Cryptococcus neoformans is the leading cause of death by fungal meningoencephalitis; however, treatment options remain limited. Here we report the construction of 264 signature-tagged gene-deletion strains for 129 putative kinases, and examine their phenotypic traits under 30 distinct in vitro growth conditions and in two different hosts (insect larvae and mice). Clustering analysis of in vitro phenotypic traits indicates that several of these kinases have roles in known signalling pathways, and identifies hitherto uncharacterized signalling cascades. Virulence assays in the insect and mouse models provide evidence of pathogenicity-related roles for 63 kinases involved in the following biological categories: growth and cell cycle, nutrient metabolism, stress response and adaptation, cell signalling, cell polarity and morphology, vacuole trafficking, transfer RNA (tRNA) modification and other functions. Our study provides insights into the pathobiological signalling circuitry of C. neoformans and identifies potential anticryptococcal or antifungal drug targets.
Bibliographical noteFunding Information:
We thank Chaeyoon Baek, Hanseul Yang, Taehoon Kim, Sora Lee, Dasom Han, Dong-Yun Choi, Sanghun Kim, Seungyeol Lee, So-Yeon Shin, Aeri Yoo, Yong In Jeong, Yongjae Song, Won Bin Lee, Won Il Chae, Jihwan Lee, Changho Lee, Taehyung Kim and Hanna Na for their technical assistance in constructing the kinase mutant library. This work was supported by National Research Foundation of Korea grants (no. 2010-0029117, 2015R1A2A1A15055687) from MEST, the Strategic Initiative for Microbiomes in Agriculture and Food funded by Ministry of Agriculture, Food and Rural Affairs (916006-2), and the Brain Korea 21 (BK21) PLUS program (to Y.-S.B.). This work was also supported in part by a NIH/NIAID R01-AI050438-10 grant to J.H. and a project fund (C35703) to J.S.C. from Korea Basic Science Institute.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)