Lethal systemic infections caused by Candida albicans, the most common human fungal pathogen, are on the rise as new medical treatments and an aging population are increasing the pool of susceptible individuals. There is an urgent need to improve the therapeutic management of this escalating problem since current diagnostic procedures and antifungal drugs have limited effectiveness. The pathogenic effects of C. albicans are caused by its ability to grow in the host and disseminate to internal organs. Central to these processes is the plasma membrane. This essential barrier mediates secretion of virulence factors, morphogenesis, cell wall synthesis, and interfaces with the extracellular environment. The importance of the plasma membrane for virulence is underscored by the fact that it is directly or indirectly the target of the most effective antifungal drugs. Recent studies revealed that fungal plasma membranes are composed of discrete subdomains whose function in virulence and drug action is not known. Therefore, the Specific Aims are focused on the newly discovered plasma membrane subdomains called MCC/eisosomes. They consist of integral membrane proteins (MCC portion) and adjacent peripheral membrane proteins (eisosome). These unique domains are distinct from lipid rafts in that they are stable 300 nm-sized punctate patches that are associated with membrane invaginations. Our hypothesis is that MCC/eisosomes are essential for proper plasma membrane function and that their analysis will provide new paradigms for plasma membrane organization and the mechanisms of pathogenesis. In support of this, preliminary studies demonstrate that the MCC protein Sur7 is broadly important for morphogenesis, cell wall integrity, invasive growth, and virulence. Another key phenotype is that sur7? cells are >1,000-fold sensitive to copper, which correlates with decreased growth in macrophage phagosomes that are enriched in copper. The major goals are to identify the important proteins in these domains (Aim 1), to determine how the assembly and disassembly of MCC/eisosomes is regulated and can be perturbed by drugs (Aim 2), and to define the roles of MCC/eisosomes in virulence (Aim 3). The results are expected to aid development of new therapeutic approaches by identifying novel plasma membrane functions in fungal pathogenesis. Furthermore, these results will increase our understanding of current antifungal drugs and improve the prospects for more effective use.

Public Health Relevance

New medical treatments and an aging population are increasing the pool of individuals that are susceptible to lethal systemic infections caused by Candida albicans, the most common human fungal pathogen. Improved therapeutic approaches are needed to meet this escalating problem due to the limitations of current antifungal drugs. The proposed studies on the C. albicans plasma membrane, the essential barrier that surrounds the cell, are expected to improve therapeutic success by providing a better understanding of current antifungal drugs and by identifying new targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047837-12
Application #
8532804
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Duncan, Rory A
Project Start
2000-07-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
12
Fiscal Year
2013
Total Cost
$370,223
Indirect Cost
$135,223
Name
State University New York Stony Brook
Department
Genetics
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Douglas, Lois M; Konopka, James B (2014) Fungal membrane organization: the eisosome concept. Annu Rev Microbiol 68:377-93
Okada, Hiroki; Ohnuki, Shinsuke; Roncero, Cesar et al. (2014) Distinct roles of cell wall biogenesis in yeast morphogenesis as revealed by multivariate analysis of high-dimensional morphometric data. Mol Biol Cell 25:222-33
Epp, Elias; Nazarova, Elena; Regan, Hannah et al. (2013) Clathrin- and Arp2/3-independent endocytosis in the fungal pathogen Candida albicans. MBio 4:e00476-13
Douglas, Lois M; Wang, Hong X; Konopka, James B (2013) The MARVEL domain protein Nce102 regulates actin organization and invasive growth of Candida albicans. MBio 4:e00723-13
Douglas, Lois M; Wang, Hong X; Keppler-Ross, Sabine et al. (2012) Sur7 promotes plasma membrane organization and is needed for resistance to stressful conditions and to the invasive growth and virulence of Candida albicans. MBio 3:
Wang, Hong X; Douglas, Lois M; Aimanianda, Vishukumar et al. (2011) The Candida albicans Sur7 protein is needed for proper synthesis of the fibrillar component of the cell wall that confers strength. Eukaryot Cell 10:72-80
Zhang, Chengda; Konopka, James B (2010) A photostable green fluorescent protein variant for analysis of protein localization in Candida albicans. Eukaryot Cell 9:224-6
Alvarez, Francisco J; Douglas, Lois M; Konopka, James B (2009) The Sur7 protein resides in punctate membrane subdomains and mediates spatial regulation of cell wall synthesis in Candida albicans. Commun Integr Biol 2:76-7
Douglas, Lois M; Martin, Stephen W; Konopka, James B (2009) BAR domain proteins Rvs161 and Rvs167 contribute to Candida albicans endocytosis, morphogenesis, and virulence. Infect Immun 77:4150-60
Hoyer, Lois L; Konopka, James (2008) Candida here, and Candida there, and Candida everywhere! Future Microbiol 3:271-3

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