Surface-Associated Plasminogen Binding of Cryptococcus neoformans Promotes Extracellular Matrix Invasion

BACKGROUND:The fungal pathogen Cryptococcus neoformans is a leading cause of illness and death in persons with predisposing factors, including: malignancies, solid organ transplants, and corticosteroid use. C. neoformans is ubiquitous in the environment and enters into the lungs via inhalation, where it can disseminate through the bloodstream and penetrate the central nervous system (CNS), resulting in a difficult to treat and often-fatal infection of the brain, called meningoencephalitis. Plasminogen is a highly abundant protein found in the plasma component of blood and is necessary for the degradation of fibrin, collagen, and other structural components of tissues. This fibrinolytic system is utilized by cancer cells during metastasis and several pathogenic species of bacteria have been found to manipulate the host plasminogen system to facilitate invasion of tissues during infection by modifying the activation of this process through the binding of plasminogen at their surface. METHODOLOGY:The invasion of the brain and the central nervous system by penetration of the protective blood-brain barrier is a prerequisite to the establishment of meningoencephalitis by the opportunistic fungal pathogen C. neoformans. In this study, we examined the ability of C. neoformans to subvert the host plasminogen system to facilitate tissue barrier invasion. Through a combination of biochemical, cell biology, and proteomic approaches, we have shown that C. neoformans utilizes the host plasminogen system to cross tissue barriers, providing support for the hypothesis that plasminogen-binding may contribute to the invasion of the blood-brain barrier by penetration of the brain endothelial cells and underlying matrix. In addition, we have identified the cell wall-associated proteins that serve as plasminogen receptors and characterized both the plasminogen-binding and plasmin-activation potential for this significant human pathogen. CONCLUSIONS:The results of this study provide evidence for the cooperative role of multiple virulence determinants in C. neoformans pathogenesis and suggest new avenues for the development of anti-infective agents in the prevention of fungal tissue invasion

Cryptococcal Cell Morphology Affects Host Cell Interactions and Pathogenicity

Cryptococcus neoformans is a common life-threatening human fungal pathogen. The size of cryptococcal cells is typically 5 to 10 µm. Cell enlargement was observed in vivo, producing cells up to 100 µm. These morphological changes in cell size affected pathogenicity via reducing phagocytosis by host mononuclear cells, increasing resistance to oxidative and nitrosative stress, and correlated with reduced penetration of the central nervous system. Cell enlargement was stimulated by coinfection with strains of opposite mating type, and ste3aΔ pheromone receptor mutant strains had reduced cell enlargement. Finally, analysis of DNA content in this novel cell type revealed that these enlarged cells were polyploid, uninucleate, and produced daughter cells in vivo. These results describe a novel mechanism by which C. neoformans evades host phagocytosis to allow survival of a subset of the population at early stages of infection. Thus, morphological changes play unique and specialized roles during infection

Aberrant Mitochondrial Homeostasis in the Skeletal Muscle of Sedentary Older Adults

The role of mitochondrial dysfunction and oxidative stress has been extensively characterized in the aetiology of sarcopenia (aging-associated loss of muscle mass) and muscle wasting as a result of muscle disuse. What remains less clear is whether the decline in skeletal muscle mitochondrial oxidative capacity is purely a function of the aging process or if the sedentary lifestyle of older adult subjects has confounded previous reports. The objective of the present study was to investigate if a recreationally active lifestyle in older adults can conserve skeletal muscle strength and functionality, chronic systemic inflammation, mitochondrial biogenesis and oxidative capacity, and cellular antioxidant capacity. To that end, muscle biopsies were taken from the vastus lateralis of young and age-matched recreationally active older and sedentary older men and women (N = 10/group; ♀  =  ♂). We show that a physically active lifestyle is associated with the partial compensatory preservation of mitochondrial biogenesis, and cellular oxidative and antioxidant capacity in skeletal muscle of older adults. Conversely a sedentary lifestyle, associated with osteoarthritis-mediated physical inactivity, is associated with reduced mitochondrial function, dysregulation of cellular redox status and chronic systemic inflammation that renders the skeletal muscle intracellular environment prone to reactive oxygen species-mediated toxicity. We propose that an active lifestyle is an important determinant of quality of life and molecular progression of aging in skeletal muscle of the elderly, and is a viable therapy for attenuating and/or reversing skeletal muscle strength declines and mitochondrial abnormalities associated with aging

The elegans of spindle assembly

The Caenorhabditis elegans one-cell embryo is a powerful system in which to study microtubule organization because this large cell assembles both meiotic and mitotic spindles within the same cytoplasm over the course of 1 h in a stereotypical manner. The fertilized oocyte assembles two consecutive acentrosomal meiotic spindles that function to reduce the replicated maternal diploid set of chromosomes to a single-copy haploid set. The resulting maternal DNA then unites with the paternal DNA to form a zygotic diploid complement, around which a centrosome-based mitotic spindle forms. The early C. elegans embryo is amenable to live-cell imaging and electron tomography, permitting a detailed structural comparison of the meiotic and mitotic modes of spindle assembly

Infection pulmonaire invasive à <em>Trichoderma longibrachiatum</em>, à propos d’un cas

National audienceIntroduction : Trichoderma longibrachiatum est un champignon filamenteux appartenant à la famille des hyalohyphomycètes, rarement isolé lors d’infections fongiques invasives chez l’Homme mais quelques cas ont déjà été décrits chez des sujets immunodéprimés. Observation : Un homme de 69 ans a développé un syndrome fébrile une semaine après la fin d’une chimiothérapie pour le traitement d’une leucémie aiguë myéloïde alors qu’il était en aplasie profonde (GB Aspergillus Galactomannan test), un scanner thoracique est réalisé. L’aspect scannographique (signe du halo) était évocateur d’une aspergillose pulmonaire invasive (API), motivant la réalisation d’un lavage broncho-alvéolaire (LBA). Le LBA a mis en évidence des filaments mycéliens régulièrement septés. La culture a permis l’isolement et l’identification de Trichoderma sp. Le séquençage par biologie moléculaire de la région polymorphe ITS3-4 de l’ADN fongique extrait à partir de la culture fongique a permis d’identifier l’espèce T. longibrachiatum. L’examen anatomopathologique d’un fragment de biopsie pulmonaire a par la suite confirmé le diagnostic de mycose pulmonaire invasive d’aspect compatible avec une aspergillose. Devant la proximité hilaire droite du foyer infectieux, faisant craindre un risque hémorragique, une lobectomie inférieure droite a été réalisée. Des filaments mycéliens ont été mis en évidence à l’examen direct de la pièce opératoire, et la présence de Trichoderma longibrachiatum a été confirmée par la culture puis la biologie moléculaire (séquençage de l’ADN fongique extrait à partir de la pièce opératoire) alors que la PCR Aspergillus était négative. La détermination des CMI par la méthode E-test® (Biomérieux) a révélé une bonne sensibilité pour le voriconazole (0,38μg/ml), l’amphotéricine B (3μg/ml) et la caspofungine (0,094 μg/ml). Le traitement a reposé sur une association Voriconazole + Caspofungine (10 jours) relayé par du voriconazole per os et le patient est toujours en rémission hématologique en mars 2015. Conclusion : ce patient qui avait tous les caractères cliniques, biologiques et scannographiques d’une API était finalement porteur d’une infection à fongique invasive à Trichoderma longibrachiatum.</em

Role of additional chromosomal changes in the prognostic value of t(4;14) and del(17p) in multiple myeloma: the IFM experience

International audienc