Communication of the ECMM-ISHAM Working Group on Pseudallescheria/Scedosporium Infections. Update on Scedosporium/Pseudallescheria Infections

Date du colloque&nbsp;: 04/2008</p

Pseudallescheria and Scedosporium: Emerging Oopportunists

International audienc

The neurotropic black yeast Exophiala dermatitidis has a possible origin in the tropical rain forest

The black yeast Exophiala dermatitidis is known as a rare etiologic agent of neurotropic infections in humans, occurring particularly in East and Southeast Asia. In search of its natural habitat, a large sampling was undertaken in temperate as well as in tropical climates. Sampling sites were selected on the basis of the origins of previously isolated strains, and on the basis of physiological properties of the species, which also determined a selective isolation protocol. The species was absent from outdoor environments in the temperate climate, but present at low abundance in comparable habitats in the tropics. Positive outdoor sites particularly included faeces of frugivorous birds and bats, in urban as well as in natural areas. Tropical fruits were found E. dermatitidis positive at low incidence. Of the human-made environments sampled, railway ties contaminated by human faeces and oily debris in the tropics were massively positive, while the known abundance of the fungus in steam baths was confirmed. On the basis of the species' oligotrophy, thermotolerance, acidotolerance, moderate osmotolerance, melanization and capsular yeast cells a natural life cycle in association with frugivorous animals in foci in the tropical rain forest, involving passage of living cells through the intestinal tract was hypothesized. The human-dominated environment may have become contaminated by ingestion of wild berries carrying fungal propagule

Contribution of GABAergic interneurons to amyloid-β plaque pathology in an APP knock-in mouse model

The amyloid-β (Aβ) peptide, the primary constituent of amyloid plaques found in Alzheimer’s disease (AD) brains, is derived from sequential proteolytic processing of the Amyloid Precursor Protein (APP). However, the contribution of different cell types to Aβ deposition has not yet been examined in an in vivo, non-overexpression system. Here, we show that endogenous APP is highly expressed in a heterogeneous subset of GABAergic interneurons throughout various laminae of the hippocampus, suggesting that these cells may have a profound contribution to AD plaque pathology. We then characterized the laminar distribution of amyloid burden in the hippocampus of an APP knock-in mouse model of AD. To examine the contribution of GABAergic interneurons to plaque pathology, we blocked Aβ production specifically in these cells using a cell type-specific knock-out of BACE1. We found that during early stages of plaque deposition, interneurons contribute to approximately 30% of the total plaque load in the hippocampus. The greatest contribution to plaque load (75%) occurs in the stratum pyramidale of CA1, where plaques in human AD cases are most prevalent and where pyramidal cell bodies and synaptic boutons from perisomatic-targeting interneurons are located. These findings reveal a crucial role of GABAergic interneurons in the pathology of AD. Our study also highlights the necessity of using APP knock-in models to correctly evaluate the cellular contribution to amyloid burden since APP overexpressing transgenic models drive expression in cell types according to the promoter and integration site and not according to physiologically relevant expression mechanisms

PARL deficiency in mouse causes Complex III defects, coenzyme Q depletion, and Leigh-like syndrome

The mitochondrial intramembrane rhomboid protease PARL has been implicated in diverse functions in vitro, but its physiological role in vivo remains unclear. Here we show that ablation in mouse causes a necrotizing encephalomyelopathy similar to Leigh syndrome, a mitochondrial disease characterized by disrupted energy production. Mice with conditional PARL deficiency in the nervous system, but not in muscle, develop a similar phenotype as germline KOs, demonstrating the vital role of PARL in neurological homeostasis. Genetic modification of two major PARL substrates, PINK1 and PGAM5, do not modify this severe neurological phenotype. brain mitochondria are affected by progressive ultrastructural changes and by defects in Complex III (CIII) activity, coenzyme Q (CoQ) biosynthesis, and mitochondrial calcium metabolism. PARL is necessary for the stable expression of TTC19, which is required for CIII activity, and of COQ4, which is essential in CoQ biosynthesis. Thus, PARL plays a previously overlooked constitutive role in the maintenance of the respiratory chain in the nervous system, and its deficiency causes progressive mitochondrial dysfunction and structural abnormalities leading to neuronal necrosis and Leigh-like syndrome

MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer’s disease

Neuronal cell loss is a defining feature of Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. We xenografted human or mouse neurons into the brain of a mouse model of AD. Only human neurons displayed tangles, Gallyas silver staining, granulovacuolar neurodegeneration (GVD), phosphorylated tau blood biomarkers, and considerable neuronal cell loss. The long noncoding RNA MEG3 was strongly up-regulated in human neurons. This neuron-specific long noncoding RNA is also up-regulated in AD patients. MEG3 expression alone was sufficient to induce necroptosis in human neurons in vitro. Down-regulation of MEG3 and inhibition of necroptosis using pharmacological or genetic manipulation of receptor-interacting protein kinase 1 (RIPK1), RIPK3, or mixed lineage kinase domain-like protein (MLKL) rescued neuronal cell loss in xenografted human neurons. This model suggests potential therapeutic approaches for AD and reveals a human-specific vulnerability to AD

Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer's disease

Dysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer's disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate local neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown. We show increased FC in the human cingulate cortex several years before amyloid deposition. We find the same early cingulate FC disruption and neuronal hyperactivity in AppNL-F mice. Crucially, these network disruptions are accompanied by decreased astrocyte calcium signaling. Recovery of astrocytic calcium activity normalizes neuronal hyperactivity and FC, as well as seizure susceptibility and day/night behavioral disruptions. In conclusion, we show that astrocytes mediate initial features of AD and drive clinically relevant phenotypes

Enzymatic Mechanisms Involved in Evasion of Fungi to the Oxidative Stress: Focus on Scedosporium apiospermum

The airways of patients with cystic fibrosis (CF) are frequently colonized by various filamentous fungi, mainly Aspergillus fumigatus and Scedosporium species. To establish within the respiratory tract and cause an infection, these opportunistic fungi express pathogenic factors allowing adherence to the host tissues, uptake of extracellular iron, or evasion to the host immune response. During the colonization process, inhaled conidia and the subsequent hyphae are exposed to reactive oxygen species (ROS) and reactive nitrogen species (RNS) released by phagocytic cells, which cause in the fungal cells an oxidative stress and a nitrosative stress, respectively. To cope with these constraints, fungal pathogens have developed various mechanisms that protect the fungus against ROS and RNS, including enzymatic antioxidant systems. In this review, we summarize the different works performed on ROS- and RNS-detoxifying enzymes in fungi commonly encountered in the airways of CF patients and highlight their role in pathogenesis of the airway colonization or respiratory infections. The potential of these enzymes as serodiagnostic tools is also emphasized. In addition, taking advantage of the recent availability of the whole genome sequence of S. apiospermum, we identified the various genes encoding ROS- and RNS-detoxifying enzymes, which pave the way for future investigations on the role of these enzymes in pathogenesis of these emerging species since they may constitute new therapeutics targets

Biodiversity of the genus Cladophialophora

Cladophialophora is a genus of black yeast-like fungi comprising a number of clinically highly significant species in addition to environmental taxa. The genus has previously been characterized by branched chains of ellipsoidal to fusiform conidia. However, this character was shown to have evolved several times independently in the order Chaetothyriales. On the basis of a multigene phylogeny (nucLSU, nucSSU, RPB1), most of the species of Cladophialophora (including its generic type C. carrionii) belong to a monophyletic group comprising two main clades (carrionii- and bantiana-clades). The genus includes species causing chromoblastomycosis and other skin infections, as well as disseminated and cerebral infections, often in immunocompetent individuals. In the present study, multilocus phylogenetic analyses were combined to a morphological study to characterize phenetically similar Cladophialophora strains. Sequences of the ITS region, partial Translation Elongation Factor 1-α and β-Tubulin genes were analysed for a set of 48 strains. Four novel species were discovered, originating from soft drinks, alkylbenzene-polluted soil, and infected patients. Membership of the both carrionii and bantiana clades might be indicative of potential virulence to humans