GSE178277
The WOPR family protein Ryp1 is a key regulator of gene expression, development, and virulence in the thermally dimorphic fungal pathogen Coccidioides posadasii
Coccidioides spp. are fungal pathogens endemic to Southern California, Arizona, and other desert regions where they cause a spectrum of symptoms known as Valley Fever in otherwise healthy individuals. In the soil, Coccidioides grows in a hyphal form that produces vegetative spores (arthroconidia). When arthroconidia are inhaled by mammals they undergo an elaborate developmental transition consisting of germination, multiple rounds of nuclear division, and segmentation to form large spherules filled with vegetative endospores. Very little is understood about the molecular basis of spherule formation. Here we characterize the role of the conserved transcription factor Ryp1 in Coccidioides spherule formation. We show that Coccidioides ryp1 mutants are unable to form mature spherules, instead arresting at an early stage of spherulation. We analyze the transcriptional profile of wild-type and ?ryp1 mutant cells under hyphal and spherule-promoting conditions, thereby defining a set of hyphal- or spherule-enriched transcripts that are dependent on Ryp1 for their expression. Ryp1-dependent transcripts include key virulence factors such as SOWgp, which encodes the spherule outer wall glycoprotein. In the mouse model of coccidioidomycosis, we find that the ?ryp1 mutant is completely avirulent, indicating that Ryp1-dependent pathways are essential for the ability of Coccidioides to cause disease. Vaccination of C57BL/6 mice with live ?ryp1 spores does not provide any protection from lethal C. posadasii intranasal infection, consistent with our findings that the ?ryp1 mutant fails to make mature spherules. Taken together, this work identifies the first transcriptional regulator that drives mature spherulation and virulence in Coccidioides. Overall design: Two biological replicates each of wild type C. posadasii var. Silveira and the ryp1 mutant were grown at 37C and RT, for a total of 8 samples.