Cryptosporidium life cycle small molecule probing implicates translational repression and an Apetala 2 transcription factor in macrogamont differentiation

• DOI: 10.1371/journal.ppat.1011906
• Publication Date: 2024-04-26T17:38:23Z
• Authors: Muhammad M. Hasan; Ethan B. Mattice; José E. Teixeira; Rajiv S. Jumani; Erin E. Stebbins; Connor E. Klopfer; Sebastian E. Franco; Melissa S. Love; Case W. McNamara; Christopher D. Hu...
• Keywords: Sexual Differentiation

The apicomplexan parasite Cryptosporidium is a leading cause of childhood diarrhea in developing countries. Current treatment options are inadequate and multiple preclinical compounds being actively pursued as potential drugs for cryptosporidiosis. Unlike most apicomplexans, spp. sequentially replicate asexually then sexually within single host to complete their lifecycles. Anti-cryptosporidial generally identified or tested through vitro phenotypic assays that only assess the asexual stages. Therefore, specifically target sexual stages remain unexplored. In this study, we leveraged ReFRAME drug repurposing library against newly devised multi-readout imaging assay identify small-molecule modulate macrogamont differentiation maturation. RNA-seq studies confirmed selective modulation 10 (9 inhibitors 1 accelerator). collective transcriptomic profiles these indicates translational repression accompanies differentiation, which validated experimentally. Additionally, cross comparison data with promoter sequence analysis stage-specific genes converged on key role an Apetala 2 (AP2) transcription factor (cgd2_3490) into macrogamonts. Finally, annotation hits elevated supply energy equivalence cell critical formation.