Candida albicans is ubiquitously present in the microflora of the body and its success as both a commensal and a pathogen relies on its ability to adapt to changes in host physiology. However, despite its prevalence as an opportunistic pathogen, the mechanisms contributing to phenotypic plasticity and pathogenesis are poorly defined. This proposal will establish the role of sexual reproduction for increasing phenotypic diversity and promoting infection of multiple sites in the mammalian host. In addition, it will explore if components of the sexual signaling pathway represent novel targets for antifungal therapies. C. albicans was originally thought to be obligately asexual but an efficient and elaborate mating program has now been established that can generate recombinant forms of the organism. Mating in C. albicans is unique in that it is regulated by phenotypic switching;only opaque forms of the organism can undergo sexual reproduction. In addition, meiosis has not been observed and instead cells undergo a program of concerted chromosome loss to complete a parasexual mating cycle. Progeny from the parasexual cycle are recombinant strains that exhibit divergent phenotypes with the potential for increased virulence in the host. This possibility will be addressed by analysis of a set of progeny strains using in vitro and in vivo assays. Many of the products of the parasexual cycle are aneuploid strains carrying extra copies of chromosomes. As drug-resistant isolates of C. albicans often exhibit changes in chromosome copy number our studies will also determine if parasexual progeny include those with increased drug resistance. Sexual reproduction in C. albicans and related yeast is thought to occur exclusively between a and a mating partners. However, preliminary experiments show a novel mechanism exists for same-sex mating within unisexual populations of the organism. Autocrine pheromone signaling is responsible for promoting self-mating and the mechanism of autocrine signaling will be established by genetic approaches. These studies also have important implications for mechanisms of sexual reproduction in related Candida species that propagate exclusively as unisexual populations. Finally, our studies will investigate if components of the sexual machinery can be targeted to promote killing of fungal cells. Preliminary experiments suggest that sexual pheromones act to reduce the cellular integrity of responding cells. The mechanism of signaling will be defined and the possibility tested that cell killing by common antifungal drugs can be potentiated by targeting of pheromone-signaling pathways.

Public Health Relevance

Candida albicans is the most common fungal pathogen in humans, causing both debilitating mucosal infections and life-threatening systemic infections. Our research focuses on several aspects of the newly identified mating cycle in C. albicans: (1) An understanding of the basic biology of the C. albicans mating cycle and how it promotes survival in a mammalian host, (2) The ability of the mating cycle to generate recombinant strains with altered virulence or drug resistance, and (3) The potential for components of the mating circuitry to represent novel targets for antifungal therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI081704-05
Application #
8703591
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Duncan, Rory A
Project Start
2010-08-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
$381,650
Indirect Cost
$134,150
Name
Brown University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
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
Ene, Iuliana V; Bennett, Richard J (2014) The cryptic sexual strategies of human fungal pathogens. Nat Rev Microbiol 12:239-51
Sherwood, Racquel Kim; Scaduto, Christine M; Torres, Sandra E et al. (2014) Convergent evolution of a fused sexual cycle promotes the haploid lifestyle. Nature 506:387-90
Hickman, Meleah A; Zeng, Guisheng; Forche, Anja et al. (2013) The 'obligate diploid' Candida albicans forms mating-competent haploids. Nature 494:55-9
Porman, Allison M; Hirakawa, Matthew P; Jones, Stephen K et al. (2013) MTL-independent phenotypic switching in Candida tropicalis and a dual role for Wor1 in regulating switching and filamentation. PLoS Genet 9:e1003369
Si, Haoyu; Hernday, Aaron D; Hirakawa, Matthew P et al. (2013) Candida albicans white and opaque cells undergo distinct programs of filamentous growth. PLoS Pathog 9:e1003210
Mallick, Emily M; Bennett, Richard J (2013) Sensing of the microbial neighborhood by Candida albicans. PLoS Pathog 9:e1003661
Shintaku, Tatsushi; Glass, Kyle A; Hirakawa, Matthew P et al. (2013) Human endothelial cells internalize Candida parapsilosis via N-WASP-mediated endocytosis. Infect Immun 81:2777-87
Lin, Ching-Hsuan; Kabrawala, Shail; Fox, Emily P et al. (2013) Genetic control of conventional and pheromone-stimulated biofilm formation in Candida albicans. PLoS Pathog 9:e1003305

Showing the most recent 10 out of 14 publications