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)
Type
Research Project (R01)
Project #
5R01AI047837-13
Application #
8704377
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Duncan, Rory A
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost
Name
State University New York Stony Brook
Department
Genetics
Type
Schools of Medicine
DUNS #
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Douglas, Lois M; Konopka, James B (2016) Plasma membrane organization promotes virulence of the human fungal pathogen Candida albicans. J Microbiol 54:178-91
Wang, Hong X; Douglas, Lois M; Veselá, Petra et al. (2016) Eisosomes promote the ability of Sur7 to regulate plasma membrane organization in Candida albicans. Mol Biol Cell 27:1663-75
Naseem, Shamoon; Frank, David; Konopka, James B et al. (2015) Protection from systemic Candida albicans infection by inactivation of the Sts phosphatases. Infect Immun 83:637-45
Farnoud, Amir M; Toledo, Alvaro M; Konopka, James B et al. (2015) Raft-like membrane domains in pathogenic microorganisms. Curr Top Membr 75:233-68
Naseem, Shamoon; Araya, Esteban; Konopka, James B (2015) Hyphal growth in Candida albicans does not require induction of hyphal-specific gene expression. Mol Biol Cell 26:1174-87
Naseem, Shamoon; Konopka, James B (2015) N-acetylglucosamine Regulates Virulence Properties in Microbial Pathogens. PLoS Pathog 11:e1004947
Li, Lifang; Naseem, Shamoon; Sharma, Sahil et al. (2015) Flavodoxin-Like Proteins Protect Candida albicans from Oxidative Stress and Promote Virulence. PLoS Pathog 11:e1005147
Mor, Visesato; Rella, Antonella; Farnoud, Amir M et al. (2015) Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids. MBio 6:e00647
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

Showing the most recent 10 out of 31 publications