Determining Genetic Signatures of the Cryptococcal Response to Zoloft by an Integrated Approach Combining Transcriptome, Translatome and Genetic Screens
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Systemic fungal infections affect millions of people worldwide and there are limited antifungal therapeuticoptions. Cryptococcal meningitis is an invariably lethal fungal infection if untreated. The existing antifungaldrugs are not always effective and the mortality rates of this disease are up to 70%. Finding new therapeuticsand understanding their mechanisms of action is thus a critical need. Sertraline (Zoloft) is a widely prescribeddrug used to treat mood disorders including depression. We discovered that sertraline (SRT) kills the deadlyfungal pathogen Cryptococcus neoformans both in vitro and in animal models at clinically achievableconcentrations. Furthermore, SRT and the commonly used antifungal fluconazole (FLC) act synergistically oradditively against C. neoformans in vitro and in vivo. Our results showing SRT and FLC were highly effectiveagainst Cryptococcus when combined in vitro and in animal models provided the basis for a clinical trial ofusing SRT and FLC as a therapy for cryptococcal meningitis (ClinicalTrials.gov NCT01802385). Early resultsfrom the trial show positive indications for SRT’s clinical efficacy. A new clinical trial of adding SRT to thestandard antifungal treatment against coccidioidomycosis has been launched. Although the mode of action ofSRT for mood-treatment in humans is well-known, how SRT kills C. neoformans and other fungi is not known.This impedes the effort to develop novel class of antifungals or to optimize the use of SRT as an antifungal.Here we will use two unbiased approaches to determine the molecular target(s) of SRT in C. neoformans, andto understand how SRT and FLC potentiate each other’s effect. First, we will identify specific changes intranscription and translation following treatment of C. neoformans with SRT, FLC, and SRT+FLC by RNA-seqand ribosome profiling (ribo-seq). This will allow us to understand fungal responses to SRT and SRT+FLC.Second, we will determine the genes that affect cryptococcal susceptibility to SRT by screening collections ofC. neoformans deletion strains. These approaches will allow us to identify promising targets/pathways tofurther examine the effect of disruption or overexpression of specific genes on cryptococcal susceptibility toSRT and SRT+FLC in this application. An understanding of SRT’s mechanism of action and how it synergizeswith FLC are expected to guide the development of new therapeutic strategies that are more effective againstCryptococcus and potentially against other refractory fungal pathogens. Discoveries made by achieving theseaims could additionally impact the development of therapies directed against other eukaryotic pathogens. Forexample, SRT is active against the parasite Leishmania and other protozoa. Establishing a rational basis forusing SRT as an antifungal agent alone or in combinatorial therapy based on determining SRT’s targets andultimately mechanism of action can help fill a critical gap for much-needed new anti-fungal therapeutics.
