The goal of this study is to identify proteins and mechanisms that regulate filamentous growth and pathogenesis in the oral microbe Candida albicans, the primary pathogen causing oral candidiasis. One of the major regulators of filamentous growth in Candida and other fungal species are signal transduction pathways. The signaling pathway on which the proposal is focused is the Cek1 MAPK pathway, which plays a critical role in hyphal invasive growth. We will investigate the cell-surface signaling mucin Msb2 that regulates this pathway to determine how Msb2 is activated in C. albicans, what proteins regulate Msb2 function, what Msb2 is sensing at the cell surface, and what roles it might play in regulating filamentous growth, biofilm formation, and immune system interactions. We will test quorum-sensing molecules and expression of Sap proteases for Msb2-dependent Cek1 activation. We will also test whether the extracellular glycodomain of Msb2, which we show is released from cells, plays a role in biofilm/mat formation and cell-surface architecture. Signaling mucins such as Msb2 are an evolutionary conserved class of cell-surface glycoproteins that have only recently been studied in microbial species. Signaling pathways sense changes in the extracellular environment and relay those changes to the inside of the cell. Because signaling pathways exert global control over cellular behaviors, they represent attractive targets to shut down or inhibit cellular differentiation programs or target genes. Given the serious threat of this fungal pathogen to human health, and given that current strategies to treat Candidal infections are in many cases ineffectual, our long-term goal is a deeper understanding of the pathogenic response in this microbe in order to identify a new class of drug targets.

Public Health Relevance

Candida albicans is a human fungal pathogen that can become a serious threat to human health especially in immunocompromised people. The pathogenesis of C. albicans is related to its ability to form invasive filaments, and initiation of filamentation is governed by the cell surface signaling mucin Msb2. The aims of this project are to define what proteins regulate Msb2 function, what Msb2 is sensing at the cell surface, and what roles it might play in biofilm formation and immune system interactions in order to achieve our long-term goals for a deeper understanding of the pathogenic response in this microbe in order to identify a new class of drug targets aimed at the cell surface Msb2 protein.)

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE022720-01A1
Application #
8458676
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
2013-09-13
Project End
2018-08-31
Budget Start
2013-09-13
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$381,747
Indirect Cost
$131,747
Name
State University of New York at Buffalo
Department
Dentistry
Type
Schools of Dentistry
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Puri, Sumant; Lai, William K M; Rizzo, Jason M et al. (2014) Iron-responsive chromatin remodelling and MAPK signalling enhance adhesion in Candida albicans. Mol Microbiol 93:291-305
Adhikari, Hema; Cullen, Paul J (2014) Metabolic respiration induces AMPK- and Ire1p-dependent activation of the p38-Type HOG MAPK pathway. PLoS Genet 10:e1004734