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The Negative Cofactor 2 complex is a master regulator of drug resistance in Aspergillus fumigatus [RNA-seq]

ABSTRACT: The Negative cofactor 2 (NCT) complex is an evolutionally conserved heterodimeric transcription factor. In Aspergillus fumigatus, the NCT complex consists of two subunits NctA and NctB. Through a genome-wide screening of a transcription factor null mutant strains, we found that loss of the NCT complex leads to a multi-drug resistance phenotype including the azoles (itraconazole, voriconazole and posaconazole) as well as the salvage therapeutic amphotericin B, and terbinafine. To obtain further insight into the molecular mechanisms driving the azole-resistance in the NCT complex null mutants, we analyzed genome-wide gene expression profiles of the nctA and the nctB null mutants using RNA-seq. Our expression profiling revealed that disruption of the genes lead to upregulation of several ergosterol biosynthetic genes, their transcriptional activators, and the azole efflux pump cdr1B. Taken together, these results suggest that the NCT complex plays a role as a master regulator of drug resistance in A. fumigatus.

ORGANISM(S): Aspergillus fumigatus

PROVIDER: GSE133464 | GEO | 2019/12/31

REPOSITORIES: GEO

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Project description:Aspergillus fumigatus can cause Invasive Pulmonary Aspergillosis (IPA), the most severe form of Aspergillus-related infections. Fungicidal azoles and fungistatic caspofungin (CAS) are the first- and second-line therapies, respectively, used to treat IPA. However, azole-resistance is on the rise and new therapeutic alternatives need to be implemented. Recently, we showed that treatment of A. fumigatus with CAS or micafungin, but not voriconazole, induces production of the oxylipin 5,8-diHODE by the fungal oxygenase PpoA. Here we investigated the influence of ppo genes, that encode fatty acid oxygenases responsible for oxylipin biosynthesis, on CAS tolerance. The ppo mutants showed a very complex pattern of CAS susceptibility. PpoA and PpoC influence on CAS tolerance is mediated by MpkA phosphorylation and protein kinase A (PKA) activity. RNAseq transcriptional profiling and label-free quantitative proteomics (spectral counts) of the ppoA, and ppoC mutants showed that differentially expressed genes and proteins are related to secondary metabolites and carbohydrate metabolism. We tested several mutants of these differentially expressed genes encoding transcription factors and signal transduction proteins and some of them are more susceptible to CAS. We also characterized two clinical isolates, CNM7555 and IFM41607, that have decreased and increased susceptibility to CAS. CNM7555 does not have increased oxylipin production in the presence of CAS while the oxylipin induction upon CAS exposure is increased in the IFM41607, suggesting oxylipins are not the single mechanism involved in CAS tolerance in these isolates. Upon CAS exposure, CNM7555 has increased MpkA phosphorylation and PKA activity than IFM41607. Modulation of secondary metabolite production and carbohydrate metabolism is also essential in these clinical isolates for acquiring CAS tolerance. Our results reveal different aspects and genetic determinants involved in A. fumigatus CAS tolerance.

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The Negative Cofactor 2 complex is a master regulator of drug resistance in Aspergillus fumigatus [RNA-seq]

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