Candida albicans is the most common etiological agent of candidiasis, now the fourth leading cause of nosocomial infections. Even with aggressive drug therapy the prognosis for the patient is not good with mortality rates ranging from 30-50%, not to mention the significant economic burden associated with treatment. C. albicans is able to undergo reversible morphological transitions between unicellular yeast-like and filamentous forms and it is this attribute that is considered pivotal to its pathogenic potential. However, the current understanding of the role played by morphogenesis in C. albicans virulence is based primarily on data obtained from studies using genetically defined mutant strains unable to undergo this developmental programme. To overcome these concerns, we have constructed a tet-NRG1 regulatable strain (SSY50-B) in which morphogenetic conversions can be externally manipulated both in vitro and in vivo. Virulence studies performed using this strain have provided the most compelling evidence to date linking morphogenesis and virulence in this opportunistic pathogen. This application aims to further explore the mechanisms by which NRG1 regulates C. albicans filamentation and virulence for which we propose three specific aims: i) to use a genetic screen to identify NRG1-regulated genes that play key roles in C. albicans filamentation and pathogenesis, ii) to assess the individual roles of the NRG1-regulated genes in virulence by constructing """"""""knock out"""""""" mutant strains and testing them in a murine model of disseminated candidiasis and iii) to screen small molecule libraries to identify compounds that inhibit filamentation and virulence by mimicking C. albicans Nrglp function. ? ? Relevance to public health: Candida albicans is the main causative agent of candidiasis, the most frequent fungal infection and now the fourth leading cause of infections in US hospitals, with high mortality rates and soaring economic burden. The main idea behind this study is to further investigate the relationship between filamentation and virulence, as controlled by key regulatory genes, which may serve as the basis for the development of novel strategies for the treatment of these infections. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI063256-03
Application #
7392348
Study Section
Special Emphasis Panel (ZRG1-IDM-M (02))
Program Officer
Duncan, Rory A
Project Start
2006-05-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
3
Fiscal Year
2008
Total Cost
$269,572
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
800189185
City
San Antonio
State
TX
Country
United States
Zip Code
78249
Romo, Jesus A; Pierce, Christopher G; Esqueda, Marisol et al. (2018) In Vitro Characterization of a Biaryl Amide Anti-virulence Compound Targeting Candida albicans Filamentation and Biofilm Formation. Front Cell Infect Microbiol 8:227
Romo, Jesus A; Pierce, Christopher G; Chaturvedi, Ashok K et al. (2017) Development of Anti-Virulence Approaches for Candidiasis via a Novel Series of Small-Molecule Inhibitors of Candida albicans Filamentation. MBio 8:
Cleary, Ian A; Reinhard, Sara M; Lazzell, Anna L et al. (2016) Examination of the pathogenic potential of Candida albicans filamentous cells in an animal model of haematogenously disseminated candidiasis. FEMS Yeast Res 16:fow011
Pierce, Christopher G; Chaturvedi, Ashok K; Lazzell, Anna L et al. (2015) A Novel Small Molecule Inhibitor of Candida albicans Biofilm Formation, Filamentation and Virulence with Low Potential for the Development of Resistance. NPJ Biofilms Microbiomes 1:
Pierce, Christopher G; Saville, Stephen P; Lopez-Ribot, Jose L (2014) High-content phenotypic screenings to identify inhibitors of Candida albicans biofilm formation and filamentation. Pathog Dis 70:423-31
Cleary, I A; MacGregor, N B; Saville, S P et al. (2012) Investigating the function of Ddr48p in Candida albicans. Eukaryot Cell 11:718-24
Cleary, Ian A; Lazzell, Anna L; Monteagudo, Carlos et al. (2012) BRG1 and NRG1 form a novel feedback circuit regulating Candida albicans hypha formation and virulence. Mol Microbiol 85:557-73
Cleary, Ian A; Reinhard, Sara M; Miller, C Lindsay et al. (2011) Candida albicans adhesin Als3p is dispensable for virulence in the mouse model of disseminated candidiasis. Microbiology 157:1806-15
Chaturvedi, Ashok K; Lazzell, Anna L; Saville, Stephen P et al. (2011) Validation of the tetracycline regulatable gene expression system for the study of the pathogenesis of infectious disease. PLoS One 6:e20449
Uppuluri, Priya; Pierce, Christopher G; Thomas, Derek P et al. (2010) The transcriptional regulator Nrg1p controls Candida albicans biofilm formation and dispersion. Eukaryot Cell 9:1531-7

Showing the most recent 10 out of 13 publications