia or Gonorrhea. We cannot conclude that specific risk factors are associated with positive test results for Gonorrhea and Chlamydia. For the physicians involved in the clinical decision-making regarding the female patients at the Veron clinic, more data are needed to determine appropriate populations for screening of Gonorrhea and Chlamydia as well as appropriate educational tools on sexually transmitted infections.Ph. D.
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Gbenafa-Agossa, Clémence. "Prévalence et facteurs de risque des infections génitales à Neisseria gonorrhoeae et Chlamydia trachomatis chez les travailleuses de sexe au Bénin en 2003-2004 et évaluation d'un test rapide dans le dépistage de la gonococcie génitale." Master's thesis, Université Laval, 2006. http://hdl.handle.net/20.500.11794/18455.
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Yau, Chong-yee Miranda. "Comparison of two automated DNA amplification systems with culture for detection of Chlamydia trachomatis and Neisseria gonorrhoeae infections in symptomatic men." Hong Kong : University of Hong Kong, 2000. http://sunzi.lib.hku.hk/hkuto/record.jsp?B23829709.
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Romefort, Bénédicte Gras-Le Guen Christèle. "L'impact du délai pré-thérapeutique sur la mortalité et la morbidité des méningites bactériennes de l'enfant étude rétrospective à Nantes de 1997 à 2005 /." [S.l.] : [s.n.], 2007. http://castore.univ-nantes.fr/castore/GetOAIRef?idDoc=16461.
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Soyer, Magali. "Mécanismes moléculaires de la colonisation de l’endothélium par Neisseria meningitidis." Thesis, Paris 5, 2012. http://www.theses.fr/2012PA05T080.
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Les infections bactériennes touchant la circulation sanguine conduisent à un vaste éventail de graves pathologies, comme les chocs septiques ou les infections locales (endocardites et méningites). Neisseria meningitidis colonise avec succès l’endothélium vasculaire et cause des sepsis sévères. Ces infections résultent de la colonisation des cellules endothéliales de l’hôte, étape clef de la pathophysiologie à laquelle les travaux présentés dans ce manuscrit se sont intéressés. La colonisation de l’endothélium par N. meningitidis est un processus complexe qui implique l’adhésion et la multiplication des bactéries à la surface des cellules endothéliales dans le contexte particulier de la circulation sanguine, où des forces mécaniques sont générées par le flux sanguin sur les objets circulants. Bien que de nombreuses études se soient intéressées à l’interaction entre les cellules endothéliales et N. meningitidis, plusieurs aspects demeurent incertains comme par exemple l’impact des contraintes générées par le flux sanguin et la participation relative des deux partenaires de l’interaction dans la colonisation de l’endothélium par N. meningitidis.L’adhésion de la bactérie à la surface des cellules endothéliales est dépendante de facteurs bactériens (les pili de type IV, PT4) et induit une réponse de la part de la cellule hôte, qui se traduit par un remodelage de la membrane plasmique et une réorganisation du cytosquelette d’actine sous les microcolonies. Dans un premier temps, ces travaux de thèse montrent que la réponse cellulaire induite par N. meningitidis participe activement à la colonisation. En effet, la formation de projections membranaires permet à chaque bactérie de la microcolonie d’établir des contacts avec la cellule hôte, nécessaires à la résistance des microcolonies face aux forces mécaniques générées par le flux sanguin. De plus, nous montrons que la protéine PilV, composant des PT4, est impliquée dans le remaniement de la membrane plasmique et la réorganisation du cytosquelette. Nous avons développé une méthode combinant vidéo-microscopie et analyse de fluorescence pour décrypter les événements précoces prenant place lors du contact entre les bactéries et la surface des cellules hôtes. Nous avons alors montré que le remodelage de la membrane induit par N. meningitidis ne dépend pas de la réorganisation du cytosquelette d’actine au site d’infection mais plutôt des propriétés intrinsèques de la bicouche lipidique.Dans un second temps, nous nous sommes intéressés aux étapes tardives de l’infection, c'est-à-dire à l’initiation d’un nouveau cycle de colonisation. Bien que solidement ancrées à la surface des cellules par l’intermédiaire des projections membranaires, quelques bactéries se détachent des microcolonies pour coloniser des nouveaux sites au sein de l’hôte. Nous avons démontré l’importance de modifications post-traductionnelles de la piline majeure dans cette étape de l’infection et caractérisé les mécanismes impliqués.Cette étude a permis d’affiner les mécanismes impliqués dans l’induction de la réponse cellulaire induite par N. meningitidis et son impact sur la colonisation efficace de l’endothélium par ce pathogèneBacterial infections targeting the bloodstream lead to a wide array of severe clinical manifestations, such as septic shock or focal infections (endocarditis and meningitis). Neisseria meningitidis colonizes successfully the vascular wall and causes severe sepsis. Such infections result from an efficient colonization of host endothelial cells, a key step in meningococcal diseases which has been the subject of the work presented here. Endothelium colonization by N. meningitidis is a complex process implying bacterial adhesion and multiplication on the endothelial cell surface in the specific context of the bloodstream, where mechanical forces generated by the blood flow are applied on circulating bacteria. Even though many studies focused on the interaction between N. meningitidis and the endothelial cell, many aspects remain elusive, such as the impact of shear stress generated drag forces and the relative contribution of the two partners involved in this interaction.Adhesion to the endothelial cell surface is dependent on bacterial factors called type IV pili (Tfp) and leads to induction of a host cell response, characterized by a local remodeling of the plasma membrane and reorganization of actin cytoskeleton underneath bacterial microcolonies. First, we have shown that the cellular response induced by N. meningitidis actively participate in the colonization process. Indeed, membrane deformation allows contact with every bacterium inside the microcolony, which is necessary for microcolony resistance to mechanical forces. Additionally, we have demonstrated that the PilV protein, a Tfp component, is involved in plasma membrane remodeling and actin cytoskeleton reorganization. We designed a method combining high resolution live-cell fluorescence video-microscopy and fluorescence quantification to decipher the early events induced on contact of bacterial aggregates with the host cell surface. Using this technique we have shown that membrane remodeling does not rely on actin cytoskeleton reorganization but rather on intrinsic properties of the lipid bilayer. Second, we focused on latter steps of the infection process when initiation of a new colonization cycle is initiated. While firmly attached to the host cell surface through the membranous projections, some bacteria can detach from the microcolony to disseminate throughout the host. We have demonstrated the importance of post-translational modification of the major piline in this step and characterized the underlying mechanisms.This work allows refinement of the molecular mechanisms involved in the induction of the cellular response induced by N. meningitidis and its impact on successful endothelium colonization by this pathogen
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Cisse, Daouda. "Surveillance de seconde génération du VIH chez les travailleuses du sexe et leurs partenaires sexuels masculins au Sénégal : étude dans deux zones d'intervention du Projet SIDA 3." Thesis, Université Laval, 2006. http://www.theses.ulaval.ca/2006/23649/23649.pdf.
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Leteurtre, Stéphane. "Etat de gravité des enfants en réponse à l'agression : évaluation des scores de gravité existants et élaboration d'un score de dysfonctions d'organes." Lille 2, 2005. http://www.theses.fr/2005LIL2S006.
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Le premier objectif était de comparer les scores de gravité généraux aux scores spécifiques de l'infection méningoccocique. Le second objectif était d'élaborer un score de dysfonctions d'organes (DO) pédiatrique, un tel score n'existant pas. METHODES. Deux études prospectives monocentriques ont permis de comparer les scores de gravité généraux aux scores spécifiques de l'infection méningoccocique. Deux études prospectives multicentriques internationales ont permis de développer et valider un score de DO. RESULTATS. Le score de gravité général PRISM était aussi performant que les scores spécifiques. Deux scores de DO (scores PEMOD et PELOD) ont été développés avec deux stratégies statistiques différentes. Le score PELOD, plus discriminant, a ensuite été validé. CONCLUSION. Les scores de gravité généraux peuvent être utilisés sur des populations d'enfants présentant une infection méningoccocique sévère. Le score PELOD est le premier score de DO disponible en réanimation pédiatriqueThe first aim was to compare generic and specific scoring systems in children with meningococcal septic shock. The second was to develop and validate a paediatric organ dysfunction (OD) score, since such a score was not yet available for critically ill children. METHODS. Two prospective studies were performed to compare generic and specific scores during meningococcal septic shock. Two prospective, observational, multicentre studies were performed to develop and validate a paediatric OD score. RESULTS. The generic PRISM score was not surpassed by specific scores. Two paediatric OD scores (PEMOD and PELOD scores) were developed with two statistical methods. The PELOD score, which was more discriminant, was then validated. CONCLUSION. Generic scoring systems can be used for outcome prediction in children with meningococcal septic shock. The PELOD score is the first OD score available in paediatric intensive care unit
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Leon, Segundo R., Eddy R. Segura, Kelika A. Konda, Juan A. Flores, Alfonso Silva-Santisteban, Jerome T. Galea, Thomas J. Coates, Jeffrey D. Klausner, and Carlos F. Caceres. "High prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae infections in anal and pharyngeal sites among a community-based sample of men who have sex with men and transgender women in Lima, Peru." BMJ Publishing Group Ltd, 2016. http://hdl.handle.net/10757/595419.
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This study aimed to characterise the epidemiology of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections among men who have sex with men (MSM) and transgender women (TW) in Lima, Peru.
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Gbenafa, Agossa Clémence. "Prévalence et facteurs de risque des infections génitales à Neisseria Gonorrhoeae et Chlamydia Trachomatis chez les travailleuses du sexe au Bénin en 2003-2004 et évaluation d'un test rapide dans le dépistage de la gonococcie génitale." Thesis, Université Laval, 2006. http://www.theses.ulaval.ca/2006/23891/23891.pdf.
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Zhang, Qian. "The role of exopolyphosphatase in Neisseria meningitidis infection." Thesis, Imperial College London, 2009. http://hdl.handle.net/10044/1/4340.
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The development of vaccines against serogroup B Neisseria meningitidis to reduce the morbidity and mortality of meningococcal disease is a major public health priority. We developed a novel genetic screen for immunogens present on the bacterial surface using human immune sera with bactericidal activity. We found that two mutants lacking nmb1467 survived in high concentrations of sera from two patients, while the wild-type strain was killed. Biochemical assays using purified recombinant NMB1467 indicated that nmb1467 encodes an exopolyphosphatase (PPX) with the ability to hydrolyse inorganic polyphosphate (poly P). In addition, we demonstrated that the Δppx mutant has at least 2-fold more poly P than the wild-type strain. Therefore, we designated NMB1467 as PPX. We showed that N. meningitidis mutant lacking the ppx had an increased resistance against normal human complement system. Substitution of the glutamic acid at residue 147 of PPX with an alanine significantly reduced the enzymatic activity in vitro, and contributed to increased level of poly P in N. meningitidis and the resistance of bacteria against the complement-mediated killing. Levels of polysaccharide capsule and lipopolysaccharide (LPS) sialylation, two important virulence factors, were not affected by the loss of ppx in N. meningitidis. Using flow cytometry, we demonstrated that binding of factor H (fH), the negative regulator of the alternative pathway of complement activation, to the bacterial surface was increased in the strain lacking PPX. By Western blot analysis, we did not detect a significant change in the expression of the fH receptor, indicting another mechanism is involved in the fH binding to the bacterial surface and resistance of bacteria against complement-mediated killing.
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Dutta, Ray Tathagat. "Novel Complement Blocking Antibodies Against Serogroup B N. meningitidis: A Dissertation." eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/495.
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N. meningitidis is a common commensal of the human upper respiratory tract and a leading cause of bacterial meningitis and septicemia worldwide. The classical pathway of complement (C) is essential for both naturally acquired and vaccine induced immunity against N. meningitidis. Qualitative and/or quantitative differences in anti-meningococcal antibodies (Abs) in serum is one reason for variations in C-dependent bactericidal Ab activity among individuals. I showed that IgG isolated from select individuals could block killing of group B meningococci by Abs that were otherwise bactericidal. Ligand overlay immunoblots revealed that these blocking IgG Abs were directed against a meningococcal antigen called H.8, Killing of meningococci in reactions containing bactericidal mAbs and human blocking Abs was restored when blocking Ab binding to meningococci was inhibited (or competed for) using either synthetic peptides corresponding to H.8 or a non-blocking mAb against H.8. Further, genetic deletion of H.8 from target organisms abrogated blocking. The Fc region of the blocking IgG was required for blocking because F(ab)2 fragments alone generated by pepsin treatment were ineffective. Blocking required IgG glycosylation; deglycosylation of blocking IgG with peptide:N-glycanase (PNGase) eliminated blocking. C4 deposition mediated by a bactericidal mAb directed against a meningococcal vaccine candidate, called factor H-binding protein (fHbp), was reduced by blocking Ab. Anti-fHbp-mediated C4 deposition was unaffected, however, by deglycosylated blocking IgG. Although preliminary, our data suggests blocking of serum bactericidal activity by human anti-H.8 blocking antibody may require mannan-binding lectin (MBL), which itself is a complement activator. Also, whether MBL recruits a complement inhibitor(s) that facilitates blocking remains to be determined. In conclusion, we have identified H.8 as a meningococcal target for novel blocking antibodies that are commonly found in human serum. Blocking Ab may reduce the efficacy of meningococcal vaccines. We propose that outer membrane vesicle-containing meningococcal vaccines may be more efficacious if purged of subversive immunogens such as H.8.
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Pollard, Andrews John. "Age-related changes in immunity to Neisseria meningitidis." Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.314059.
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Chamberlain, Lisa M. "Pathogenesis and immunity in experimental infection with Neisseria gonorrhoeae." Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320009.
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Qvarnström, Yvonne. "Sulphonamide Resistance in Neisseria meningitidis and Commensal Neisseria Species." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3750.
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Extensive use of the sulphonamide drugs against the bacterium Neisseria meningitidis has resulted in drug resistance development. Sulphonamide resistance in N. meningitidis is caused by alterations in the chromosomal folP gene, coding for DHPS (dihydropteroate synthase). One type of resistant DHPS has high sequence divergence compared to DHPS from susceptible strains. This divergent DHPS has a duplication of two amino acids, crucial for resistance, and an altered amino acid in position 68, important for both resistance and substrate binding. When introduced into a susceptible DHPS, these two alterations did not incur resistance and resulted in abnormal substrate binding properties. This indicated that the divergent DHPS was not directly developed by mutations, but rather had been acquired by horizontal transfer of folP from another species. Commensal Neisseria species are implied as the origin of the horizontally transferred resistance. Sulphonamide-resistant commensal Neisseria isolates were detected in throat swabs from healthy individuals not exposed to these drugs; however, transformation of resistance from these commensals to N. meningitidis was restricted in the laboratory. A comparison of the genomic region surrounding folP revealed differences in gene organisation and in the DNA uptake sequence between N. meningitidis and distantly related commensals. These differences are likely to restrict transformation between distantly related Neisseria species. DHPS participates in the folate biosynthesis pathway. The enzyme preceding DHPS in the pathway, HPPK (hydroxymethyl-dihydropterin pyrophosphokinase), from N. meningitidis was characterised and a method for studying substrate channelling from HPPK to DHPS was developed. The information gained could be exploited in the search for new antibiotics. In conclusion, well-adapted sulphonamide-resistant strains of N. meningitidis and commensal Neisseria are established in the bacterial population and resistance can be horizontally spread by natural transformation. This may explain the abundance of sulphonamide-resistant N. meningitidis, although these drugs are no longer used against this bacterium.
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Page, K. "The modulatory effects of commensal neisseriae on upper respiratory tract infections." Thesis, University of the West of England, Bristol, 2014. http://eprints.uwe.ac.uk/22932/.
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The human nasopharynx is a reservoir of both commensal and pathogenic bacteria that can be easily transmitted from one individual to another. It has long been hypothesised that host commensal flora give protection from carriage of pathogens and invasive disease. The commensal Neisseria lactamica has previously been associated with protection against the closely related human pathogen Neisseria meningitidis, which is thought to be due to the acquisition of cross-reactive immunity to N. meningitidis. The objective of this study was to identify the extent of protection by N. lactamica in the absence of host immune cells, using an in vitro model of the human nasopharyngeal epithelium with the Detroit 562 (D562) cell line. N. lactamica has been demonstrated to attenuate the induction of innate inflammatory cytokines and chemokines from D562 cells challenged with N. meningitidis. For the first time in this study, N. lactamica was found to attenuate the induction of IL6, IL8 and TNFα from D562 cells challenged with the unrelated Gram-positive human pathogen Streptococcus pneumoniae. Attenuation by N. lactamica did not extend to suppression of MAPK pathways when stimulated with chemical agonists, but was able to suppress inflammation induced through the intracellular PAMP receptor TLR3, which is not involved in meningococcal or pneumococcal inflammation. This suggests a global mechanism of attenuation in host cells by N. lactamica. N. lactamica was further demonstrated to reduce association with and invasion of D562 epithelial cells by N. meningitidis serogroup B (MenB) by up to 60% and 90%, respectively. This suppression was dependent on live N. lactamica and did not require invasion of host cells by the commensal, suggesting an active mechanism employed by N. lactamica. The occasional human commensal coloniser Neisseria polysaccharea was found to reduce adhesion and invasion of MenB to a similar degree, however the related commensal Neisseria cinerea was not. The reduction in MenB association with host cells protected host cells from MenB-induced apoptosis, which was mediated by activation of caspase 3. This study demonstrates that commensal Neisseria spp. N. lactamica and N. polysaccharea protect the host at the nasopharyngeal epithelium from experimental colonisation and invasive disease by MenB. Additionally, commensal neisseriae protect against inflammation and cell death induced by the unrelated pathogen S. pneumoniae. Therefore, commensal neisseriae warrant further study to evaluate their effectiveness for use as probiotics to protect against bacterial pathogens responsible for meningitis.
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Tamarelle, Jeanne. "Composition et dynamique du microbiote vaginal : facteurs associés et rôle dans l’infection par Chlamydia trachomatis The vaginal microbiota and its association with human papillomavirus, Chlamydia trachomatis, Neisseria gonorrhoeae and Mycoplasma genitalium infections: a systematic review and meta-analysis Vaginal microbiota composition and association with prevalent Chlamydia trachomatis infection: a cross- sectional study of young women attending a STI clinic in France Nonoptimal Vaginal Microbiota After Azithromycin Treatment for Chlamydia trachomatis Infection." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLV097.
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Chlamydia trachomatis (CT) est une bactérie sexuellement transmissible responsable d’infections génitales hautes pouvant conduire à une infertilité tubaire ou à des grossesses extra-utérines. C’est l’infection sexuellement transmissible la plus fréquente dans le monde, y compris en France. Les données épidémiologiques indiquent que l’incidence de cette infection est en augmentation malgré les mesures de contrôle mises en place, ce qui motive la révision des recommandations actuelles de dépistage de l’infection à CT. Le microbiote vaginal pourrait jouer un rôle majeur dans la prévention des IST via la compétition écologique et la production de métabolites, dont l’acide lactique. Le microbiote vaginal correspond à un équilibre dynamique fragile et susceptible d’être modifié par un ensemble d’expositions, parmi lesquelles les pratiques sexuelles et d’hygiène intime, l’exposition aux antibiotiques mais aussi la présence de pathogènes. L’objectif général de cette thèse est d’étudier ce triangle d’associations entre expositions, microbiote vaginal et infection par CT, à travers l’étude de la composition et de la dynamique du microbiote vaginal. Nous avons cherché à répondre aux questions suivantes : existe-t-il des marqueurs de l’infection par CT au niveau du microbiote vaginal ? La composition et la structure du microbiote vaginal sont-elles modifiées par l’infection par CT et la prise d’antibiotiques ? Quels sont les expositions associées à des perturbations du microbiote vaginal ? Une première étape a consisté à réaliser un état de l’art et d'estimer l’association entre microbiote vaginal et infection par CT dans la littérature, ainsi que pour trois autres IST d’importance clinique, et à évaluer le rôle de plusieurs facteurs dans l’hétérogénéité des mesures d’association observées. Dans un second temps, nous avons estimé cette association en s'appuyant sur la caractérisation moléculaire du microbiote vaginal, dans deux études en France et aux Etats-Unis. Nous avons montré qu’il y avait une surreprésentation des communautés bactériennes dominées par Lactobacillus iners (CST III) et de celles dépourvues de Lactobacillus spp. (CST IV) chez les femmes infectées par CT. En étudiant l’évolution du microbiote vaginal dans l’étude américaine, après traitement par azithromycine et clairance de CT, nous avons montré que le microbiote vaginal ne parvenait pas à évoluer vers un état optimal. Ce résultat laisse supposer qu’il persiste après traitement un risque vis-à-vis des réinfections. Enfin, dans deux études longitudinales à échantillonnage fréquent aux Etats-Unis, nous avons étudié les expositions associées à l’incidence et à la clairance d’un CST IV. Nous avons montré que lorsque le microbiote vaginal n’était pas dominé par L. iners, les facteurs associés à l’incidence d’un CST IV et à sa clairance étaient essentiellement les menstruations, tandis que chez les femmes dont le microbiote vaginal est dominé par L. iners, les menstruations mais aussi l’usage de lubrifiant, les douches vaginales, l’origine ethnique, l’âge et les rapports sexuels non protégés étaient associés à l’incidence d’un CST IV ou à sa clairance. Ainsi, ce travail de thèse a permis d'une part de confirmer l’association entre microbiote vaginal dépourvu de Lactobacillus et infection par CT en population en s'appuyant sur le séquençage génomique, et d'autre part de distinguer l’espèce L. iners des autres espèces de Lactobacillus et d’évaluer le risque associé au CST III. En permettant une meilleure compréhension de l’histoire naturelle de CT et des dynamiques du microbiote vaginal, nous espérons proposer des pistes pour améliorer les stratégies de contrôle de l’infection par CT et d’autres IST. Le potentiel innovant du projet réside dans l’usage de méthodes moléculaires nous permettant d’affiner notre approche de la santé en intégrant la prédisposition individuelle aux infections sexuellement transmissibles, ainsi ouvrant la voie vers la médecine personnaliséeChlamydia trachomatis (CT) is a sexually transmitted bacteria responsible for cervicitis, urethritis, and pelvic inflammatory diseases leading to subsequent tubal infertility and ectopic pregnancies. It is the most frequent sexually transmitted infection worldwide, including in France. Epidemiological data indicate that the incidence rate is increasing despite the implementation of control measures, which motivates the revision of current screening strategies. The vaginal microbiota could play a major role in preventing sexually transmitted infections through ecological competition and metabolites, such as lactic acid production. The vaginal microbiota corresponds to a fine-tuned equilibrium likely to be modified by exposures such as sexual practices, hygiene practices, antibiotics but also presence of pathogens. The overall objective of this thesis is to study the association in this triangle composed of external exposures, vaginal microbiota and CT infection, through the study of the vaginal microbiota composition and dynamics. We aimed at answering these questions: are there biomarkers of CT infection in the vaginal microbiota? Are the vaginal microbiota composition and structure modified by CT infection and antibiotic consumption? What are the exposures associated with perturbations of the vaginal microbiota? To answer these questions, the first step consisted of a state of the art to estimate the association between vaginal microbiota and CT infection in the literature, as well as three other clinically relevant sexually transmitted infections, and to evaluate the role of several factors in the observed heterogeneity between studies. In a second step, we estimated this association using molecular characterization of the vaginal microbiota in two studies in France and in the United States. We showed that Lactobacillus iners-dominated communities (CST III) and Lactobacillus-deprived communities (CST IV) were over-represented among CT-positive women. By studying the vaginal microbiota after azithromycin treatment and CT clearance in the American study, we showed that the vaginal microbiota did not evolve towards an optimal state, suggesting that women may stay at risk of CT reinfections. Finally, in two longitudinal studies using frequent sampling in the United States, we studied exposures associated with incidence and clearance of a CST IV. We showed that when the vaginal microbiota was not dominated by L. iners, menses was the main factor associated with incidence and clearance of a CST IV, while for women whose vaginal microbiota is dominated by L. iners, menses but also lubricant use, douching, ethnic origins, age and condomless vaginal sex were associated with CST IV incidence and/or clearance. Therefore, this thesis allowed on the one hand to confirm the association between Lactobacillus-deprived vaginal microbiota and CT infection using genome sequencing, and on the other hand to single out L. iners from other Lactobacillus spp. and to evaluated the risk associated with CST III. By enabling a better understanding of the natural history of CT and of the vaginal microbiota dynamics, we hope to contribute to improving strategies for the control of CT infection and other STIs. The innovative potential of the project lies in the use of molecular methods, which allows refining of our approach of health management by integrating individual predisposition to sexually transmitted infections, thus paving the way for personalized medicine
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Tomich, Lísia Gomes Martins de Moura. "Impacto da vacinação contra o meningococo C na morbidade da doença meningocócica." Universidade Federal de Goiás, 2016. http://repositorio.bc.ufg.br/tede/handle/tede/6289.
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Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq
INTRODUCTION: Routine infant immunization with meningococcal C conjugate vaccine (MenC-V) started in Brazil in November 2010, administered at three, five and 12 months of age with no catch-up for older age-groups. However, by March 2010, a vaccination campaign with MenC-V was performed in Salvador in individuals under five years-old, and from 10 to 24 yearsold. In São Paulo state, the outbreaks occurred in teenagers and young adults prompting one-time vaccination campaign from 2010 to 2014 targeting these age-groups. OBJECTIVE: To assess the direct and indirect impact (herd effect) of vaccination on invasive meningococcal disease (MD) for capsular group C (MenC) four years after the introduction of MenC-V in three scenarios: i) Brazil as a whole (routine vaccination in childhood only); ii) Brazil except for Salvador (vaccination campaign with teenagers during the year of MenC-V introduction); and iii) São Paulo state (vaccination campaign for adolescents and young adults during 2010-2014 to control outbreaks). METHODS: We performed an ecological quasi-experimental design from 2008 to 2014 using data from the National Reference Laboratory for Meningitis, and data from the National Information System for Notifiable Diseases. A deterministic linkage was performed between the two databases to improve the accuracy of the detection of MD, especially in capsular groups. An interrupted time-series analysis was conducted using the Holt-Winters technique to control for pre-existing trends and seasonal variations. The MenC vaccination impact was evaluated as the percentage of reduction in the incidence rates of MenC in the post-vaccination period (2012 to 2014), using the pre-vaccination period (2008 to 2010) to estimate what would be expected on the post-vaccination period, whether the vaccination had not been introduced. For Salvador, we analyzed the effect of the vaccination on the number of MenC cases. RESULTS: A total of 18,136 invasive MD cases were analyzed. For Brazil as a whole, the vaccination reduced 67.4% (lower 95%CI 42.5%) the rates for MenC for infants under 12 months, 92.3% (lower 95%CI 77.7%) for the age-group 12-23 months, and 65.7% (lower 95%CI 28%) for children aged 2-4 years. Indirect impact (20-24.7%) was observed in the age-group 5-19 years. When excluding Salvador from the analysis of Brazil, the indirect impact was observed only for children in the age-group 5-9 years. In the scenario of São Paulo state, similarly to Brazil, significant impact was observed in the target age-groups, in addition to indirect impact in the age group 5-9 years. In Salvador, in addition to the effect on the vaccinated population a sharp and sustainable decline of MenC cases was observed in all age-groups not target for vaccination. Overall, 1,170 cases of MenC were averted in Brazil after the introduced of Men-C vaccination. CONCLUSION: The strategy of catch-up for adolescents and young adults, especially during the year of MenC-V introduction may lead to rapid and sustainable herd effect.
A vacina meningocócica conjugada contra o grupo capsular C (MenC-V) foi introduzida no calendário de imunização infantil brasileiro em novembro de 2010, sendo administrada aos três, cinco e 12 meses de idade sem catch-up para os demais grupos etários. Entretanto, em março de 2010, uma campanha de vacinação com MenC-V foi realizada em Salvador para indivíduos menores de cinco anos de idade e de 10 a 24 anos. No estado de São Paulo os surtos ocorreram em adolescentes e adultos jovens, determinando campanhas de vacinações de bloqueio nessa faixa etária nos anos de 2010 a 2014. OBJETIVO: Avaliar o impacto direto e indireto (rebanho) da vacinação nas taxas de incidência de doença meningocócica (DM) invasiva pelo grupo capsular C (MenC) após quatro anos da introdução da MenC-V em três cenários: i) Brasil como um todo (imunização de rotina somente de crianças); ii) Brasil exceto Salvador (campanha de vacinação em adolescentes no ano de introdução da MenCV); e iii) estado de São Paulo (vacina de rotina na infância e vacinações de bloqueio em adolescentes e adultos jovens para controlar surtos). MÉTODOS: Foi realizado um estudo ecológico quasi-experimental para avaliar o impacto da vacinação em série histórica de 2008 a 2014 usando os bancos de dados do Laboratório Nacional de Referência para Meningites Bacterianas, Instituto Adolfo Lutz (IAL) e o Sistema de Informação de Agravos de Notificação (Sinan). Um processo de vinculação (linkage) determinístico entre as duas bases foi realizado para melhorar a acurácia da detecção de casos de DM, especialmente de grupo capsulares. Uma análise de série temporal interrompida foi conduzida utilizando a técnica de Holt-Winters para controlar por tendência pré-existente e variações sazonais. O desfecho foi taxa de MenC. O impacto da vacinação foi avaliado pelo percentual de redução da incidência de MenC no período pós-vacinal (2012 a 2014), utilizando o período pré-vacinal (2008 a 2010) para estimar o que seria esperado no período pós-vacinal, caso a vacinação não tivesse sido introduzida. Para Salvador foi analisado o efeito da MenC-V no número de casos de MenC. RESULTADOS: Um total de 18.136 casos de DM invasiva foram analisados. Para o Brasil como um todo, a vacinação reduziu significativamente a DM por MenC na faixa etária alvo, com redução de 67,4% (limite inferior do IC95% 42,5%) em menores de 12 meses, 92,3% (limite inferior do IC95% 77,7%) para faixa etária de 12-23 meses e 65,7% (limite inferior do IC95% 28%) em crianças de 2-4 anos, e efeito rebanho foi observado na faixa etária de 5 a 19 anos com 20-24,7%. Quando se exclui Salvador na análise do Brasil, impacto indireto significativo foi observado somente em crianças de 5-9 anos. No cenário São Paulo, semelhante ao Brasil, observou-se impacto estatisticamente significante nas faixas etárias alvo do PNI, além do efeito rebanho na faixa etária de 5-9 anos de idade. Para Salvador, o impacto da vacinação apresentou um declínio acentuado e sustentável em todas as faixas etárias fora do alvo da vacinação. Ao todo, 1.170 casos de MenC foram evitados no período estudado. CONCLUSÃO: A estratégia de vacinação de catch-up em adolescentes e adultos jovens, especialmente no ano de introdução da MenC-V, promoveu um rápido e sustentável rebanho.
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Simms, Amy Nicole. "Examination of Neisseria gonorrhoeae opacity protein expression during experimental murine genital tract infection /." Download the dissertation in PDF, 2005. http://www.lrc.usuhs.mil/dissertations/pdf/Simms2005.pdf.
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McClure, Ryan Scott. "A global RNA analysis of Neisseria gonorrhoeae in vitro and during human infection." Thesis, Boston University, 2013. https://hdl.handle.net/2144/11137.
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Thesis (Ph.D.)--Boston UniversityThe mucosal disease, gonorrhea, caused by the Gram-negative pathogen Neisseria gonorrhoeae, is estimated to have at least 700,000 cases annually in the United States and 62 million cases worldwide. A strict human pathogen, N. gonorrhoeae infects several mucosal sites throughout the body making proper gene regulation crucial. The goal of these studies was to define the global transcriptional response of N. gonorrhoeae during infection by analyzing its transcriptome during in vitro growth, during incubation with human epithelial cells, and during in vivo mucosal infection of the human female genital tract. Using RNA sequencing, we identified several new small RNA transcripts expressed in vitro that have the potential to regulate target mRNAs. Our studies were aided by the development of a novel computer program, Rockhopper, designed specifically for analysis of prokaryotic transcriptomes. Secondary methods were used to corroborate a strong correlation between Rockhopper analysis and N. gonorrhoeae transcriptional start sites, operon structures and gene expression levels. We also utilized Rockhopper to analyze the gonococcal transcriptome expressed during incubation with a human endocervical cell line. During such incubation, N. gonorrhoeae was demonstrated to regulate a large number of stress response and respiratory genes. Corresponding analysis of host cells during incubation with N. gonorrhoeae revealed increased expression of host pathways involved in innate immunity, adaptive immunity, cancer and apoptosis. Finally, analysis of gonococcal RNA from four vaginal lavage samples of female patients exposed to partners infected with N. gonorrhoeae was performed. This analysis demonstrated a similar profile of gonococcal stress response genes compared to incubation with epithelial cells. In addition, several novel sRNAs expressed by the gonococcus only during in vivo infection were also identified. Analysis of the same vaginal lavage samples demonstrated that a number of human genes involved in immune pathways and cancer are expressed during mucosal gonococcal infection. These studies are the first to analyze gene regulation in N. gonorrhoeae globally during infection and greatly expand our knowledge of how the host and pathogen respond to infection. Furthermore, they have the potential to aid in the development of novel antibacterial therapeutics or new vaccine targets for this disease.
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Charles-Orszag, Arthur. "Cellular and molecular mechanisms of human endothelial cell plasma membrane remodeling by Neisseria meningitidis." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB045/document.
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Neisseria meningitidis est une bactérie diderme qui colonise le nasopharynx humain de façon commensale. Occasionnellement, elle franchit la barrière nasopharyngée et accède à la circulation sanguine où elle peut provoquer un choc septique et/ou une méningite Le pouvoir pathogène de N. meningitidis est lié à sa capacité à interagir avec les cellules endothéliales humaines. Après avoir adhéré aux cellules grâce à des organelles filamenteux, les pili de type IV, les bactéries induisent une déformation de la membrane plasmique de la cellule hôte sous la forme de protrusions riches en actine ressemblant à des filopodes. Ces protrusions permettent aux bactéries de résister aux forces de cisaillements générées par le flux sanguin et de proliférer à la surface des cellules. Contrairement à de nombreuses autres bactéries pathogènes, cette déformation de la membrane plasmique ne nécessite pas de polymérisation d’actine. Cependant, les mécanismes cellulaires et moléculaires de cette déformation sont inconnus. Dans cette étude, nous montrons que lorsque des bactéries individuelles adhèrent à la cellule hôte, la membrane plasmique se déforme en adhérant le long des fibres de pili de type IV de façon similaire au mouillage d’un liquide sur un solide. Les pili de type IV agissent donc comme un échafaudage extracellulaire qui guide les protrusions de membrane plasmique indépendamment du cytosquelette d’actine. Nous montrons également que la capacité de la membrane plasmique à se déformer le long de structures adhésives nanométriques est une propriété intrinsèque des cellules endothéliales. Ces travaux décrivent le mécanisme d’une étape importante de la pathophysiologie de N. meningitidis et mettent en évidence des propriétés nouvelles de la membrane plasmique des cellules humaines qui pourraient être impliquées dans d’autres processus fondamentaux de biologie cellulaireNeisseria meningitidis is a diderm bacterium that is naturally found in the human nasopharynx as a commensal. Occasionally, it can cross the mucosa and reach the underlying blood vessels where it enters the circulation. Once in the bloodstream, it can cause severe septic shock and/or meningitis. The ability of N. meningitidis to cause disease is tightly linked to its ability to interact with human endothelial cells. In particular, upon bacterial adhesion via filamentous organelles called type IV pili, bacteria remodel the host cell plasma membrane in the form of actin-rich, filopodia-like protrusions. These protrusions allow bacteria to resist blood flow-generated shear stress and proliferate on top of the host cells. Unlike many other bacterial pathogens, plasma membrane remodeling induced by N. meningitidis does not require actin polymerization. Yet, the cellular and molecular mechanisms of this process are unknown. Here, we show that upon adhesion of individual bacteria, the host cell plasma membrane deforms by adhering along type IV pili fibers in a wetting-like fashion. Therefore, type IV pili act as an extracellular scaffold that guide plasma membrane protrusions in an F-actin-independent manner. We further show that the ability of the plasma membrane to deform along nanoscale adhesive structures is an intrinsic property of endothelial cells. Therefore, this study uncovers the mechanism of a key step of N. meningitidis pathophysiology and reveals novel properties of human cell plasma membrane that could be at play in other fundamental cellular processes
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DeRocco, Amanda Jean. "Molecular Analysis of Transferrin Binding Protein B in Neisseria Gonorrhoeae." VCU Scholars Compass, 2007. http://scholarscompass.vcu.edu/etd_retro/52.
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The transferrin iron acquisition system of Neisseria consists of two dissimilar proteins, transferrin binding protein A and B (TbpA and TbpB). TbpA and TbpB both specifically and independently bind human transferrin (Tf). TbpA is a TonB-dependent transporter, expression of which is necessary for Tf iron acquisition. In contrast, the lipoprotein TbpB is not necessary for iron internalization; however it makes this process more efficient. The role of TbpB in the transferrin iron acquisition system has not been completely elucidated. It has been suggested that TbpB is entirely surface exposed and tethered to the outer membrane by its lipid moiety. We inserted the hemagluttinin antigen (HA) epitope into TbpB in an effort to examine surface accessible and functional domains of the lipoprotein. We determined that TbpB was entirely surface exposed from just beyond the mature N-terminus. It was previously reported that the N- and C-terminus of TbpB independently bind Tf. HA epitope analysis defined both the N-terminal and C-terminal binding domains. TbpB was previously reported to play an important role in the release of Tf from the receptor. We established that TbpB exhibited a biphasic dissociation pattern; a C-terminal rapid release followed by a slower N-terminal release. These results suggested that the C-terminus plays a role in ligand turnover of the wild-type receptor. Little is known about the transport of TbpB to the outer membrane. In an attempt to identify the signals/mechanisms required for TbpB localization, the signal sequence of the protein was altered. In the absence of lipid modification, TbpB remained associated with the cell, localized to the periplasm. We also noted that internal cysteine residues were not critical for TbpB localization. Our results suggested that TbpB was transported by a lipoprotein-specific mechanism. Additionally, we demonstrated the major outer membrane secretin, PilQ, was not necessary for proper localization of TbpB. The mechanism responsible for this process remains elusive. This body of work represents the first comprehensive study of TbpB topology and function, utilizing the lipoprotein expressed in its native membrane. These results may translate to other, similar lipoprotein receptors of the pathogenic Neisseria, helping to shed light on these poorly understood proteins.
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White, Deborah Ann. "Genetic and immunological studies on the expression in Escherichia coli of the class 1 outer membrane protein from Neisseria meningitidis." Thesis, University of Southampton, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.316448.
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Hockenberry, Alyson M., Danielle M. Hutchens, Al Agellon, and Magdalene So. "Attenuation of the Type IV Pilus Retraction Motor Influences Neisseria gonorrhoeae Social and Infection Behavior." AMER SOC MICROBIOLOGY, 2016. http://hdl.handle.net/10150/622766.
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Retraction of the type IV pilus (Tfp) mediates DNA uptake, motility, and social and infection behavior in a wide variety of prokaryotes. To date, investigations into Tfp retraction-dependent activities have used a mutant deleted of PilT, the ATPase motor protein that causes the pilus fiber to retract. Delta pilT cells are nontransformable, nonmotile, and cannot aggregate into microcolonies. We tested the hypothesis that these retraction-dependent activities are sensitive to the strength of PilT enzymatic activity by using the pathogen Neisseria gonorrhoeae as a model. We constructed an N. gonorrhoeae mutant with an amino acid substitution in the PilT Walker B box (a substitution of cysteine for leucine at position 201, encoded by PilT(L201C)). Purified PilT(L201C) forms a native hexamer, but mutant hexamers hydrolyze ATP at half the maximal rate. N. gonorrhoeae PilT(L201C) cells produce Tfp fibers, crawl at the same speed as the wild-type (wt) parent, and are equally transformable. However, the social behavior of PilT(L201C) cells is intermediate between the behaviors of wt and Delta pilT cells. The infection behavior of PilT(L201C) is also defective, due to its failure to activate the epidermal growth factor receptor (EGFR)-heparin-binding EGF-like growth factor (HB-EGF) pathway. Our study indicates that pilus retraction, per se, is not sufficient for N. gonorrhoeae micro-colony formation or infectivity; rather, these activities are sensitive to the strength of PilT enzymatic activity. We discuss the implications of these findings for Neisseria pathogenesis in the context of mechanobiology. IMPORTANCE Type IV pili are fibers expressed on the surface of many bacteria. Neisseria gonorrhoeae cells crawl, take up DNA, and communicate with each other and with human cells by retracting these fibers. Here, we show that an N. gonorrhoeae mutant expressing an enzymatically weakened type IV pilus retraction motor still crawls and takes up DNA normally. However, mutant cells exhibit abnormal social behavior, and they are less infective because they fail to activate the epidermal growth factor receptor. Our study shows that N. gonorrhoeae social and infection behaviors are sensitive to the strength of the retraction motor enzyme.
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Diallo, Kanny. "The molecular epidemiology and ecology of Neisseria species in the African meningitis belt." Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:d7a7f86f-579f-4996-8984-c4831075f505.
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Neisseria meningitidis (Nm) is one of the major causes of bacterial meningitis in the African meningitis belt (AMB). This organism is part of the genus Neisseria, which includes ten human restricted species, mostly harmless commensals of the nasopharynx; however, Nm is capable of causing invasive meningococcal disease. The transition from carriage to pathogenic state remains perplexing, and strict virulece factors have yet to be identified. It has been hypothesised that non-pathogenic Neisseria (NPN) carried asymptomatically in the oroopharynx could play a role in modulating carriage of Nm, and therefore, its likelihood of invasion. In chapter 3, the diversity of the genus was characterised within a collection of 46 034 nasopharyngeal samples obtained across the AMB: five different species were identified, with Nm and NPNs displaying inversely related risk factors fo carriage. Chapter 5 presents the whole genome sequence (WGS) analysis of 107 Neisseria isolates unclassified by other methods. This higher genetic resolution, complemented with the use of a novel speciation approach, revealed seven novel Neisseria species, mostly collected in African countries. The invasive potential may also be due to the presence of particular genetic factors in the meningococcal genome. Chapter 4 presents the WGS comparison of 23 carried and invasive serogroup A Nm collected in Chad during the 2011 meningitis epidemic. Isolates from both phenotypic groups were found to be part of the same bacterial populations; however, discrete clusters were identified, associated with distinct age groups. These results indicate that genomic analyses are essential to appropriately study Neisseria diversity, and that lower resolution methods have greatly underestimated the diversity of the genus in Africa. The identification of Nm clusters associated with certain niches and of the differences in carriage risk factors suggests that variation in the environment, including the presence of NPNs, may be key in modulating carriage of Nm.
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Deghmane, Ala-Eddine. "Régulation de l'adhésion de Neisseria Meningitidis sur les cellules cibles humaines : rôle du gène régulateur crgA." Paris 11, 2002. http://www.theses.fr/2002PA112228.
Full textAbstract:
Neisseria meningitidis (Nm) est une bactérie commensale de la voie respiratoire humaine, mais qui provoque occasionnellement des infections invasives. Elle est responsable de méinigites et de septicémies. L'interaction bactérie-cellule hôte est essentielle pour la pathogénie de Nm et l'adhésion des bactéries sur les cellules épithéliales et endothéliales est une étape primordiale dans le processus infectieux de cette bactérie. L'adhésion de Nm sur les cellules cibles est souvent schématiquement divisée en deux étapes (i) Adhesion initiale qui la première approche d'un attachement localisé sur les cellules cibles. Elle est essentiellement médiée par les pili et l'éventuelle adhésine PilC1. (ii) Adhésion intime, qui implique un contact étroit entre la membrane bactérienne externe et la membrane cytoplasmique cellulaire. Plusieurs structures de la membrane bactérienne externes, préalablement masquées par la capsule, ont été proposées comme étant impliquées dans cette étape. L'expression du gène pilC1 est induite lors du contact cellulaire, pendant l'étape d'adhésion initiale. Cette induction dépend d'un démarrage de transcription localisé dans une séquence spécifique de 150 pb présente en amont de sa phase codante. Cette séquence spécifique a été nommée CREN (pour contact regulatory element of Neisseria). L'expression de pilCI reconnaît ensuite un feed-back négatif qui le ramène à un niveau de base. L'expression de pilE, ainsi que l'opéron sia responsable de la biosynthèse de la capsule polysaccharidique, semblent être modulés à la baisse plus la bactérie avance vers le contact intime. Dans ce travail, nous nous somme intéressé à comprendre le mécanisme qui contrôle la transition de l'adhésion initiale vers l'adhésion intime dans Nm. Un nouveau membre des régulateurs transcriptionelles de la famille LysR nommé CrgA (crgA pour contact regulated gene A) a été mis en évidence. CrgA, comme pilC1, est induit lors du contact cellulaire de façon CREN dépendante, et il est vraisemblablement impliqué dans la transition de l'adhésion initiale vers l'adhésion intime. CrgA contrôle directement négativement l'expression des gènes crgA, pilC1, pilE et sia. Les sites de fixation de CrgA sur ces promoteurs ont été identifiés. L'analyse fonctionnelle de CrgA a été également entreprise à travers l'étude des caractéristiques de différents mutants crgA délétés en phase. Les résultats obtenus montrent que les régions N- et C-terminales de CrgA sont importantes pour la fixation de la protéine sur l'ADN. La région C-terminale est de plus importante dans l'oligomérisation et l'interaction de CrgA avec l'ARN polymérase. La région centrale pourrait être impliqué dans la reconnaissance et / ou la réponse à un co-inducteurNeisseria meningitidis (Nm) is a human commensal bacterium of the nasopharynx, that occasionally provokes infections. It is responsible for septicaemia and meningitis. Bacterium-host cell interaction is essential for Nm pathogenesis and adhesion of bacteria to the epithelial and endothelial cells is crucial step in the infectious process. Nm adhesion to target cells is schematically divided into two steps: (i) Initial adhesion, which is the first approach of localised attachment to target cells, essentially mediated by pili and the adhesin PilC1. (ii) Intimate adhesion that involves close contact between Nm and target cell membrane. Several structures of the bacterial outer membrane, masked by the capsule during initial adhesion, have been proposed to be involved in this step. PilC1 gene is induced during initial adhesion upon contact with target cells. Induction of pilC1 depends on a transcription start point localised into a specific cis-acting sequence of 150 bp, localised upstream of pilC1. This specific sequence was named CREN (for contact regulatory element of Neisseria). Expression of pilC1, subsequently undergoes negative feed-back to basal level. PilE (encoding the pilin major subunit), as well as capsule, also seem to be down-regulated when bacteria progress to intimate adhesion. In this work, we were interested to understand the mechanism controlling the switch from initial to intimate adhesion. We identified a new member of the LysR transcriptional regulators named CrgA (crgA for contact regulated gene A). CrgA which is induced as pilC1 in CREN- dependant manner, upon contact with target cells, and most likely involved in the switch from initial to intimate adhesion. CrgA directly down-regulates the expression of crgA, pilC1, pilE and the capsular polysaccharide biosynthesis sia operon, in trans-dependant manner. DNA-binding sites on these promoters were identified. Functional analysis of CrgA protein has been also carried out via the analysis of the characteristics of inframe-deleted crgA mutants. N- and C-terminal regions of CrgA seem to be involved for DNA-binding. Moreover, the C-terminal region also seems to be crucial CrgA oligomerisation and interaction with RNA polymerase. Central region of CrgA is probably involved in recognition and / or response to an unknown co-inducer. In silico analysis of the genomic sequence of Nm, permitted to identify several genes harbouring the CREN element in their promoter regions
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Brehony, Carina. "The temporal and geographical distribution and diversity of disease-associated Neisseria meningitidis genetic types in Europe." Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:78a6afcc-4eb4-49fc-9d06-4cb36ddb8156.
Full textAbstract:
Meningococcal disease, caused by the bacterium Neisseria meningitidis, is an important cause of morbidity and mortality in young children and adolescents worldwide. There are 12 serogroups with most disease due to meningococci expressing one of five capsular polysaccharide antigens corresponding to serogroups A, B, C, Y and W135. In Europe, the majority of disease-causing strains are of serogroups B and C. No comprehensive vaccine is available against the bacterium due to the difficulty in producing serogroup B vaccines. A number of countries, e.g. UK and the Republic of Ireland have implemented routine meningococcal conjugate C (MCC) vaccine strategies. Due to the high proportion of disease accounted for by serogroup B in Europe and other developed countries, much research is currently being carried out to unearth vaccine candidates that would be protective and give as wide coverage as possible. Such candidates include the antigens PorA, FetA and factor H-binding protein. Potential drawbacks with antigens such as these which are under immune selection are high degrees of variability and lack of cross-immunity. Determination of the distribution, both geographically and temporally, of antigens and their association with clonal complex can aid in the formulation of novel vaccines and assess their potential coverage across Europe. Serological typing schemes involving characterisation of the polysaccharide capsule (serogroup) and outer membrane proteins such as PorA (serosubtype) and PorB (serotype) have been used for a number of years with some success. However, drawbacks associated with these methods include insufficient discrimination, limitations in panels of monoclonal antibodies used in the typing procedures and difficulty in comparison of results among labs. Consequently, in recent years genotypic methods such as multi-locus enzyme electrophoresis (MLEE) and subsequently multi-locus sequence typing (MLST) have been developed. These methods measure the variation in slowly evolving housekeeping genes whereas serological methods measure variation in antigens which are under immune pressure and are therefore more diverse. Combination of phenotypic and genotypic typing methods can offer high levels of discrimination. Molecular studies into meningococcal diversity have offered many important insights into its population biology, which have implications for prevention and control of meningococcal disease. These have included the identification of hyperinvasive lineages and the correlation of genetic type with antigenic type and disease epidemiology. The EU-MenNet programme was established as a pan-European infrastructure for the research and surveillance of European meningococcal disease. Its aim was to coordinate and disseminate the latest molecular isolate characterisation techniques (MLST) and electronic data transfer via the Internet to exploit epidemiological and population genetic studies. Within the EU-MenNet, the European Meningococcal MLST Centre (EMMC) was set up to carry out molecular typing — MLST, PorA and FetA — of European disease isolates from 18 countries over three years 2000, 2001 and 2002. The output of this project will be the largest representative molecular epidemiological study of meningococcal disease in Europe. Assessment of the data produced will give insights into the geographic and temporal distribution and structuring of disease-associated clonal complexes and antigens and their associations. This will give an indication of the meningococcal disease population in Europe and will be invaluable for the current, and ongoing, development and introduction of new meningococcal vaccines.
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Dusart, P. J. "The effects of Neisseria meningitidis infection on endothelial E-selectin, and consequences for neutrophil adhesion and transmigration." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1458121/.
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Severe septicaemia due to the bacterium Neisseria meningitidis is characterised by substantial recruitment and activation of neutrophils on inflamed endothelium, and is associated with vascular damage. N.meningitidis associates with endothelial cells, E-selectin, and neutrophils in patient biopsies, and E-selectin can co-localise beneath adherent bacteria in vitro. This thesis aims to investigate whether N.meningitidis affects E-selectin distribution on the endothelial surface and whether meningococcal-E-selectin interactions have functional consequences on neutrophil rolling, adhesion and transmigration across vascular endothelium. Lentiviral constructs were created containing full-length E-selectin (ES) or a cytoplasmic domain deficient mutant (ΔC). Transfection of primary HUVEC demonstrated that ES E-selectin forms spontaneous clusters, while ΔC is expressed in a diffuse membrane pattern. Capsulated N.meningitidis was unreliable at inducing E-selectin clustering and co-localisation. In contrast, an unencapsulated SiaD- strain could co-localise with endogenous IL-1β induced E-selectin, although not with transfected ES or ΔC. Thus the E-selectin cytoplasmic domain affects both the molecule’s distribution on the endothelial membrane, and also N.meningitidis mediated redistribution, which additionally requires some factor present on IL-1β stimulated, but not ES or ΔC transfected, endothelium. Functional aspects of N.meningitidis interactions with E-selectin on neutrophil behaviour were also investigated. Brief co-culture of N.meningitidis with ES transfected HUVEC induced increased neutrophil adhesion under static conditions and greater transmigration under physiological flow. Neutrophil adhesion to N.meningitidis stimulated ΔC transfected HUVEC however, was no greater than untransfected cells. ΔC HUVEC also only saw a small increase in transmigration despite having comparable adhesion and rolling velocity to ES cells under flow. Taken together these results show that the E-selectin cytoplasmic domain has an important yet unstudied role in neutrophil adhesion and transmigration. These data should lead to a better understanding of the underlying processes surrounding neutrophil mediated endothelial damage caused by N.meningitidis, and could have broader relevance for other inflammatory responses, particularly in sepsis.
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Sanders, Holly. "Investigation of the potential of PorA and FetA as meningococcal vaccine components." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:0eb395b0-6ee4-4765-9b91-004d3a7cb1a6.
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In the search for a vaccine providing comprehensive protection against meningococcal disease, one vaccine currently under development contains the immunogenic proteins PorA and FetA in meningococcal outer membrane vesicles (OMVs). To achieve high levels of coverage against disease-causing isolates, the antigenic variability of these proteins could be overcome using knowledge of meningococcal epidemiology and population structure. In this study, the possible implications of variable expression levels of PorA and FetA on vaccine efficacy were investigated. Producing OMVs containing consistent amounts of FetA is difficult due to iron-repressed expression; therefore, meningococcal strains were constructed which constitutively expressed FetA at increased levels for OMV vaccine production and analysis. In mice, OMVs from modified strains induced antibodies against both PorA and FetA. These antibodies acted synergistically in a serum bactericidal assay; however, antibodies against FetA were weakly bactericidal alone. The potential to increase levels of PorA- and FetA-specific bactericidal antibodies with a prime-boost strategy, using OMV and protein inoculums, was also tested. While successful for a weakly-immunogenic PorA variant, a similar strategy did not increase bactericidal activity against FetA. Although antibodies against FetA can be induced following OMV immunisation, sufficient antigen expression in target bacteria is also required for bactericidal killing; therefore, the variability and regulation of porA and fetA transcription was investigated in a range of isolates. Despite differences in regulation among clonal complexes, variable expression is unlikely to be an issue for vaccine coverage. In particular, regulation of fetA by iron is reduced in many isolates due to a deletion in the sequence bound by the regulatory protein, Fur. Therefore, a vaccine targeting PorA and FetA may provide high levels of protection against meningococcal disease; however, an alternative formulation or immunisation strategy is required to improve coverage against FetA.
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Strange, Heather Ruth. "Mechanism of Iron Transport Employed by Neisseria Gonorrhoeae: Contribution of Ferric Binding Protein A." VCU Scholars Compass, 2007. http://scholarscompass.vcu.edu/etd_retro/80.
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FbpA is the periplasmic binding protein of the transferrin and lactoferrin-iron transport systems. FbpA is conserved among neisserial species and is required for Neisseria gonorrhoeae to sustain growth on transferrin and lactoferrin. The identification of other putative TonB-dependent outer membrane transporters suggests that gonococci may employ other uncharacterized iron uptake systems that do not require FbpA. Previous work in our lab demonstrated that gonococcal strain FA19 utilizes iron from a number of xenosiderophores of the catecholate and hydroxamate classes. In this study we created conditional FbpA mutants to evaluate whether FbpA plays a role in the ability of gonococci to utilize iron from xenosiderophores. Strain FA19 was able to acquire iron from the xenosiderophores enterobactin and salmochelin in an FbpA-dependent and TonB-independent manner. We were also able to detect an extracellular population of FbpA indicating that FbpA may play a novel role in the internalization of iron in the absence of a dedicated transporter.
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Basi, Reddy Sreenivasulu Reddy, and s3046678@student rmit edu au. "A novel gold nanoparticle-based approach for the rapid diagnosis of meningococcal infection." RMIT University. Applied Sciences, 2008. http://adt.lib.rmit.edu.au/adt/public/adt-VIT20080730.165053.
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The bacterial meningitis caused by Neisseria meningitidis is responsible for considerable morbidity and mortality throughout the world. Given the limitations of existing diagnostic tests and the severity of the illness associated with the disease, there is a clear requirement for a rapid and specific diagnostic assay. This thesis describes the development of nanoparticle based tests for the detection of Neisseria meningitidis specific cell surface markers. As an initial target antigen, a recombinant form of highly conserved outer membrane protein, OMP85 was used. Within the OMP85 protein sequence, a predicted antigenic sequence between residues 720 and 745 was identified and found to be unique to this organism. This amino acid sequence was synthesised as peptide (SR1) with a gly-gly-cysteine spacer sequence at the N-terminus using t-boc chemistry. Also, the major virulence factor, capsular polysaccharide of N. meningitidis serogroup B bacteria was purified. Polyclonal antibodies were raised against purified OMP85 antigen in rabbits and against SR1 peptide and also against formalin inactivated N. meningitidis serogroup B whole cell bacteria in sheep. This panel of different antibodies including the commercial anti-capsular monoclonal antibodies were examined for cross reactivity against a range of closely related Gram negative bacteria. Based on these cross-reactivity studies, a highly specific anti-NM antibody was developed following purification of the anti-SR1 antiserum by immuno-affinity chromatography. Purified OMP85 antigen and anti-OMP85 antibody were successfully conjugated on 13, 30, 40, 50 and 60 nm gold nanoparticles by an electrostatic adsorption method. Coupling of the gold nanoparticles results in a shift of the respective surface plasmon peak toward longer wavelengths (in the range of 600-800 nm) resulting in a change of the colour of the colloidal suspension from red to purple to blue. An attempt was made to develop a rapid diagnostic assay based on gold nanoparticle induced colour shift assay for N. meningitidis by utilising the specific interaction of OMP85 and anti-OMP85 antibody conjugated to gold nanoparticles as a model system. However, this system was not reproducible and is likely to be due to problems with stability of gold nanoparticles during the conjugation process. As an alternative approach, a highly selective quartz crystal microbalance (QCM)-based immunosensor was designed using the same OMP85/anti-OMP85 antibody system. A method was developed using polyvinylidene fluoride (PVDF) coated QCM crystals with protein A for the directional orientation of the antibodies. To further enhance the sensitivity of the test, OMP85-conjugated gold nanoparticles were used as signal amplification probes for the reproducible detection of the target down to 300 ng/mL, corresponding to a five fold increase in sensitivity compared to detection of OMP85 antigen alone. Also, this sensor has successfully been employed to detect whole cell bacteria at a concentration as low as 100 cfu/mL. Thus, in this study using the real-time QCM measurements, a novel strategy has been developed for the sensitive detection of both N. meningitidis bacteria and the protein antigen at very low concentrations, using gold nanoparticles as signal amplification probes.
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Hung, Miao-Chiu. "The role of novel Neisseria meningitidis antigens in the pathogenesis of infection and their potential as vaccine candidates." Thesis, University of Southampton, 2012. https://eprints.soton.ac.uk/388465/.
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Neisseria meningitidis is a major cause of bacterial meningitis and septicaemia. Although vaccines against meningococcal A, C, Y and W are available, there is no vaccine for serogroup B infection. The vaccine potential of two proteins, Neisseria meningitidis-macrophage infectivity potentiator (MIP, NMB1567) and Neisseria meningitidis-adhesin complex protein (ACP, NMB2095) were investigated. The gene encoding each protein was cloned in the pRSETA system and propagated in E.coli DH5α. Recombinant MIP (rMIP) and recombinant ACP (rACP) proteins were expressed in E. coli BL21(DE3)pLysS and purified to high purity and yield by nickel column affinity chromatography under native and denaturing conditions, respectively. For animal immunisation, the pure proteins were refolded into i) liposomes and ii) Zwittergent 3-14 micelles, both with and without the adjuvant monophosphoryl lipid A (MPLA), iii) adsorbed onto aluminium hydroxide and iv) diluted in saline alone. Antisera of immunised animals were subjected to immunological analyses. High antibody titres against recombinant proteins and against protein in the outer membrane (OM) were detected by ELISA and western blot. Both proteins induced serum bactericidal antibody (SBA) against homologous strain (titres from 256-1024). However, the optimal preparations for eliciting heterologous SBA were proteins in saline or liposomes alone without addition of adjuvants (titres of 256-1024). Both proteins were highly conserved amongst meningococci and showed similar expression levels amongst a collection of 13 strains surveyed. In particular, the role of ACP in pathogenesis was investigated by generating ACP knockout mutant (MC58ΔACP) and complementation strains for in vitro infection assays using a variety of human cells. MC58ΔACP showed significantly decreased association with epithelial cells, endothelial cells and meningioma cells compared to MC58 in a capsulated background (p<0.05). Using an acapsular ACP mutant strain, the protein mediated internalisation of meningococci by epithelial cells and endothelial cells. In particular, a tropism for epithelial cell interactions mediated by ACP expression was observed. In conclusion, both MIP and ACP are highly conserved, surface-exposed proteins capable of eliciting cross-protective SBA and they deserve to be considered as vaccine antigens, possibly in a multi-component vaccine. Notably, ACP is a new adhesin and invasin that shows specific cell tropism and antibodies against ACP might provide multi-level protection against meningococcal infection.
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Manriquez, Rojas Valeria. "Role of the innate immune response in vascular damage caused by Neisseria meningitidis infection Vascular colonization by Neisseria meningitidis triggers a delayed and inefficient neutrophil response Intermittent pili-mediated forces fluidize Neisseria meningitidis aggregates promoting vascular colonization Adhesion to nanofibers drives cell membrane remodeling through 1D wetting." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB076.
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Neisseria meningitidis est un diplocoque à Gram négatif responsable de méningite et de choc septique. Alors que la méningite est la forme d'infection la plus fréquente, la septicémie fulminante est responsable de 90% de la mortalité imputable à N. meningitidis. La septicémie méningococcique est caractérisée par une éruption purpurique due à des lésions vasculaires. Les observations au niveau histologique révèlent des méningocoques associés aux cellules endothéliales, des thromboses, des hémorragies périvasculaires et des infiltrations de cellules inflammatoires. Les mécanismes conduisant à ces lésions vasculaires ainsi que les raisons pour lesquelles le système immunitaire inné est incapable de contrôler l'infection avant l'atteinte de ce stade pathologique sont inconnus. Dans ce travail de doctorat, nous abordons ces questions en utilisant un modèle murin humanisée par xénogreffe de peau humaine chez des animaux immunodéficients. Nous rapportons que la prolifération bactérienne dans les capillaires est rapide et mène à l'occlusion des vaisseaux en moins de 3 heures post-infection. Dans ce contexte, les macrophages périvasculaires jouent un rôle de sentinelles car ils phagocytent efficacement les bactéries intraluminales adhérentes, aux stades précoces de l'infection et sont essentiels pour recruter les neutrophiles au site d'infection. L'imagerie intravitale et les expériences de déplétion des neutrophiles indiquent que ceux-ci jouent un rôle important dans la destruction des bactéries adhérentes par un processus de migration inverse c'est à dire de l'extérieur vers l'intérieur des vaisseaux et, par conséquent, diminuent les dommages vasculaires induits par les bactéries. L'analyse de la cinétique de recrutement des neutrophiles montre que ceux-ci atteignent un pic de recrutement entre 16h et 24h post-infection chez la souris infectée par voie intravasculaire, comme c'est le cas lors d'une infection naturelle alors que cela ne prend seulement 3h lorsque les bactéries sont injectées par voie intradermique. Ces résultats montrent que la détection intraluminale des bactéries par les macrophages périvasculaires conduit finalement au recrutement des neutrophiles et au contrôle des lésions vasculaires, mais cette réponse dépendante des macrophages périvasculaires est initiée trop tard pour être pleinement efficaceNeisseria meningitidis is a gram-negative diplococcus responsible for meningitis and septic shock. While meningitidis is the most frequent form of infection, fulminant septicemia is responsible for 90% of the mortality imputable to N. meningitidis. Meningococcal sepsis is characterized by a purpuric rash due to vascular damages. Observations at the histological level reveal meningococci associated to endothelial cells, thrombosis, perivascular hemorrhage and inflammatory cells infiltrates. The mechanisms leading to this vascular damage and the reasons for which the innate immune system is unable to control the infection before reaching this pathological stage are unknown. In this doctoral work, we address these questions using a humanized skin xenograft mouse model of Neisseria meningitidis infection. We report that bacterial proliferation inside capillaries is rapid leading to vessel occlusion in less than 3 hours post-infection. In this context, perivascular macrophages play a role of sentinels as they efficiently phagocytose adhering intraluminal bacteria at early stages of infection and are essential to recruit neutrophils to the site of infection. Intravital imaging and neutrophils depletion experiments indicate that neutrophils play an important role in killing adherent bacterial through a reverse migration process and as a consequence decrease the vascular damages induced by the bacteria. Interestingly, detailed analysis of the kinetics of neutrophil recruitment show that while neutrophil numbers reach a peak between 16h and 24h post-infection in mice challenged by the intravascular route as during the natural infection, this takes only 3h when bacteria are injected intra-dermally. These results show that intraluminal detection of bacteria by perivascular macrophages eventually leads to neutrophil recruitment and vascular damage control but this perivascular macrophage-dependent response is initiated too late to be fully efficient
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Ramasamy, Maheshi Nirmala. "B cell responses to conjugate and polysaccharide meningococcal vaccines." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:0086ad26-89c4-4234-a02f-f0e7f50e4551.
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The primary approach to the control of meningococcal disease remains effective vaccination programmes in susceptible populations. Vaccines against serogroups A, C, W and Y offer broad protection against meningococci and both polysaccharide and conjugate quadrivalent vaccines are licensed for use in the UK. Previous studies have assessed the antibody response to meningococcal polysaccharide and conjugate vaccines, but there is limited information on the nature of the B cell response to these antigens. As part of a clinical trial using both polysaccharide (MenACWY-PS) and conjugate (MenACWY-CRM) vaccines in adult volunteers, this DPhil reports the analysis of subsets of antigen specific B-cells produced in response to either vaccine. Prior MenACWY-PS impaired the response to a subsequent dose of MenACWY-CRM. This may be due to MenACWY-PS driving terminal differentiation of antigen specific cells into plasma cells, without replenishment of the memory B cell pool. In addition, despite prior data indicating that it may act as a thymus dependent antigen, the serogroup A polysaccharide component of MenACWY-PS appears to behave in the same way as serogroup C, W & Y polysaccharide components. Antibody molecules recognise and bind to a multitude of conformational epitopes. This variability is enabled by the complexities of immunoglobulin variable domain gene recombination which can generate a vast potential repertoire of unique antibody molecules. However, the diversity of the antibody repertoire is more restricted against specific antigens and within defined B cell subsets. In this DPhil, ‘next generation’ sequencing technologies were used to investigate the diversity of the B cell variable domain before and after vaccination of adult volunteers. Individuals at baseline were found to have distinct antibody repertoires. Vaccination with a Haemophilus influenzae type b (Hib) conjugate vaccine resulted in an oligoclonal antibody response, with enrichment for Hib specific canonical antibody sequences.
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Yang, Manli [Verfasser], Thomas [Gutachter] Dandekar, and Thomas [Gutachter] Rudel. "Chlamydia trachomatis metabolism during infection and metatranscriptome analysis in Neisseria gonorrhoeae coinfected STD patients / Manli Yang ; Gutachter: Thomas Dandekar, Thomas Rudel." Würzburg : Universität Würzburg, 2019. http://d-nb.info/1215033753/34.
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Hayat, Azam. "The molecular interactions between two activation pathways of complement are essential for a protective innate immune response to Neisseria meningitidis infection." Thesis, University of Leicester, 2012. http://hdl.handle.net/2381/10991.
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The complement system forms a vital part of the immune system providing host defence against various pathogens, including N. meningitidis. The roles of the lectin and the alternative pathway of complement activation in meningococcal disease have been studied. Serum bactericidal assay against N.meningitidis suggested that both MBL and MASP-3 are essential for driving SBA on meningococci through a close association with the alternative pathway. A highly significant difference in survival between MASP-2-/- and MASP-2+/+ wild-type mice was observed following N. meningitidis infection with a lethal intraperitoneal dose, showing that MASP-2-/- mice were significantly protected against meningococcal infection. MASP-2-/- mice also exhibited a significantly lower meningococcal burden in blood and different organs when compared to MASP-2+/+ wild-type mice. The mRNA expression levels of inflammatory cytokines such as MIP-2, IFN-γ, IL-6 and IL-10 were significantly lower in different organs of MASP-2-/- mice compared to the MASP-2+/+ control group. Therapeutic benefits of anti MASP-2 antibodies that inhibit the lectin pathway functional activity was also tested, and the findings showed that C57BL/6 wild-type mice treated with inhibitory MASP-2 antibody showed a significantly better survival when compared with wild mice treated with an irrelevant isotype control antibody following infection with a high dose of N.meningitidis. Furthermore, significantly reduced mortality rates were observed following application of recombinant properdin in a murine model of meningococcal infection. Finally, a combination therapy using inhibitory MASP-2 antibody and recombinant properdin was analysed in murine model of meningococcal infection using C57BL/6 wild-type mice. Following N.meningitidis infection, mouse groups which received both properdin and inhibitory MASP-2 antibody showed better survival with less disease severity scores when compared to infected untreated control mouse group, or mouse groups which received recombinant properdin or inhibitory MASP-2 antibody alone.
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Heydarian, Motaharehsadat [Verfasser], Vera [Gutachter] Kozjak-Pavlovic, Thomas [Gutachter] Rudel, and Heike [Gutachter] Walles. "Development of human 3D tissue models for studying \(Neisseria\) \(gonorrhoeae\) infection / Motaharehsadat Heydarian ; Gutachter: Vera Kozjak-Pavlovic, Thomas Rudel, Heike Walles." Würzburg : Universität Würzburg, 2021. http://d-nb.info/1231714557/34.
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Chakraborti, Srinjoy. "Therapeutic Antibody Against Neisseria gonorrhoeae Lipooligosaccharide, a Phase-variable Virulence Factor." eScholarship@UMMS, 2005. http://escholarship.umassmed.edu/gsbs_diss/905.
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Neisseria gonorrhoeae (Ng) which causes gonorrhea has become multidrug-resistant, necessitating the development of novel therapeutics and vaccines. mAb 2C7 which targets an epitope within an important virulence factor, the lipooligosaccharide (LOS), is a candidate therapeutic mAb. Ninety-four percent of clinical isolates express the 2C7-epitope which is also a vaccine target.
Ng expresses multiple LOS(s) due to phase-variation (pv) of LOS glycosyltransferase (lgt) genes. mAb 2C7 reactivity requires a lactose extension from the LOS core Heptose (Hep) II (i.e. lgtG ‘ON’ [G+]). Pv results in HepI with: two (2-), three (3-), four (4-), or five (5-) hexoses (Hex). How HepI glycans impact Ng infectivity and mAb 2C7 function are unknown and form the bases of this dissertation.
Using isogenic mutants, I demonstrate that HepI LOS glycans modulate mAb 2C7 binding. mAb 2C7 causes complement (C’)-dependent bacteriolysis of three (2-Hex/G+, 4-Hex/G+, and 5-Hex/G+) of the HepI mutants in vitro. The 3-Hex/G+ mutant (resistant to C’-dependent bacteriolysis) is killed by neutrophils in the presence of mAb and C’. In mice, 2- and 3-Hex/G+ infections are significantly shorter than 4- and 5-Hex/G+ infections. A chimeric mAb 2C7 that hyperactivates C’, attenuates only 4- and 5-Hex/G+ infections.
This study enhances understanding of the role of HepI LOS pv in gonococcal infections and shows that longer HepI glycans are necessary for prolonged infections in vivo. This is the first study that predicts in vitro efficacy of mAb 2C7 against all four targetable HepI glycans thereby strengthening the rationale for development of 2C7-epitope based vaccines and therapeutics.
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Chakraborti, Srinjoy. "Therapeutic Antibody Against Neisseria gonorrhoeae Lipooligosaccharide, a Phase-variable Virulence Factor." eScholarship@UMMS, 2017. https://escholarship.umassmed.edu/gsbs_diss/905.
Full textAbstract:
Neisseria gonorrhoeae (Ng) which causes gonorrhea has become multidrug-resistant, necessitating the development of novel therapeutics and vaccines. mAb 2C7 which targets an epitope within an important virulence factor, the lipooligosaccharide (LOS), is a candidate therapeutic mAb. Ninety-four percent of clinical isolates express the 2C7-epitope which is also a vaccine target.
Ng expresses multiple LOS(s) due to phase-variation (pv) of LOS glycosyltransferase (lgt) genes. mAb 2C7 reactivity requires a lactose extension from the LOS core Heptose (Hep) II (i.e. lgtG ‘ON’ [G+]). Pv results in HepI with: two (2-), three (3-), four (4-), or five (5-) hexoses (Hex). How HepI glycans impact Ng infectivity and mAb 2C7 function are unknown and form the bases of this dissertation.
Using isogenic mutants, I demonstrate that HepI LOS glycans modulate mAb 2C7 binding. mAb 2C7 causes complement (C’)-dependent bacteriolysis of three (2-Hex/G+, 4-Hex/G+, and 5-Hex/G+) of the HepI mutants in vitro. The 3-Hex/G+ mutant (resistant to C’-dependent bacteriolysis) is killed by neutrophils in the presence of mAb and C’. In mice, 2- and 3-Hex/G+ infections are significantly shorter than 4- and 5-Hex/G+ infections. A chimeric mAb 2C7 that hyperactivates C’, attenuates only 4- and 5-Hex/G+ infections.
This study enhances understanding of the role of HepI LOS pv in gonococcal infections and shows that longer HepI glycans are necessary for prolonged infections in vivo. This is the first study that predicts in vitro efficacy of mAb 2C7 against all four targetable HepI glycans thereby strengthening the rationale for development of 2C7-epitope based vaccines and therapeutics.
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Tano, Eva. "Survival of infectious agents and detection of their resistance and virulence factors." Doctoral thesis, Uppsala universitet, Institutionen för medicinska vetenskaper, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-248786.
Full textAbstract:
In the first study, three different transport systems for bacteria were evaluated. The CLSI M40-A guideline was used to monitor the maintenance of both mono- and polymicrobial samples during a simulated transportation at room temperature that lasted 0-48 h. All systems were able to maintain the viability of all organisms for 24 h, but none of them could support all tested species after 48 h. The most difficult species to recover was Neisseria gonorrhoeae, and in polymicrobial samples overgrowth was an observed problem. The aim of the second study was to study the presence of TSST-1 and three other important toxin genes in invasive isolates of Staphylococcus aureus collected during the years 2000-2012 at two tertiary hospitals. The genes encoding the staphylococcal toxins were detected by PCR, and whole-genome sequencing was used for analyzing the genetic relatedness between isolates. The results showed that the most common toxin was TSST-1, and isolates positive for this toxin exhibited a clear clonality independent of year and hospital. The typical patient was a male aged 55-74 years and with a bone or a joint infection. The third study was a clinical study of the effect of silver-based wound dressings on the bacterial flora in chronic leg ulcers. Phenotypic and genetic silver-resistance were investigated before and after topical silver treatment, by determining the silver nitrate MICs and by detecting sil genes with PCR. The silver-based dressings had a limited effect on primary wound pathogens, and the activity of silver nitrate on S. aureus was mainly bacteriostatic. A silver-resistant Enterobacter cloacae strain was identified after only three weeks of treatment, and cephalosporin-resistant members of the Enterobacteriaceae family were relatively prone to developed silver-resistance after silver exposure in vitro. The last study was undertaken in order to develop an easy-to-use method for simulating the laundering process of hospital textiles, and apply the method when evaluating the decontaminating efficacy of two different washing temperatures. The laundering process took place at professional laundries, and Enterococcus faecium was used as a bioindicator. The results showed that a lowering of the washing temperature from 70°C to 60°C did not affect the decontamination efficacy; the washing cycle alone reduced the number of bacteria with 3-5 log10 CFU, whereas the following tumble drying reduced the bacterial numbers with another 3-4 log10 CFU, yielding the same final result independent of the washing temperature. To ensure that sufficient textile hygiene is maintained, the whole laundering process needs to be monitored. The general conclusion is that all developmental work in the bacterial field requires time and a large strain collection.
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Yang, Tao [Verfasser], and Thomas [Gutachter] Rudel. "Functional insights into the role of a bacterial virulence factor and a host factor in Neisseria gonorrhoeae infection / Tao Yang ; Gutachter: Thomas Rudel." Würzburg : Universität Würzburg, 2021. http://d-nb.info/1236503406/34.
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