Transcriptional control of sex determination in the intestinal parasite Cryptosporidium parvum

Monday, September 9, 2024 at 12 PM EST

Katelyn Walzer, PhD
Research Associate,
Post-Doctoral Fellow, Striepen Lab,
University of Pennsylvania,
School of Veterinary Medicine

Hybrid seminar in Hill 132 and via Zoom: https://upenn.zoom.us/j/91485597704

 

ABSTRACT:

Cryptosporidium is a leading cause of diarrheal disease and infects millions of people worldwide each year. With no vaccine and inadequate treatment, a great need exists for new therapeutics. Transmission of the parasite occurs via the fecal-oral route, and the entire life cycle takes place in a single host. Cryptosporidium propagates in the intestinal epithelium through a programmed countdown to sexual commitment, with three asexual cycles followed by the production of male and female gametes. This makes both asexual and sexual replication essential for continuous infection and transmission. However, the molecular mechanisms governing these stage transitions remain unknown. This seminar will detail how we used single-cell RNA sequencing of infected cultures and mice to determine the complete life cycle transcriptome of Cryptosporidium parvum. The analysis of 9,310 individual parasite transcriptomes revealed a highly organized program for the assembly of components at each stage and showed an abrupt transcriptional switch from asexual to male or female fate, with no evidence for a pre-commitment stage. We identified transcription factor Myb-M as the earliest male fate determinant, in an organism that lacks genetic sex determination. Conditional ablation of Myb-M resulted in the loss of male gametes in culture while observed numbers of asexual and female parasites remained similar to control. In mice, conditional ablation of Myb-M led to a complete block of sex and oocyst production. Conditional overexpression of Myb-M induced the male pathway in all parasites, leading to the expression of male specific-genes and the formation of terminally differentiated males, ablating further parasite replication and growth. These findings demonstrate that Myb-M is necessary and sufficient to drive male fate. Overall, our work provides the first comprehensive view of C. parvum gene expression across the entire life cycle and identifies Myb-M as a master regulator of sex determination and prime drug target.

BIO:

Katelyn Walzer first became interested in eukaryotic parasites as an undergraduate in Jon Boyle’s lab at the University of Pittsburgh. As Jon’s second undergraduate student, she worked on the comparative genomics of Toxoplasma gondii and its closest relative, nonpathogenic Hammondia hammondi. After earning her Bachelor of Science as a dual major in Biological Sciences and English Writing, she pursued her PhD in Genetics and Genomics at Duke University under the tutelage of Jen-Tsan Ashley Chi. Her dissertation work focused on the development of single-cell approaches to study the transcriptional heterogeneity of Plasmodium falciparum parasites during their asexual and sexual cycles. Of note, she identified genes expressed in either male or female parasites as early as mid-stage sexual development, providing more robust markers for Plasmodium sex-specific differentiation. Currently, Katelyn is a research associate in Boris Striepen’s lab at the University of Pennsylvania School of Veterinary Medicine, where she works on transcriptional regulation of the Cryptosporidium life cycle. During her postdoctoral fellowship, Katelyn developed the Cryptosporidium single-cell atlas and identified Myb-M as the factor for maleness. Her current work focuses on how Myb-M drives male fate and how male-specific AP2 transcription factors direct male development.

WEBSITE: https://www.striepenlab.org/people