Biology subjects

Zsindely, N.

Publications and source records attributed to Zsindely, N..

3 recordsLinked to original sources

bioRxiv2024

The Neosartorya (Aspergillus) fischeri antifungal protein NFAP2 has low potential to trigger resistance development in Candida albicans in vitro

Due to the increase in the number of drug-resistant Candida albicans strains, new antifungal compounds with limited potential for development of resistance are urgently needed. NFAP2, an antifungal protein (AFP) secreted by Neosartorya (Aspergillus) fischeri, is a promising candidate. We investigated the ability of C. albicans to develop resistance to NFAP2 in a microevolution experiment compared with generic fluconazole (FLC). C. albicans adapted to only 1 x minimum inhibitory concentration (MIC) of NFAP2 compared with 32 x MIC of FLC. Genome analysis revealed non-silent mutations in only two genes in NFAP2-resistant strains and in several genes in FLC-resistant strains. Resistance development to NFAP2 did not influence cell morphology. The susceptibility of NFAP2-resistant strains did not change to FLC, amphotericin B, micafungin, terbinafine. These strains did not show altered susceptibility to AFPs from Penicillium chrysogenum, except one which had less susceptibility to P. chrysogenum antifungal protein B. FLC-resistant strains had decreased susceptibility to terbinafine and NFAP2, but not to other drugs and AFPs from P. chrysogenum. NFAP2- and FLC-resistant strains showed decreased and increased NFAP2 binding and uptake, respectively. The development of resistance to NFAP2 decreased tolerance to cell wall, heat, and UV stresses. The development of FLC resistance increased tolerance to cell wall stress and decreased tolerance to heat and UV stresses. Resistance to NFAP2 did not have significant metabolic fitness cost and could not increase virulence, compared with resistance to FLC. ImportanceDue to the increasing number of (multi)drug-resistant strains, only a few effective antifungal drugs are available to treat infections caused by opportunistic Candida species. Therefore, the incidence of hard-to-treat candidiasis has increased dramatically in the past decade, and the demand to identify antifungal compounds with minimal potential to trigger resistance is substantial. The features of NFAP2 make it a promising candidate for the topical treatment of Candida infection. Data on the development of resistance to AFPs in C. albicans are lacking. In this study, we provide evidence that NFAP2 has low potential to trigger resistance in C. albicans in vitro and the developed resistance mechanisms to NFAP2 are not associated with severe phenotypic changes compared with development of resistance to generic FLC. These results suggest the slow emergence of NFAP2-resistant Candida strains and that NFAP2 can reliably be used long-term in the clinic.

microbiology↗

bioRxiv2021

Oral epithelial cells distinguish between Candida species with high or low pathogenic potential through miRNA regulation

Oral epithelial cells monitor microbiome composition and initiate immune response upon dysbiosis, as in case of Candida imbalances. Comparison of healthy oral epithelial cell responses revealed that the inability of C. parapsilosis to induce a robust antifungal response was due to activation of various inflammation-independent pathways, while C. albicans robustly activated inflammation cascades. Regarding posttranscriptional regulation, several miRNAs were altered by both species. For C. parapsilosis, the applied dose directly correlated with changes in transcriptomic responses. Carbohydrate metabolism, hypoxia- and cardiovascular development-related responses dominate after C. parapsilosis stimulus, whereas C. albicans altered inflammatory responses. Subsequent analyses of HIF1- and HSC-activation pathways predicted target genes through which miRNA-dependent regulation of yeast-specific functions may occur, supporting the observed responses. Thus, C. parapsilosis is recognized as a commensal at low doses by the oral epithelium; however, increased fungal burden activates different pathways, some of which overlap with inflammatory processes induced by C. albicans. Impact statementAltered miRNA regulation discriminates between C. albicans and C. parapsilosis in human oral epithelial cells

microbiology↗

bioRxiv2017

Systematic genetic interaction studies identify histone demethylase Utx as potential target for ameliorating Huntington’s disease

Huntingtons Disease (HD) is a dominantly inherited neurodegenerative disease caused by alterations in the huntingtin gene (htt). Transcriptional dysregulation is an early event in HD progression. Protein acetylation and methylation particularly on histones regulates chromatin structure thereby preventing or facilitating transcription. Although protein acetylation has been found to affect HD symptoms, little is known about the potential role of protein methylation in HD pathology. In recent years, a series of proteins have been described that are responsible for methylating and demethylating histones as well as other proteins. We carried out systematic genetic interaction studies testing lysine and arginine methylases and demethylases in a Drosophila melanogaster HD model. We found that modulating methylation enzymes that typically affect histone positions H3K4, H3K36 or H3K79 had varying effects on HD pathology while modulating ones that typically affect constitutive heterochromatin marks at H3K9 and H4K20 generally had limited impact on HD pathology. In contrast, modulating enzymes acting on the facultative heterochromatin mark at H3K27 had specific effects on HD pathology, with reduction of the demethylase Utx rescuing HTT induced pathology while reducing PRC2 complex core methylase components led to more aggressive pathology. Further exploration of the mechanism underlying the methylation-specific interactions suggest that these lysine and arginine methylases and demethylases are likely exerting their influence through non-histone targets. These results highlight a novel therapeutic approach for HD in the form of Utx inhibition.

neuroscience↗