Phenotypic landscape of a fungal meningitis pathogen reveals its unique biology
Boucher, M.; Banerjee, S.; Joshi, M.; Wei, A.; Huang, M.; Lei, S.; Ciranni, M.; Condon, A.; Langen, A.; Goddard, T.; Caradonna, I.; Goranov, A.; Homer, C.; Mortensen, Y.; Petnic, S.; Reilly, M.; Xiong, Y.; Susa, K.; Pastore, V. P.; Zaro, B.; Madhani, H.
Show 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.
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