Contribution of galactofuranose to the virulence of the opportunistic pathogen Aspergillus fumigatus.
The filamentous fungus Aspergillus fumigatus is responsible for a lethal disease called invasive aspergillosis that affects immunocompromised patients. This disease, like other human fungal diseases, is generally treated by compounds targeting the primary fungal cell membrane sterol. Recently, glucan synthesis inhibitors were added to the limited antifungal arsenal and encouraged the search for novel targets in cell wall biosynthesis. Although galactomannan is a major component of the A. fumigatus cell wall and extracellular matrix, the biosynthesis and role of galactomannan are currently unknown. By a targeted gene deletion approach, we demonstrate that UDP-galactopyranose mutase, a key enzyme of galactofuranose metabolism, controls the biosynthesis of galactomannan and galactofuranose containing glycoconjugates. The glfA deletion mutant generated in this study is devoid of galactofuranose and displays attenuated virulence in a low-dose mouse model of invasive aspergillosis that likely reflects the impaired growth of the mutant at mammalian body temperature. Furthermore, the absence of galactofuranose results in a thinner cell wall that correlates with an increased susceptibility to several antifungal agents. The UDP-galactopyranose mutase thus appears to be an appealing adjunct therapeutic target in combination with other drugs against A. fumigatus. Its absence from mammalian cells indeed offers a considerable advantage to achieve therapeutic selectivity.
Schmalhorst
Philipp S
PS
Department of Cellular Chemistry (OE 4330), Hannover Medical School, 30625 Hannover, Germany.
Krappmann
Sven
S
Vervecken
Wouter
W
Rohde
Manfred
M
Müller
Meike
M
Braus
Gerhard H
GH
Contreras
Roland
R
Braun
Armin
A
Bakker
Hans
H
Routier
Françoise H
FH
D000818:Animals; D001228:Aspergillosis / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D001232:Aspergillus fumigatus / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity; D001831:Body Temperature / Q000502:physiology; D049109:Cell Proliferation; D002473:Cell Wall / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D025141:Drug Resistance, Fungal / Q000235:genetics; D005260:Female; D005663:Furans / Q000378:metabolism*; D005690:Galactose / Q000378:metabolism* / Q000031:analogs & derivatives; D015966:Gene Expression Regulation, Fungal / Q000235:genetics; D016867:Immunocompromised Host / Q000502:physiology; D019751:Intramolecular Transferases / Q000235:genetics / Q000378:metabolism*; D008351:Mannans / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009894:Opportunistic Infections / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D014774:Virulence / Q000235:genetics
D005663:Furans; D008351:Mannans; C012990:galactomannan; D019751:Intramolecular Transferases; C098051:UDP-galactopyranose mutase; D005690:Galactose