Fungal diseases in humans are extremely common. They include mild cosmetic symptoms, recurrent skin and mucosal surface infections, and the rarer life-threatening diseases caused by disseminated fungi particularly in immunocompromised patients such as those suffering from AIDS, undergoing chemotherapy or corticosteroid therapy, and organ transplant recipients. Currently there is a limited repertoire of drugs available to treat fungi. Some species are naturally resistance to these drugs and resistance can be acquired in clinical settings. Thus, there is an urgent need to develop new treatments for fungal diseases. The objective of this proposal is to identify suitable targets for drug development in fungi, using a model organism Cryptococcus neoformans (in phylum Basidiomycota). This fungus is very diverged and different from commonly studied pathogenic or model species like Candida albicans, Saccharomyces cerevisiae or Schizosaccharomyces pombe (in phylum Ascomycota), and thus discoveries made in this organism are expected to extend across all pathogenic fungi.
The specific aim of the proposed research is to identify essential genes of C. neoformans, using two experimental approaches. Essential genes are those required for viability: because mutants cannot grow, the identification of essential genes is a technical challenge. Here these genes will be identified by an innovative genetic screen and through a bioinformatic prioritization to essential genes found in fungi but not in humans. The proposal will also generate a resource of heterozygous strains suitable for small molecule studies utilizing haplo-insufficiency. The discovery of these essential genes represents new avenues for the development of antifungal agents.

Public Health Relevance

The significance of this research and the benefit to human health is providing a comprehensive understanding of conserved essential genes for all fungi, with insights into the molecular basis that distinguishes fungi from their closest relatives, the animal kingdom. The long-term objective of identifying essential fungal genes is in their use in rational drug design, thus providing new therapeutic avenues for the treatment of human infectious diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Pathogenic Eukaryotes Study Section (PTHE)
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Duncan, Rory A
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University of Missouri Kansas City
Anatomy/Cell Biology
Schools of Arts and Sciences
Kansas City
United States
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Zhu, Pinkuan; Idnurm, Alexander (2018) The contribution of the White Collar complex to Cryptococcus neoformans virulence is independent of its light-sensing capabilities. Fungal Genet Biol 121:56-64
Verma, Surbhi; Shakya, Viplendra P S; Idnurm, Alexander (2018) Exploring and exploiting the connection between mitochondria and the virulence of human pathogenic fungi. Virulence 9:426-446
Yang, Dong-Hoon; Jung, Kwang-Woo; Bang, Soohyun et al. (2017) Rewiring of Signaling Networks Modulating Thermotolerance in the Human Pathogen Cryptococcus neoformans. Genetics 205:201-219
Ianiri, Giuseppe; Boyce, Kylie J; Idnurm, Alexander (2017) Isolation of conditional mutations in genes essential for viability of Cryptococcus neoformans. Curr Genet 63:519-530
Idnurm, Alexander; Bailey, Andy M; Cairns, Timothy C et al. (2017) A silver bullet in a golden age of functional genomics: the impact of Agrobacterium-mediated transformation of fungi. Fungal Biol Biotechnol 4:6
Ianiri, Giuseppe; Idnurm, Alexander; Castoria, Raffaello (2016) Transcriptomic responses of the basidiomycete yeast Sporobolomyces sp. to the mycotoxin patulin. BMC Genomics 17:210
Lee, Jeongyeo; Kim, Jungeun; Choi, Jae-Pil et al. (2016) Intracellular Ca(2+) and K(+) concentration in Brassica oleracea leaf induces differential expression of transporter and stress-related genes. BMC Genomics 17:211
Lin, Jianfeng; Idnurm, Alexander; Lin, Xiaorong (2015) Morphology and its underlying genetic regulation impact the interaction between Cryptococcus neoformans and its hosts. Med Mycol 53:493-504
Idnurm, Alexander; Lin, Xiaorong (2015) Rising to the challenge of multiple Cryptococcus species and the diseases they cause. Fungal Genet Biol 78:1-6
Idnurm, Alexander; Hood, Michael E; Johannesson, Hanna et al. (2015) Contrasted patterns in mating-type chromosomes in fungi: hotspots versus coldspots of recombination. Fungal Biol Rev 29:220-229

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