is a saprotrophic fungus; its primary habitat is the soil. In its ecological niche, the fungus has learned how to adapt and proliferate in hostile environments. This capacity has helped the fungus to ...resist and survive against human host defenses and, further, to be responsible for one of the most devastating lung infections in terms of morbidity and mortality. In this review, we will provide (i) a description of the biological cycle of
; (ii) a historical perspective of the spectrum of aspergillus disease and the current epidemiological status of these infections; (iii) an analysis of the modes of immune response against
in immunocompetent and immunocompromised patients; (iv) an understanding of the pathways responsible for fungal virulence and their host molecular targets, with a specific focus on the cell wall; (v) the current status of the diagnosis of different clinical syndromes; and (vi) an overview of the available antifungal armamentarium and the therapeutic strategies in the clinical context. In addition, the emergence of new concepts, such as nutritional immunity and the integration and rewiring of multiple fungal metabolic activities occurring during lung invasion, has helped us to redefine the opportunistic pathogenesis of
.
The cell wall is composed of a polysaccharide-based three-dimensional network. Considered for a long time as an inert exoskeleton, the cell wall is now seen as a dynamic structure that is ...continuously changing as a result of the modification of culture conditions and environmental stresses. Although the cell wall composition varies among fungal species, chemogenomic comparative analysis have led to a better understanding of the genes and mechanisms involved in the construction of the common central core composed of branched β1,3 glucan-chitin. Because of its essential biological role, unique biochemistry and structural organization and the absence in mammalian cells of most of its constitutive components, the cell wall is an attractive target for the development of new antifungal agents. Genomic as well as drug studies have shown that the death of the fungus can result from inhibition of cell wall polysaccharide synthases. To date, only β1,3 glucan synthase inhibitors have been launched clinically and many more targets remain to be explored.
More than 90% of the cell wall of the filamentous fungus
Aspergillus fumigatus
comprises polysaccharides. Biosynthesis of the cell wall polysaccharides is under the control of three types of enzymes: ...transmembrane synthases, which are anchored to the plasma membrane and use nucleotide sugars as substrates, and cell wall-associated transglycosidases and glycosyl hydrolases, which are responsible for remodeling the de novo synthesized polysaccharides and establishing the three-dimensional structure of the cell wall. For years, the cell wall was considered an inert exoskeleton of the fungal cell. The cell wall is now recognized as a living organelle, since the composition and cellular localization of the different constitutive cell wall components (especially of the outer layers) vary when the fungus senses changes in the external environment. The cell wall plays a major role during infection. The recognition of the fungal cell wall by the host is essential in the initiation of the immune response. The interactions between the different pattern-recognition receptors (PRRs) and cell wall pathogen-associated molecular patterns (PAMPs) orientate the host response toward either fungal death or growth, which would then lead to disease development. Understanding the molecular determinants of the interplay between the cell wall and host immunity is fundamental to combatting
Aspergillus
diseases.
Vast efforts have been devoted to the development of antifungal drugs targeting the cell wall, but the supramolecular architecture of this carbohydrate-rich composite remains insufficiently ...understood. Here we compare the cell wall structure of a fungal pathogen Aspergillus fumigatus and four mutants depleted of major structural polysaccharides. High-resolution solid-state NMR spectroscopy of intact cells reveals a rigid core formed by chitin, β-1,3-glucan, and α-1,3-glucan, with galactosaminogalactan and galactomannan present in the mobile phase. Gene deletion reshuffles the composition and spatial organization of polysaccharides, with significant changes in their dynamics and water accessibility. The distribution of α-1,3-glucan in chemically isolated and dynamically distinct domains supports its functional diversity. Identification of valines in the alkali-insoluble carbohydrate core suggests a putative function in stabilizing macromolecular complexes. We propose a revised model of cell wall architecture which will improve our understanding of the structural response of fungal pathogens to stresses.
Tasting the fungal cell wall Latge, Jean-Paul
Cellular microbiology,
July 2010, Letnik:
12, Številka:
7
Journal Article
Recenzirano
Odprti dostop
The search for common host mechanisms that recognize human fungal pathogens as non-self has led to an increased interest in cell wall polysaccharides since they are absent from mammals and at least ...for some of them, common to all fungal species. Even though the receptors recognizing mannans and β-1,3-glucans have been extensively studied to date, the epitope of the polysaccharide ligand is often not well defined. In addition, receptors recognizing other cell wall major components such as chitin, α-1,3-glucan or galactose polymers remain to be identified. Moreover, the fungal adhesins playing a role in adhesion to host have been only explored in yeasts. Eventhough progresses have been made in the last 10 years, a comprehensive understanding of the interactions between the host membrane receptors and the fungal cell wall components is still lacking.
The frequency of antifungal resistance, particularly to the azole class of ergosterol biosynthetic inhibitors, is a growing global health problem. Survival rates for those infected with resistant ...isolates are exceptionally low. Beyond modification of the drug target, our understanding of the molecular basis of azole resistance in the fungal pathogen Aspergillus fumigatus is limited. We reasoned that clinically relevant antifungal resistance could derive from transcriptional rewiring, promoting drug resistance without concomitant reductions in pathogenicity. Here we report a genome-wide annotation of transcriptional regulators in A. fumigatus and construction of a library of 484 transcription factor null mutants. We identify 12 regulators that have a demonstrable role in itraconazole susceptibility and show that loss of the negative cofactor 2 complex leads to resistance, not only to the azoles but also the salvage therapeutics amphotericin B and terbinafine without significantly affecting pathogenicity.
Chronic lung infections with opportunistic bacterial and fungal pathogens are a major cause of morbidity and mortality especially in patients with cystic fibrosis. Pseudomonas aeruginosa is the most ...frequently colonizing bacterium in these patients, and it is often found in association with the filamentous fungus Aspergillus fumigatus. P. aeruginosa is known to inhibit the growth of A. fumigatus in situations of direct contact, suggesting the existence of interspecies communication that may influence disease outcome. Our study shows that the lung pathogens P. aeruginosa and A. fumigatus can interact at a distance via volatile-mediated communication and expands our understanding of interspecific signaling in microbial communities.
Microbiota studies have shown that pathogens cannot be studied individually anymore and that the establishment and progression of a specific disease are due not to a single microbial species but are the result of the activity of many species living together. To date, the interaction between members of the human microbiota has been analyzed in situations of direct contact or liquid-mediated contact between organisms. This study showed unexpectedly that human opportunistic pathogens can interact at a distance after sensing volatiles emitted by another microbial species. This finding will open a new research avenue for the understanding of microbial communities.
•Aspergillus fumigatus requires metal ion uptake in the host environment.•Metal-homeostatic circuits are complex and multifactorial.•Imbalances in metal homeostasis affect the capacity to cause ...infection.•In the host fungal pathogens face both metal withholding and toxication mechanisms.
In contrast to obligate pathogens opportunistic pathogens such as Aspergillus fumigatus do not need a specific host to propagate or survive. However several characteristics of the saprophytic life-style and the selective pressure encountered in the primary ecological niche contribute to the virulence of A. fumigatus. All fungi depend on metals for growth and proliferation, like iron, copper, zinc, manganese or calcium. In the recent past several studies explored the manifold impact of metals modulating virulence of pathogens. Components which might be scarce in the natural environment but also in the host due to nutritional immunity. This review recapitulates molecular constituents of metal ion uptake systems in A. fumigatus, their regulation and their significance at the host-pathogen battlefield.
Currently, there is a growing need for methods that can quantify and map the molecular interactions of biological samples, both with high-force sensitivity and high spatial resolution. Force–volume ...imaging is a valuable atomic force microscopy (AFM) modality for probing specific sites on biosurfaces. However, the low speed and poor spatial resolution of this method have severely hampered its widespread use in life science research. We use a novel AFM mode (i.e., peak force tapping with chemically functionalized tips) to probe the localization and interactions of chemical and biological sites on living cells at high speed and high resolution (8 min for 1 μm × 1 μm images at 512 pixels × 512 pixels). First, we demonstrate the ability of the method to quantify and image hydrophobic forces on organic surfaces and on microbial pathogens. Next, we detect single sensor proteins on yeast cells, and we unravel their mechanical properties in relation to cellular function. Owing to its key capabilities (quantitative mapping, resolution of a few nanometers, and true correlation with topography), this novel biochemically sensitive imaging technique is a powerful complement to other advanced AFM modes for quantitative, high-resolution bioimaging.
...the structure of the class I EAS protein from Neurospora crassa has been determined by NMR 5.\n Several lines of evidence suggest that the rodlet-layer, which covers the spores of both pathogenic ...and non-pathogenic fungal species, prevents immune recognition 22, 23, 25 (Figure 1). In opportunistic pathogen A. fumigatus, the rodlet-layer made up of RodA imparts resistance to NETosis (a process associated with disruption of neutrophil-membranes and release of a mixture of nuclear DNA with a granular content that acts as a neutrophil extracellular trap NET) and killing by alveolar macrophages 23, 26.
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