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Rôle de l'immunité humorale contre Aspergillus fumigatus
No full textAspergillus fumigatus, un champignon pathogène aéroporté, est responsable de diverses affections allergiques, ainsi que d'infections invasives et chroniques chez les patients souffrant de troubles immunitaires et/ou de dysfonctionnements pulmonaires sous-jacents. Les taux de morbidité et de mortalité associés à l'aspergillose, l'infection causée par A. fumigatus, restent élevés, en partie à cause des connaissances limitées sur l'immunobiologie de ce champignon. L'immunité innée joue un rôle essentiel dans la réponse anti-Aspergillus, englobant à la fois des composantes cellulaires et humorales. Si la réponse du système immunitaire cellulaire à A. fumigatus a été largement étudiée, le rôle du système immunitaire humoral reste insuffisamment exploré. Une meilleure compréhension des composants humoraux spécifiques du poumon impliqués dans ce processus pourrait contribuer au développement de nouvelles stratégies thérapeutiques et à l'identification de marqueurs humoraux potentiels de l'hôte pour l'aspergillose. Nous avons entrepris une analyse protéomique comparative du liquide de lavage broncho-alvéolaire de personnes infectées ou colonisées par A. fumigatus (Asp+) par rapport à des témoins, afin d'identifier les composants humoraux alvéolaires affectés lors de l'aspergillose. Parmi les principaux composants immunitaires identifiés, la protéine du surfactant D (SP-D) et C1q étaient absents du LBA Asp+ et la pentraxine-3 (PTX3) augmentait de manière significative. Nous avons cherché à élucider la signification biologique et les caractéristiques de leur interaction avec A. fumigatus. SP-D est un composant humoral majeur dans les alvéoles pulmonaires humaines et est connu pour reconnaître les conidies et les hyphes d'A. fumigatus, induisant l'expression de cytokines pro-inflammatoires protectrices dans les cellules phagocytaires. Nous démontrons que SP-D exerce une activité fongistatique directe en limitant la croissance des hyphes associée à une modification de la paroi cellulaire et à une sensibilité accrue au voriconazole. Une analyse transcriptomique des gènes fongiques régulés à la hausse ou à la baisse pendant l'interaction SP-D-Aspergillus a montré que la biosynthèse de nombreux métabolites secondaires et les voies d'absorption du fer étaient régulées à la baisse, tandis que le gène de biosynthèse de la gliotoxine augmentait de manière importante. C1q est une protéine du complément qui joue un rôle central dans la voie classique du complément en se liant indirectement aux agents pathogènes par l'intermédiaire des immunoglobulines. Nous montrons ici que sa nature de collectine permet une liaison directe avec A. fumigatus et nous identifions un mécanisme de défense des conidies impliqué dans la dégradation de C1q. Enfin, PTX3 est sécrétée par les phagocytes et les cellules non immunes sur les sites d'inflammation et il a été signalé qu'il jouait un rôle non redondant dans la réponse immunitaire contre A. fumigatus, mais sa compréhension reste incomplète. Nous identifions une interaction entre PTX3 et certains médiateurs solubles humoraux (C1q, SP-D et C3b) responsable d'une réduction de la réponse pro-inflammatoire. Bien qu'une réponse inflammatoire soit nécessaire pour lutter contre les infections fongiques, les lésions tissulaires associées à une inflammation accrue peuvent être délétères et faciliter l'infection par A. fumigatus. Dans l'ensemble, nous avons identifié et étudié trois acteurs majeurs de l'immunité humorale contre A. fumigatus qui ouvrent la voie à de nouvelles stratégies de diagnostic incluant des marqueurs de l'hôte et une potentielle immunothérapie adjuvante pour lutter contre l'aspergillose.Aspergillus fumigatus, an airborne fungal pathogen, is responsible for various allergic conditions, as well as invasive and chronic infections in patients with immune disorders and/or underlying pulmonary dysfunctions. The morbidity and mortality rates associated with aspergillosis, the infection caused by A. fumigatus, remain high, partly due to limited knowledge regarding the immunobiology of this fungus. Innate immunity plays a critical role in the anti-Aspergillus response, encompassing both cellular and humoral components. While the cellular immune system's response to A. fumigatus has been extensively studied, the role of the humoral immune system in combatting this fungus remains insufficiently explored. Enhancing our understanding of the lung-specific humoral components implicated in this process could contribute to the development of new therapeutic strategies and the identification of potential host humoral markers for aspergillosis. We undertook a comparative proteomic analysis of the bronchoalveolar lavage fluid from individuals infected or colonized with A. fumigatus (Asp+) versus controls, to identify alveolar humoral components affected upon A. fumigatus infection. Among the major immune components identified, were surfactant protein D (SP-D) and C1q missing from Asp+ BALF and pentraxin-3 (PTX3) significantly increase, for which we aimed at unravelling the biological significance and characteristics of their interaction with A. fumigatus. SP-D is a major humoral component in human lung-alveoli and known to recognize A. fumigatus conidia and hyphae inducing the expression of protective pro-inflammatory cytokines in the phagocytic cells. We demonstrate that SP-D exerts direct fungistatic activity by restricting hyphal growth associated to cell wall modification and increased susceptibility to voriconazole. A transcriptomic analysis of fungal genes up- and down-regulated during SP-D-Aspergillus interaction shown many secondary metabolites biosynthesis and iron-uptake being down regulated while the gliotoxin biosynthesis gene was importantly increased. C1q is a complement protein central to the classical complement pathway by indirectly binding to pathogens through pathogens. We show here that its collectin-like nature allows a direct binding to A. fumigatus but identify a conidial defense mechanism involved in C1q degradation. Finally, PTX3 is secreted by phagocytes and non-immune cells at sites of inflammation and has been reported to have a non-redundant role in the immune response against A. fumigatus yet remained incompletely understood. We identify a crosstalk between PTX3 and humoral pattern-recognition receptors (i.e. C1q, SP-D and C3b) responsible for a reduction of pro-inflammatory response. Although an inflammatory response is necessary to fight against fungal infections, the tissue damage associated with enhanced inflammation can be deleterious and facilitate A. fumigatus infection. Overall, we have identified and studies three major players of humoral immunity against A. fumigatus that are paving the way to new diagnostic strategies including host markers and potential adjunctive immunotherapy to fight against aspergillosis
Problems and hopes in the development of drugs targeting the fungal cell wall
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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
Undressing the Fungal Cell Wall/Cell Membrane - the Antifungal Drug Targets
No full textInternational audienceBeing external, the fungal cell wall plays a crucial role in the fungal life. By covering the underneath cell, it offers mechanical strength and acts as a barrier, thus protecting the fungus from the hostile environment. Chemically, this cell wall is composed of different polysaccharides. Because of their specific composition, the fungal cell wall and its underlying plasma membrane are unique targets for the development of drugs against pathogenic fungal species. The objective of this review is to consolidate the current knowledge on the antifungal drugs targeting the cell wall and plasma membrane, mainly of Aspergillus and Candida species - the most prevalent fungal pathogens, and also to present challenges and questions conditioning the development of new antifungal drugs targeting the cell wall
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
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