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Candida albicans exhibits distinct cytoprotective responses to anti-fungal drugs that facilitate the evolution of drug resistance

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Candida albicans exhibits distinct cytoprotective responses to anti-fungal drugs that facilitate the evolution of drug resistance

Massahi, Samira (2020) Candida albicans exhibits distinct cytoprotective responses to anti-fungal drugs that facilitate the evolution of drug resistance. Masters thesis, Concordia University.

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Abstract

Candida albicans is both a human commensal and opportunistic pathogen. Nosocomial infections due to pathogenic C. albicans are the fourth l argest i n North America and carry significant socioeconomic burden. Systemic Candida i nfections of i mmune-compromised individuals are frequently l ethal even when treated optimally. Drug resistance i s sometimes due to the pre-existence of genetic polymorphisms that bypass the mode of action of the drug. In other cases, resistance i s acquired via the evolution of genetic polymorphisms. There is evidence that C. albicans possesses a drug tolerance response which “buys time” for individuals to gain such beneficial mutations. Our goal i s to characterize this poorly understood epigenetic cytoprotective program at the single cell molecular level. Our hypothesis i s that i ndividuals will respond differently to drug exposure. Some will not mount a sufficient epigenetic response and die, while others will survive using different pathways. We modified a single cell platform for the fungal setting and used it to transcriptionally profile thousands of treated and untreated cells at early (tolerance) and late (resistance) timepoints. Untreated populations exhibit multivariate epigenetic responses with individuals partitioning into distinct subpopulations, each with a unique survival strategy involving efflux pumps, chaperones, transport mechanisms, and cell wall maintenance. Cell imaging will be used to validate these observations. Whole genome DNA-sequencing will be used to determine i f there i s i ncreased i nstability during the tolerance phase. Targeting the tolerance response concomitantly with standard therapies could represent an efficient approach to ablating clinical persistence.

Divisions:Concordia University > Faculty of Arts and Science > Biology
Item Type:Thesis (Masters)
Authors:Massahi, Samira
Institution:Concordia University
Degree Name:M. Sc.
Program:Biology
Date:17 April 2020
Thesis Supervisor(s):Hallett, Michael
ID Code:986797
Deposited By: Samira Massahi
Deposited On:25 Nov 2020 15:51
Last Modified:25 Nov 2020 15:51
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