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Neisseria meningitidis ˸ from nasopharyngeal colonization to metabolic adaptations during invasive infections
No full textNeisseria meningitidis ou méningocoque est une bactérie Gram négatif spécifique de l'Homme qui réside habituellement au niveau de la muqueuse rhinopharyngée sans affecter l'hôte. Chez une faible proportion de sujets colonisés, N. meningitidis traverse l'épithélium rhinopharyngé et dissémine de sa niche à la circulation sanguine. Une fois dans le sang, le méningocoque est capable de survivre, de proliférer, et d'atteindre des sites secondaires d'infection tels que les méninges ou la peau, pouvant déclencher une méningite ou une forme sévère de lésions nécrotiques de la peau appelée purpura fulminans. Dans la première partie de ce travail de thèse, nous avons étudié comment le méningocoque colonise son unique réservoir naturel en utilisant un modèle cellulaire en interface air-liquide (IAL) in vitro reproduisant les conditions rencontrées dans le rhinopharynx humain. Nous avons montré que la colonisation de ce modèle en IAL par le méningocoque nécessite la présence de mucus (un gel hydraté composé par l'assemblage de mucines fortement glycosylées) produit par les cellules épithéliales Calu-3. De plus, N. meningitidis reste dans la couche de mucus et par conséquent, ne traverse pas la barrière épithéliale. À la différence d'une infection en interface liquide-liquide où le méningocoque est en contact direct avec l'épithélium, il ne déclenche pas une forte réaction inflammatoire en IAL et exprime très peu ses facteurs de virulence. Ainsi, ce travail fournit de nouvelles informations sur l'interaction du méningocoque avec le mucus qui est la première barrière rencontrée par les bactéries in vivo et il suggère que N. meningitidis se comporte comme un commensal lorsqu'il se trouve dans la muqueuse rhinopharyngée. Par ailleurs, N. meningitidis interagit fortement avec les cellules endothéliales humaines durant la phase sanguine de l'infection, provoquant à terme la dissémination bactérienne et la déclaration de maladies mortelles pour l'hôte. Une étude récente propose que l'endothélium qui tapisse la paroi des vaisseaux sanguins pourrait servir de niche nutritionnelle pour le méningocoque, en particulier pour des nutriments soufrés (1). Cette bactérie possède deux voies majeures d'assimilation de soufre : le système d'assimilation de sulfate/ thiosulfate qui implique le transporteur CysWTA et l'opéron cysGHDNIJ ainsi que le transporteur de cystine NMA0997-1000 (NMB0787-9). Ainsi dans la seconde partie de ce travail, nous nous sommes intéressés (i) au rôle des cellules endothéliales comme niche nutritionnelle fournissant des nutriments soufrés au méningocoque et (ii) à l'importance du système d'assimilation du sulfate/thiosulfate dans la virulence du méningocoque in vivo. D'une part, nous avons montré que dans un milieu ne contenant que du sulfate comme source de soufre, le mutant cysIJ incapable de le métaboliser se multiplie uniquement lorsqu'il interagit avec les cellules endothéliales hCMEC/D3. Cela montre que N. meningitidis capte une source de soufre autre que le sulfate pendant la colonisation des cellules de l'hôte. Grâce à l'étude de plusieurs mutants, nous avons identifié le thiosulfate comme l'une des sources de soufre utilisée par le méningocoque pour proliférer durant l'infection des cellules endothéliales. D'autre part, nous avons montré que le mutant cysIJ présente un défaut de survie dans le sang de souris in vivo, suggérant que le système d'assimilation du sulfate/thiosulfate est essentiel durant la phase sanguine de l'infection. Nos résultats suggèrent que cette diminution de virulence du mutant cysIJ pourrait être due à un défaut dans la biosynthèse de glutathion qui résulte en une résistance plus faible au stress oxydant rencontré dans la circulation sanguine. Ainsi, cette étude démontre un rôle de l'endothélium humain durant les méningococcémies inconnu jusqu'alors et souligne l'importance du métabolisme du soufre dans la virulence bactérienne. (1) Capel et al., Virulence (2017).Neisseria meningitidis, also known as meningococcus, is an obligate human Gram-negative bacterium that usually lives on the nasopharyngeal mucosa without affecting the host. In a small proportion of colonized subjects, N. meningitidis disseminates from the nasopharynx to the bloodstream by crossing the nasal epithelium. Once in the blood, N. meningitidis is able to survive and disseminate to secondary infection sites, as meninges or skin, that can cause meningitis and a severe form of skin necrotic lesions named purpura fulminans. In the first part of this thesis, we focused on how the meningococcus colonizes its sole natural reservoir which is the human nasopharynx by using an in vitro air-liquid interface model mimicking conditions encountered in vivo. We showed that meningococci require mucus (a hydrated gel formed by the assembly of highly glycosylated mucins) produced by Calu-3 epithelial cells to colonize the air-liquid interface model. Bacteria are restricted to the mucus layer and consequently do not cross actively the epithelial barrier. Moreover, we observed that meningococci do not trigger strong inflammation when infecting Calu-3 epithelial cells and that major virulence factors are poorly expressed in this model. Finally, we showed that colonization of this model by N. meningitidis is facilitated in presence of another bacterial species, Streptococcus mitis. Thus, our work provides an overview of how meningococci interact with the mucus layer, the first barrier encountered in vivo and suggests a commensal-like behavior of N. meningitidis. Furthermore, N. meningitidis interacts closely with endothelial cells during bloodstream infections, leading to bacterial proliferation and dissemination into the host. A recent study proposed that endothelial cells lining the blood vessels represents a nutritional niche for N. meningitidis, particularly for sulfur-based nutrients (1). N. meningitidis possesses two major pathways for sulfur uptake: the sulfate and thiosulfate uptake system that involved the CysWTA transporter and the cysGHDNIJ genes or the L-cystine transporter NMA0997-1000 (NMB0787-9). In the second part of this thesis, we studied the role of (i) the endothelial cells as a nutritional niche providing sulfur-based nutrients to N. meningitidis and (ii) the sulfate/thiosulfate uptake system as a meningococcal virulence determinant in vivo. On the one hand, we showed that the mutant cysIJ unable to metabolize sulfate grows in absence of other sulfur sources only when interacting with endothelial cells hCMEC/D3, indicating that N. meningitidis is able to capture sulfur metabolites during host cell colonization. Furthermore, we demonstrated that thiosulfate is one of the sulfur sources exploited by the meningococcus during endothelial cells infection. On the other hand, we showed that the mutant cysIJ is growth defective in the blood of mice in vivo, indicating that the sulfate/thiosulfate uptake system is essential during bloodstream infections. Our work suggests that it may be due to defect in glutathione biosynthesis that is responsible for an increased sensitivity to oxidative stress encountered in the bloodstream. Thus, our study provides new insights into the role of the human endothelium during meningococcemia by providing thiosulfate to bacteria and highlight the importance of sulfur metabolism for bacterial virulence. (1) Capel et al., Virulence (2017)
Interaction of Neisseria meningitidis with human endothelial cells : role of eukaryotic cell receptor glycosylations
No full textNeisseria meningitidis est une bactérie commensale du rhinopharynx portée de façon asymptomatique par 10 à 35% de la population. Pour une raison encore inconnue à ce jour, cette bactérie est capable de traverser la barrière épithéliale et ainsi proliférer dans la circulation sanguine de l’hôte, où elle est capable d’adhérer aux cellules endothéliales grâce aux pili de type IV. Sur ces cellules, le méningocoque interagit spécifiquement avec le récepteur d’adhésion CD147 et le récepteur β2-adrénergique qui active la signalisation sous la colonie bactérienne adhérente, favorisant l’ancrage de celle-ci à la surface cellulaire et l’ouverture des jonctions cellulaires. Nous avons montré que l’adhésion aux cellules endothéliales humaines est dépendante des motifs spécifiques de N-glycosylation portés par les récepteurs cellulaires eucaryotes. Les résultats montrent que le troisième site de N-glycosylation du récepteur CD147 est indispensable pour permettre l’adhésion de la bactérie, et que l’interaction est permise par les résidus d’acide sialique portés par ces chaînes de glycosylation. Les acides sialiques sont également essentiels pour l’interaction du méningocoque avec le récepteur β2-adrénergique et l’activation de la signalisation cellulaire sous la colonie. Les résultats montrent que la forme Neu5Ac (acide N-acétylneuraminique) des acides sialiques retrouvée dans l’espèce humaine pourrait participer à la spécificité d’espèce de N. meningitidis, la plupart des autres espèces de mammifères présentant une forme Neu5Gc (acide N-glycolylneuraminique). Nous avons ainsi pu montrer qu’une partie de la spécificité d’espèce du méningocoque est liée à l’interaction des pili de type IV avec des sucres spécifiques.Neisseria meningitidis is a commensal bacteria found in the nasopharynx of 10 to 35% of the population. For a still unknown reason, the bacteria a able to cross the epithelial barrier and to reach the bloodstream, where it can proliferate and adhere to the human endothelial cells via the type IV pili. The meningococcus specifically interacts with the adhesion receptor CD147 and the β2-adrenergic receptor, responsible for the activation of signaling under the adherent colony. We showed that the adhesion to the human endothelial cells is dependent on specific N-glycosylation patterns carried by the cellular receptors. The results show that the third N-glycosylation site of CD147 is essential to the adhesion of the bacteria, and that the interaction is due to the presence of sialic acid residues of the N-glycosylation chains. The sialic acids are also essential for the interaction of the meningococcus with the β2-adrenergic receptor and the activation of the signaling under the colony. The results show that the sialic acid of the form Neu5Ac (N-acetylneuraminic acid) found in humans could explain de species specificity of the meningococcal infection, most of the other mammals species possessing a Neu5Gc (N-glycolylneuraminic acid) form of the sialic acid. So we showed that a part of the species specificity of the meningococcus is due to the interaction of the type IV pili with specific glycosylations
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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