Phenotypic landscape of a fungal meningitis pathogen reveals its unique biology
Michael J Boucher1, Sanjita Banerjee1, Meenakshi B Joshi1
1Dept. of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA.
Abstract:
Cryptococcus neoformans is the most common cause of fungal meningitis and the top-ranked W.H.O. priority fungal pathogen. Only distantly related to model fungi, C. neoformans is also a powerful experimental system for exploring conserved eukaryotic mechanisms lost from specialist model yeast lineages. To decipher its biology globally, we constructed 4328 gene deletions and measured-with exceptional precision--the fitness of each mutant under 141 diverse growth-limiting in vitro conditions and during murine infection. We defined functional modules by clustering genes based on their phenotypic signatures. In-depth studies leveraged these data in two ways. First, we defined and investigated new components of key signaling pathways, which revealed animal-like pathways/components not predicted from studies of model yeasts. Second, we identified environmental adaptation mechanisms repurposed to promote mammalian virulence by C. neoformans, which lacks a known animal reservoir. Our work provides an unprecedented resource for deciphering a deadly human pathogen.
Insights
This study mapped gene functions in Cryptococcus neoformans, a major fungal pathogen. It identified new virulence factors and signaling pathways, offering insights into fungal meningitis and eukaryotic evolution.
Area of Science:
- Mycology
- Genetics
- Pathogen Biology
Background:
- Cryptococcus neoformans is a leading cause of fungal meningitis and a WHO priority pathogen.
- It serves as a unique model for studying eukaryotic biology due to its distant relation to model fungi.
- Understanding its biology is crucial for combating a significant human pathogen.
Purpose of the Study:
- To comprehensively decipher the global biology of Cryptococcus neoformans.
- To identify novel signaling pathways and virulence mechanisms.
- To provide a rich resource for future research on this fungal pathogen.
Main Methods:
- Construction and fitness assessment of 4,328 gene deletion mutants.
- Phenotypic profiling across 141 diverse in vitro growth conditions.
- Evaluation of mutant fitness during murine infection models.
Main Results:
- Clustering of genes based on phenotypic signatures revealed functional modules.
- Discovery of novel, animal-like signaling pathways not previously predicted in model yeasts.
- Identification of environmental adaptation mechanisms that contribute to mammalian virulence.
Conclusions:
- This study provides an unprecedented genetic and phenotypic resource for Cryptococcus neoformans research.
- New insights into signaling pathways and virulence mechanisms have been uncovered.
- The findings advance our understanding of fungal pathogenesis and eukaryotic conserved mechanisms.
