Changes in Cryptococcus Gene Expression in Response to the Antifungal Activity of the Antidepressant Sertraline
Abstract
Cryptococcus neoformans, a heterothallic basidiomycete fungus, is one of the most invasive, opportunistic pathogens. It predominantly affects immunocompromised patients and is the most common cause of fungal meningitis worldwide, accounting for half a million deaths each year. Current antifungal treatments are limited due to poor efficacy, toxicity with long-term use, and emerging resistance to drugs such as azoles: fluconazole (FLC). Therapies against cryptococcal meningitis are especially challenging because drugs must cross the blood-brain barrier and not be pumped out of the central nervous system. Ideally, existing drugs could be repurposed if they crossed the blood-brain barrier and had antifungal activity. Zoloft (sertraline or SRT) is a widely prescribed antidepressant that kills multiple microbes, including C. neoformans. Additionally, SRT and FLC act synergistically against C. neoformans. Combination treatment of cryptococcal meningitis with SRT and FLC together is being studied in clinical trials. However, the underlying mechanism employed by SRT to kill C. neoformans remains unclear. Therefore, we chose as a strategy to dissect the antifungal action of SRT to identify changes in gene expression following treatment of C. neoformans with SRT, FLC, and SRT+FLC using strand-specific RNA-seq and ribosome profiling. Our differential gene expression results indicate that SRT kills the pathogen by a different mechanism than FLC. Furthermore, combined treatment with SRT and FLC results in differential expression of specific genes that are not induced or repressed with individual drug treatments, indicating that combined treatment drives additional changes in the fungal cells. SRT is found to have a greater impact on genes involved in membrane transport. We hypothesize that SRT could kill cells by physiological imbalance due to membrane damage in C. neoformans in a manner distinct from FLC.
Citation
Dasgupta, Ananya (2021). Changes in Cryptococcus Gene Expression in Response to the Antifungal Activity of the Antidepressant Sertraline. Doctoral dissertation, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /196394.