Systematic functional analysis of kinases in the fungal pathogen Cryptococcus neoformans
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Published on: February 21, 2019
Kyung-Tae Lee1, Yee-Seul So1, Dong-Hoon Yang1
1Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
Abstract:
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.
Insights
Researchers created 264 gene-deletion strains of Cryptococcus neoformans to study fungal meningoencephalitis. This study identified 63 kinases involved in virulence, offering potential new antifungal drug targets.
Area of Science:
- Mycology
- Molecular Biology
- Pathogenesis
Background:
- Cryptococcus neoformans causes fungal meningoencephalitis, a leading cause of fungal-related death.
- Limited treatment options exist for cryptococcal infections, highlighting the need for novel therapeutic strategies.
Purpose of the Study:
- To systematically investigate the roles of 129 putative kinases in Cryptococcus neoformans.
- To identify novel signaling pathways and virulence factors contributing to fungal pathogenesis.
- To discover potential drug targets for anticryptococcal therapies.
Main Methods:
- Construction and phenotypic analysis of 264 signature-tagged gene-deletion strains.
- In vitro screening across 30 distinct growth conditions.
- In vivo virulence assays in insect larvae and mouse models.
Main Results:
- Clustering analysis revealed kinases involved in known and novel signaling cascades.
- 63 kinases were identified with roles in virulence, including those related to growth, metabolism, stress response, signaling, morphology, trafficking, and tRNA modification.
- Pathobiological signaling circuitry of C. neoformans was elucidated.
Conclusions:
- The study provides a comprehensive understanding of kinase function in C. neoformans.
- Identified kinases represent promising targets for the development of new antifungal drugs.
- This research contributes to the development of strategies against fungal meningoencephalitis.
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