Candida albicans is an opportunistic pathogen capable of causing debilitating mucosal infections as well as life-threatening systemic infections. Individuals infected with Human Immunodeficiency Virus (HIV) are particularly susceptible to Candida infections, with 90% of this population experiencing oropharyngeal candidiasis at some stage of the disease. C. albicans is ubiquitously present in the natural microflora of the body and its success as both a commensal and a pathogen relies on its ability to rapidly adapt to changes in host physiology. This proposal will establish the role of phenotypic switching in C. albicans biology, with emphasis on the role of switching in promoting colonization and infection of distinct sites in the immunocompromised host. Phenotypic switching refers to an epigenetic phenomenon in which cells undergo a reversible and heritable change in colony morphology and gene expression. In C. albicans, elevated rates of phenotypic switching are associated with increased invasive growth and drug resistance, particularly in HIV-infected individuals, making an understanding of the mechanism(s) of switching of paramount importance. Experiments outlined in this proposal will address the mechanism of phenotypic switching between white and opaque forms of C. albicans. The white-opaque switch plays a pleiotropic role in C. albicans biology, directing tissue specificity, virulence, and biofilm formation, yet the molecular mechanism of white-opaque switching is only now beginning to be elucidated. Preliminary experiments indicate that multiple, apparently diverse, factors impact the rate of white-opaque switching indirectly by their effect on cellular growth. The unexpected connection between phenotypic switching and cell growth will be further investigated in Aim 1, as it represents a novel mechanism by which the cell can adapt to environmental stress.
The second Aim of the proposal will identify novel regulators of the white-opaque switch using an overexpression screen of transcription factors. It is expected that the construction of an overexpression library will also prove a useful genetic tool for many researchers in the field. Finally, the third Aim of the proposal will establish the temporal and spatial regulation of white- opaque switching in the mammalian host using RIVET (recombinase in vivo expression technology). Thus, taken together, the proposed studies will determine both the in vitro regulation of the white-opaque switch by environmental and host factors, as well as defining the in vivo niche where switching occurs. The completion of these studies will therefore shed light on how phenotypic switching is used by C. albicans to promote adaptation to the host and help avoid clearance by the immune system.

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 the mechanisms used by C. albicans to generate phenotypic diversity and how these processes promote survival and infection in the mammalian host. The research also addresses how C. albicans is able to switch from growing as a harmless commensal to an opportunistic pathogen that can invade virtually all the organs in the body.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI081560-01A2
Application #
7755142
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Duncan, Rory A
Project Start
2009-06-19
Project End
2011-05-31
Budget Start
2009-06-19
Budget End
2010-05-31
Support Year
1
Fiscal Year
2009
Total Cost
$201,719
Indirect Cost
Name
Brown University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Bennett, Richard J (2015) The parasexual lifestyle of Candida albicans. Curr Opin Microbiol 28:10-7
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
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
Mallick, Emily M; Bennett, Richard J (2013) Sensing of the microbial neighborhood by Candida albicans. PLoS Pathog 9:e1003661
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
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; Alby, Kevin; Hirakawa, Matthew P et al. (2011) Discovery of a phenotypic switch regulating sexual mating in the opportunistic fungal pathogen Candida tropicalis. Proc Natl Acad Sci U S A 108:21158-63
Alby, Kevin; Bennett, Richard J (2011) Interspecies pheromone signaling promotes biofilm formation and same-sex mating in Candida albicans. Proc Natl Acad Sci U S A 108:2510-5
Jones Jr, Stephen K; Bennett, Richard J (2011) Fungal mating pheromones: choreographing the dating game. Fungal Genet Biol 48:668-76
Bennett, Richard J (2010) Coming of age--sexual reproduction in Candida species. PLoS Pathog 6:e1001155

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