Candida albicans represents one of the most prevalent opportunistic pathogens that cause disease in HIV+ patients. In fact, prior to the introduction of HAART therapies, C. albicans infections were considered predictive for AIDS diagnoses. C. albicans is a fungal pathogen that can infect virtually any tissue within the host and in HIV+ patients, it causes severe oral-pharyngeal candidiasis (OPC). The ability to respond to extracellular pH is essential for C. albicans pathogenesis and the oral-pharyngeal tract, which is generally a neutral-alkaline environment, can show marked pH variation depending on a number of factors. We have identified a signal transduction pathway, which culminates with activation of the Rim101p transcription factor by proteolytic processing. Rim101p governs expression of genes required for optimal growth at neutral-alkaline pH and is required for OPC. Thus, the long-term objective of our research is to determine how the RIM101 pathway senses environmental pH and responds to promote OPC. We will determine how the upstream members of the RIM101 pathway promote pH-dependent Rim101p processing and how processing contributes to Rim101p activity. We will determine how Rim101p promotes changes in gene expression and how the targets of the RIM101 pathway contribute to the neutral-alkaline pH responses and promote pathogenesis. We will also determine how the RIM101 pathway contributes to the interaction with host epithelial cells and OPC. From these studies, we will establish a framework to understand how Rim101p contributes to the success of C. albicans as an opportunistic pathogen. Further, because the RIM101 pathway promotes OPC, the information generated from these studies may provide insights into new treatment regimens and will identify new targets, including those factors that promote Rim101p processing, for potential drug development in order to prevent or treat OPC in the HIV+ population.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064054-05
Application #
7534528
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Duncan, Rory A
Project Start
2004-12-01
Project End
2009-11-30
Budget Start
2008-12-01
Budget End
2009-11-30
Support Year
5
Fiscal Year
2009
Total Cost
$340,199
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Rast, Timothy J; Kullas, Amy L; Southern, Peter J et al. (2016) Human Epithelial Cells Discriminate between Commensal and Pathogenic Interactions with Candida albicans. PLoS One 11:e0153165
Gomez-Raja, Jonathan; Davis, Dana A (2012) The ?-arrestin-like protein Rim8 is hyperphosphorylated and complexes with Rim21 and Rim101 to promote adaptation to neutral-alkaline pH. Eukaryot Cell 11:683-93
Wolf, Julie M; Johnson, Diedre J; Chmielewski, David et al. (2010) The Candida albicans ESCRT pathway makes Rim101-dependent and -independent contributions to pathogenesis. Eukaryot Cell 9:1203-15
Zacchi, Lucia F; Schulz, Wade L; Davis, Dana A (2010) HOS2 and HDA1 encode histone deacetylases with opposing roles in Candida albicans morphogenesis. PLoS One 5:e12171
Zacchi, Lucia F; Gomez-Raja, Jonatan; Davis, Dana A (2010) Mds3 regulates morphogenesis in Candida albicans through the TOR pathway. Mol Cell Biol 30:3695-710
Wolf, Julie M; Davis, Dana A (2010) Mutational analysis of Candida albicans SNF7 reveals genetically separable Rim101 and ESCRT functions and demonstrates divergence in bro1-domain protein interactions. Genetics 184:673-94
Davis, Dana A (2009) How human pathogenic fungi sense and adapt to pH: the link to virulence. Curr Opin Microbiol 12:365-70
Baek, Yong-Un; Li, Mingchun; Davis, Dana A (2008) Candida albicans ferric reductases are differentially regulated in response to distinct forms of iron limitation by the Rim101 and CBF transcription factors. Eukaryot Cell 7:1168-79
Kullas, Amy L; Martin, Samuel J; Davis, Dana (2007) Adaptation to environmental pH: integrating the Rim101 and calcineurin signal transduction pathways. Mol Microbiol 66:858-71
Baek, Yong-Un; Martin, Samuel J; Davis, Dana A (2006) Evidence for novel pH-dependent regulation of Candida albicans Rim101, a direct transcriptional repressor of the cell wall beta-glycosidase Phr2. Eukaryot Cell 5:1550-9