Contribution of Galactofuranose to the Virulence of the Opportunistic Pathogen Aspergillus fumigatus
| Autor: | Gerhard H. Braus, Sven Krappmann, Armin Braun, Roland Contreras, Philipp S. Schmalhorst, Wouter Vervecken, Manfred Rohde, Meike Müller, Françoise H. Routier, Hans Bakker |
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| Přispěvatelé: | Publica |
| Rok vydání: | 2008 |
| Předmět: |
Population
Virulence Opportunistic Infections Aspergillosis Microbiology Body Temperature Aspergillus fumigatus Mannans Immunocompromised Host Mice 03 medical and health sciences Cell Wall Drug Resistance Fungal Gene Expression Regulation Fungal medicine Animals Furans education Intramolecular Transferases Molecular Biology Cell Proliferation 030304 developmental biology Voriconazole Mice Inbred BALB C 0303 health sciences education.field_of_study biology Pathogen 030306 microbiology Galactofuranose Galactose drug targeting Articles General Medicine Science General biology.organism_classification medicine.disease 3. Good health Disease Models Animal Biochemistry Female Sterol binding Echinocandins Bacteria medicine.drug |
| Zdroj: | EUKARYOTIC CELL |
| ISSN: | 1535-9786 1535-9778 |
| Popis: | The filamentous fungus Aspergillus fumigatus is the primary cause of invasive aspergillosis, an often fatal condition affecting people with a weakened immune system. Along with the immunocompromised population, the incidence of invasive aspergillosis is constantly growing, but therapy remains problematic. The sterol binding polyene amphotericin B and the ergosterol biosynthesis inhibitor itraconazole have long been the drugs of choice for treatment of this infection, but because of their higher efficacy and lower toxicity, new triazoles, such as voriconazole or posaconazole, are supplanting these drugs (28, 33). Additionally, a novel class of antifungal agents called the echinocandins provides further options for treatment. These compounds inhibit the synthesis of β1,3-glucan, a major cell wall component, with resultant osmotic instability and lysis (12). Their minimal toxicity and synergistic activity with voriconazole and amphotericin B make them particularly attractive for combination therapy, although clinical validation is still awaited (33, 35). Despite these advances in therapy, invasive aspergillosis is often associated with significant morbidity and mortality, emphasizing the need for novel therapeutic strategies based on the fundamental knowledge of A. fumigatus pathogenesis. The development of echinocandins illustrates the viability of targeting enzymes involved in cell wall biosynthesis and encourages the development of chitin synthesis inhibitors. Like glucan and chitin, galactomannan is an abundant component of the A. fumigatus cell wall (4). This polysaccharide, composed of a linear mannan core branched with short β1,5-linked galactofuranose (Galf) chains (22), is bound covalently to the cell wall β1,3-glucan, anchored to the lipid membrane by a glycosylphosphatidylinositol, or released in the environment during tissue invasion or growth in culture (3, 9, 14). Besides being an abundant component of the extracellular matrix, secreted galactomannans are used for serological diagnostic of invasive aspergillosis (1). The monosaccharide Galf has also been found in the N- and O-glycans of some glycoproteins as well as the glycosphingolipids of A. fumigatus (23, 29, 41, 47) and thus represents an important constituent of the cell wall of this fungus. Galf is otherwise infrequent in natural compounds but prevalent in pathogens. Moreover, since Galf is absent from higher eukaryotes and involved in the survival or virulence of various bacteria, the enzymes involved in the biosynthesis of Galf are considered attractive drug targets (32, 34). Our understanding of Galf metabolism in eukaryotes is limited. Galf is most likely incorporated into cell surface components by specific galactofuranosyltransferases that use UDP-Galf as a donor. The work of Trejo and colleagues in the early 1970s already suggested the existence of an enzyme converting UDP-galactopyranose into UDP-galactofuranose involved in the biosynthesis of the fungal cell wall (48). This enzyme, named UDP-galactopyranose mutase (UGM) and encoded by the glf gene, was described first for bacteria (17, 30, 50) and lately for several eukaryotic pathogens, including A. fumigatus (2, 5). UGM is to date the only characterized enzyme involved in the biosynthesis of galactofuranose-containing molecules in eukaryotes, whereas several galactofuranosyltransferases have been described for bacteria (15, 19, 27, 51). The identification of this enzyme, highly conserved among lower eukaryotes and present in many fungi, enables studies of the biological role of galactofuranose in these organisms. The present report highlights the role of galactofuranose in A. fumigatus growth and virulence. |
| Databáze: | OpenAIRE |
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