Network Modelling using Transcription Sequence Data Reveals Novel MAPK Interactions Important for Drug Resistance
Ontology highlight
ABSTRACT:
ORGANISM(S): Aspergillus fumigatus
PROVIDER: GSE55743 | GEO | 2015/10/06
SECONDARY ACCESSION(S): PRJNA240892
REPOSITORIES: GEO
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Project description:Aspergillus fumigatus response to caspofungin
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Project description:Fungal infections have increased dramatically in the last two decades and fighting infectious diseases require innovative approaches such as the combination of two drugs acting on different targets, or even target a salvage pathway of one of the drugs. The fungal cell wall biosynthesis is inhibited by the clinically used antifungal drug caspofungin. This antifungal activity has been found to be potentiated by humidimycin, a new natural product identified from the screening of a collection of 20,000 microbial extracts and with no major effect when used alone. The analysis of transcriptomes and selected A. fumigatus mutants indicated that humidimycin affects the high osmolarity glycerol response pathway. By combining humidimycin and caspofungin a strong increase of caspofungin efficacy was achieved, demonstrating that targeting different signaling pathways provides an excellent basis to develop novel anti-infective strategies.
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Project description:Competing endogenous RNA (ceRNA) regulations and crosstalk between various types of non-coding RNA in humans is an important and under-explored subject. Several studies have pointed out that an alteration in miRNA:target interaction can result in unexpected changes due to indirect and complex interactions. In this article, we defined a new network-based model that incorporates miRNA:ceRNA interactions with expression values. Our approach calculates network-wide effects of perturbations in the expression level of one or more nodes in the presence or absence of miRNA interaction factors such as seed type, binding energy. We carried out the analysis of large-scale miRNA:target networks from breast cancer patients. Highly perturbing genes identified by our approach coincide with breast cancer-associated genes and miRNAs. Our network-based approach takes the sponge effect into account and helps to unveil the crosstalk between nodes in miRNA:target network. The model has potential to reveal unforeseen regulations that are only evident in the network context. Our tool is scalable and can be plugged in with emerging miRNA effectors such as circRNAs, lncRNAs, and available as R package ceRNAnetsim: https://www.bioconductor.org/packages/release/bioc/html/ceRNAnetsim.html.
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Project description:Aspergillus species are a leading cause of invasive fungal infections. As resistance to first-line therapy involving triazole antifungal agents is rising, second-line therapy with echinocandins is expanding. Resistance to echinocandins is well-established to result from amino acid substitutions in the echinocandin drug target β-(1,3)-D-glucan synthase encoded by the fks1 gene. Recently, we identified several high MIC clinical isolates of A. fumigatus from patients failing echinocandin therapy that did not contain any mutation in the fks1 gene, indicating that echinocandin resistance in these isolates results from an undefined mechanism. To explore possible new mechanisms of resistance, we used a lab-derived strain, RG101, with a nearly identical susceptibility phenotype, as a model system. This strain does not contain fks1 mutations but showed prominent resistance to the echinocandin class drug caspofungin (CAS), while remaining sensitive to other echinocandins, azoles and polyenes. Glucan synthase isolated from RG101 was fully sensitive to drug. Yet, exposure to CAS during its growth yielded a modified enzyme that was insensitive (4-log orders) in kinetic inhibition assays to CAS, as well as other echinocandins. This induction of cross-resistance by CAS was also observed in clinical isolates. To determine the nature of a presumptive posttranslational modification (PTM) of the enzyme, we analyzed whole enzyme PTMs, including the known hot-spot regions, for methylation, acetylation and phosphorylation. While we did not identify any PTMs linked to resistance, analysis of the lipid microenvironment of CAS-induced resistant enzyme revealed a prominent increase in the abundance of dihydrosphingosine (DhSph) and phytosphingosine (PhSph). Exogenous addition of DhSph and PhSph to sensitive enzyme in in vitro kinetic inhibition assays recapitulated the CAS insensitivity of the cellular-derived enzyme. To further examine induction of drug-induced resistance, we used an in vitro assay to demonstrate that CAS, but not other echinocandin class drugs, prominently induced the production of mitochondrial-derived Reactive Oxygen Species (ROS) in A. fumigatus. RNASeq evaluation of whole cells confirmed a ROS signature in cells treated with CAS. Dampening the formation of ROS by antimycin A or thiourea eliminated the induction of drug resistance by CAS. We conclude that CAS-induced formation of ROS promotes a cellular stress response that alters the composition of plasma membrane lipids surrounding glucan synthase, changing its enzymatic properties to make it insensitive to echinocandins. This stress-induced response constitutes a novel mechanism of echinocandin resistance in Aspergillus, with implications for drug resistance and/or tolerance mechanisms in other fungal pathogens.
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Project description:To determine the effect of caspofungin (CSP) treatment and/or loss of the SET domain-containing CgSet4 protein on the transcriptional response of log-phase C. glabrata cells. RNA-Seq analysis was conducted on CAA medium-grown log-phase Candida glabrata wild-type (wt) and CgSET4-deleted (Cgset4D) cells in the presence and absence of caspofungin.
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Project description:The diversity of human immunodeficiency virus type 1 (HIV-1) has given rise to multiple subtypes and recombinant strains. The majority of research into antiretroviral agents and drug resistance has been performed on subtype B viruses, yet non-subtype B strains are responsible for 90% of global infections. Although it seems that combination antiretroviral regimens are effective against all HIV-1 subtypes, there is emerging evidence of subtype differences in drug resistance, relevant to antiretroviral strategies in different parts of the world. For this purpose, extensive sampling of HIV genetic diversity, curation and analyses are required to inform antiretroviral strategies in different parts of the world.
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Project description: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 binding profiles of NctA using chromatin-immunoprecipitation sequencing (ChIP-seq). Our ChIP-seq analysis revealed that NCT complex binds the promoters of several ergosterol biosynthetic genes, their transcriptional regulators, 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.
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