TY  - JOUR
A1  - Irmer, Henriette
A1  - Tarazona, Sonia
A1  - Sasse, Christoph
A1  - Olbermann, Patrick
A1  - Loeffler, Jürgen
A1  - Krappmann, Sven
A1  - Conesa, Ana
A1  - Braus, Gerhard H.
T1  - RNAseq analysis of Aspergillus fumigatus in blood reveals a just wait and see resting stage behavior
JF  - BMC Genomics
N2  - Background: 
Invasive aspergillosis is started after germination of Aspergillus fumigatus conidia that are inhaled by susceptible individuals. Fungal hyphae can grow in the lung through the epithelial tissue and disseminate hematogenously to invade into other organs. Low fungaemia indicates that fungal elements do not reside in the bloodstream for long.

Results: 
We analyzed whether blood represents a hostile environment to which the physiology of A. fumigatus has to adapt. An in vitro model of A. fumigatus infection was established by incubating mycelium in blood. Our model allowed to discern the changes of the gene expression profile of A. fumigatus at various stages of the infection. The majority of described virulence factors that are connected to pulmonary infections appeared not to be activated during the blood phase. Three active processes were identified that presumably help the fungus to survive the blood environment in an advanced phase of the infection: iron homeostasis, secondary metabolism, and the formation of detoxifying enzymes. 

Conclusions: 
We propose that A. fumigatus is hardly able to propagate in blood. After an early stage of sensing the environment, virtually all uptake mechanisms and energy-consuming metabolic pathways are shut-down. The fungus appears to adapt by trans-differentiation into a resting mycelial stage. This might reflect the harsh conditions in blood where A. fumigatus cannot take up sufficient nutrients to establish self-defense mechanisms combined with significant growth.
KW  - Saccharomyces cerevisiae
KW  - cerebral aspergillosis
KW  - gene expression
KW  - Aspergillus fumigatus
KW  - iron homeostasis
KW  - invasive pulmonary aspergillosis
KW  - Candida albicans
KW  - cell wall
KW  - lysine biosynthesis
KW  - human pathogen
KW  - murine model
KW  - virulence
KW  - mRNA-Seq
KW  - transcriptome
KW  - human pathogenic fungi
KW  - secondary metabolite gene cluster
KW  - detoxification
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151390
VL  - 16
IS  - 640
ER  - 
TY  - JOUR
A1  - Sasse, Christoph
A1  - Schillig, Rebecca
A1  - Dierolf, Franziska
A1  - Weyler, Michael
A1  - Schneider, Sabrina
A1  - Mogavero, Selene
A1  - Rogers, David P.
A1  - Morschhäuser, Joachim
T1  - The Transcription Factor Ndt80 Does Not Contribute to Mrr1-, Tac1-, and Upc2-Mediated Fluconazole Resistance in Candida albicans
N2  - The pathogenic yeast Candida albicans can develop resistance to the widely used antifungal agent fluconazole, which inhibits ergosterol biosynthesis, by the overexpression of genes encoding multidrug efflux pumps or ergosterol biosynthesis enzymes. Zinc cluster transcription factors play a central role in the transcriptional regulation of drug resistance. Mrr1 regulates the expression of the major facilitator MDR1, Tac1 controls the expression of the ABC transporters CDR1 and CDR2, and Upc2 regulates ergosterol biosynthesis (ERG) genes. Gain-of-function mutations in these transcription factors result in constitutive overexpression of their target genes and are responsible for fluconazole resistance in many clinical C. albicans isolates. The transcription factor Ndt80 contributes to the drug-induced upregulation of CDR1 and ERG genes and also binds to the MDR1 and CDR2 promoters, suggesting that it is an important component of all major transcriptional mechanisms of fluconazole resistance. However, we found that Ndt80 is not required for the induction of MDR1 and CDR2 expression by inducing chemicals. CDR2 was even partially derepressed in ndt80D mutants, indicating that Ndt80 is a repressor of CDR2 expression. Hyperactive forms of Mrr1, Tac1, and Upc2 promoted overexpression of MDR1, CDR1/CDR2, and ERG11, respectively, with the same efficiency in the presence and absence of Ndt80. Mrr1- and Tac1-mediated fluconazole resistance was even slightly enhanced in ndt80D mutants compared to wild-type cells. These results demonstrate that Ndt80 is dispensable for the constitutive overexpression of Mrr1, Tac1, and Upc2 target genes and the increased fluconazole resistance of strains that have acquired activating mutations in these transcription factors.
KW  - Candida albicans
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-69201
ER  -