Your browser doesn't support javascript.
loading
Cryptosporidium life cycle small molecule probing implicates translational repression and an Apetala 2 transcription factor in macrogamont differentiation.
Hasan, Muhammad M; Mattice, Ethan B; Teixeira, José E; Jumani, Rajiv S; Stebbins, Erin E; Klopfer, Connor E; Franco, Sebastian E; Love, Melissa S; McNamara, Case W; Huston, Christopher D.
Afiliación
  • Hasan MM; Department of Medicine, University of Vermont Larner College of Medicine, Burlington, Vermont, United States of America.
  • Mattice EB; Cell, Molecular, and Biomedical Sciences Graduate Program, University of Vermont, Burlington, Vermont, United States of America.
  • Teixeira JE; Department of Medicine, University of Vermont Larner College of Medicine, Burlington, Vermont, United States of America.
  • Jumani RS; Cell, Molecular, and Biomedical Sciences Graduate Program, University of Vermont, Burlington, Vermont, United States of America.
  • Stebbins EE; Department of Medicine, University of Vermont Larner College of Medicine, Burlington, Vermont, United States of America.
  • Klopfer CE; Department of Medicine, University of Vermont Larner College of Medicine, Burlington, Vermont, United States of America.
  • Franco SE; Cell, Molecular, and Biomedical Sciences Graduate Program, University of Vermont, Burlington, Vermont, United States of America.
  • Love MS; Department of Medicine, University of Vermont Larner College of Medicine, Burlington, Vermont, United States of America.
  • McNamara CW; Department of Medicine, University of Vermont Larner College of Medicine, Burlington, Vermont, United States of America.
  • Huston CD; Department of Medicine, University of Vermont Larner College of Medicine, Burlington, Vermont, United States of America.
PLoS Pathog ; 20(4): e1011906, 2024 Apr.
Article en En | MEDLINE | ID: mdl-38669269
ABSTRACT
The apicomplexan parasite Cryptosporidium is a leading cause of childhood diarrhea in developing countries. Current treatment options are inadequate and multiple preclinical compounds are being actively pursued as potential drugs for cryptosporidiosis. Unlike most apicomplexans, Cryptosporidium spp. sequentially replicate asexually and then sexually within a single host to complete their lifecycles. Anti-cryptosporidial compounds are generally identified or tested through in vitro phenotypic assays that only assess the asexual stages. Therefore, compounds that specifically target the sexual stages remain unexplored. In this study, we leveraged the ReFRAME drug repurposing library against a newly devised multi-readout imaging assay to identify small-molecule compounds that modulate macrogamont differentiation and maturation. RNA-seq studies confirmed selective modulation of macrogamont differentiation for 10 identified compounds (9 inhibitors and 1 accelerator). The collective transcriptomic profiles of these compounds indicates that translational repression accompanies Cryptosporidium sexual differentiation, which we validated experimentally. Additionally, cross comparison of the RNA-seq data with promoter sequence analysis for stage-specific genes converged on a key role for an Apetala 2 (AP2) transcription factor (cgd2_3490) in differentiation into macrogamonts. Finally, drug annotation for the ReFRAME hits indicates that an elevated supply of energy equivalence in the host cell is critical for macrogamont formation.
Asunto(s)
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Protozoarias / Criptosporidiosis / Cryptosporidium / Estadios del Ciclo de Vida Límite: Animals / Humans Idioma: En Revista: PLoS Pathog Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Protozoarias / Criptosporidiosis / Cryptosporidium / Estadios del Ciclo de Vida Límite: Animals / Humans Idioma: En Revista: PLoS Pathog Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos