Candida albicans is a regular component of the human microbiome, colonizing approximately 70% of healthy individuals [1]. In this commensal state, C. albicans colonizes many mucosal surfaces in the body, including the mouth, respiratory tract, and gastrointestinal tract without presenting any symptoms of disease. However, when regular host immunity is impaired, or if changes in local microflora arise, C. albicans can rapidly become an invasive, life-threatening opportunistic pathogen [2]. It is therefore crucial to understand the life-style of this flexible pathogen to protect human life. Fo most of the past century, C. albicans was believed to be asexual. This was surprising because many related ascomycete fungi are facultatively sexual. During the last two decades, a cryptic mating cycle in C. albicans has become uncovered. It began with the discovery of a genomic mating type-like locus (MTL) [4], which subsequently led to the discovery that C. albicans can mate infrequently in vitro and in vivo [5,6]. Additional work led to the discovery that a phenotypi switch, termed the 'white-opaque switch', regulates mating further [7]. To complete the mating program, C. albicans does not use meiosis, and alternatively utilizes a parasexual mechanism that includes a series of reductional mitotic divisions, resulting in diverse progeny exhibiting genetic recombination and aneuploidy [8, 9]. Why this unique, tightly regulated sexual program has evolved and its impact on disease is unknown, and is the central focus of this study. The research in this study will first address the extent of phenotypic and genomic diversity generated through the C. albicans parasexual cycle. Preliminary studies in the lab have identified that the parasexual pathway is capable of generating phenotypically diverse progeny. However, the extent of phenotypic variation, and the ability to promote adaptation to environmental stress is not clear. Research in this study will therefore focus on investigating the C. albicans parasexual cycle and its ability to produce progeny that are resistant to environmental stress. Additionally, research in this study aims to identify the role that aneuploidy arising through parasex plays in shaping phenotypic output. The sexual program utilized by C. albicans incorporates distinct morphological transitions, including the white-opaque switch, filamentous growth and biofilm formation. The experiments posed in the second portion of this proposal aims to identify how the sexual program itself directly affects the ability of C. albicans to interact with the mammalian host and cause disease. Overall, the experiments proposed in this aim serve to build on the recently identified C. albicans mating cycle, and to identify its role in both generating adaptive progeny, as well directly directing disease.
Candida albicans is a fungus that is capable of harmlessly inhabiting numerous sites within the human body, and also causing serious life-threatening infections. Because of the high mortality rate associated with Candida infections, it is important to understand the unique life-style utilized by this organism. This proposal will therefore identif how the recently discovered sexual cycle of C. albicans can promote adaptation and disease in a mammalian host.
| Ene, Iuliana V; Farrer, Rhys A; Hirakawa, Matthew P et al. (2018) Global analysis of mutations driving microevolution of a heterozygous diploid fungal pathogen. Proc Natl Acad Sci U S A 115:E8688-E8697 |
| Hirakawa, Matthew P; Chyou, Darius E; Huang, Denis et al. (2017) Parasex Generates Phenotypic Diversity de Novo and Impacts Drug Resistance and Virulence in Candida albicans. Genetics 207:1195-1211 |
| Regan, Hannah; Scaduto, Christine M; Hirakawa, Matthew P et al. (2017) Negative regulation of filamentous growth in Candida albicans by Dig1p. Mol Microbiol 105:810-824 |
| Byrd, Angel S; O'Brien, Xian M; Laforce-Nesbitt, Sonia S et al. (2016) NETosis in Neonates: Evidence of a Reactive Oxygen Species-Independent Pathway in Response to Fungal Challenge. J Infect Dis 213:634-9 |
| Sun, Yuan; Gadoury, Christine; Hirakawa, Matthew P et al. (2016) Deletion of a Yci1 Domain Protein of Candida albicans Allows Homothallic Mating in MTL Heterozygous Cells. MBio 7:e00465-16 |
| Hirakawa, Matthew P; Martinez, Diego A; Sakthikumar, Sharadha et al. (2015) Genetic and phenotypic intra-species variation in Candida albicans. Genome Res 25:413-25 |
| Jones Jr, Stephen K; Hirakawa, Matthew P; Bennett, Richard J (2014) Sexual biofilm formation in Candida tropicalis opaque cells. Mol Microbiol 92:383-98 |
