Candida albicans is the most common etiological agent of candidiasis, now the fourth leading cause of nosocomial infections carrying high levels of mortality despite currently available therapy. The human host and C. albicans have a long history of association. Consequently, this high degree of co-existence has led to the evolution of layers of defense mechanisms in the host and layers of virulence mechanisms in this opportunistic pathogen. It is clear that mechanisms of host immunity and pathogen virulence intertwine, giving rise to the highly complex nature of host-fungus interactions. However, the interplay between host immunity and fungal virulence has traditionally been ignored in the in the study of C. albicans pathogenesis and most investigations into these topics are overwhelmingly """"""""one-sided"""""""". We have constructed a genetically engineered strain of C. albicans (tet-NRG1) that allows """"""""in vivo"""""""" modulation of morphology and virulence, and here we propose to use this strain to gain insight into the mechanisms involved in immune defense against systemic infection.
The specific aims of this application are: i) to analyze the immune response and characterize protective immune mechanisms during infection with our C. albicans tet-NRG1 strain at different stages of the infectious process, and under conditions leading to colonization (when cells are maintained in the yeast morphology) or active disease (when filamentation is allowed to occur); ii) to investigate the mechanisms of innate and adaptive immunity by which primary infection with this strain protects against a subsequent challenge with a wild type virulent C. albicans strain; and iii) to examine the patterns of expression and role of Toll-like receptors in the innate and adaptive immunity responsible for protection against primary and secondary infections. 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. Our long term goal is to understand how the interplay between host immunity and candidal virulence determines the outcome of infection. Results are likely to lead to the development of new ? immune-based strategies for the prevention and treatment of systemic candidiasis that are urgently needed. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI064562-01A2
Application #
7150408
Study Section
Special Emphasis Panel (ZRG1-IDM-L (02))
Program Officer
Duncan, Rory A
Project Start
2006-07-15
Project End
2010-06-30
Budget Start
2006-07-15
Budget End
2007-06-30
Support Year
1
Fiscal Year
2006
Total Cost
$353,750
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
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
Uppuluri, Priya; Chaturvedi, Ashok K; Jani, Niketa et al. (2012) Physiologic expression of the Candida albicans pescadillo homolog is required for virulence in a murine model of hematogenously disseminated candidiasis. Eukaryot Cell 11:1552-6
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; Chaturvedi, Ashok K; Lopez-Ribot, Jose L (2009) Design of a simple model of Candida albicans biofilms formed under conditions of flow: development, architecture, and drug resistance. Mycopathologia 168:101-9
Carlisle, Patricia L; Banerjee, Mohua; Lazzell, Anna et al. (2009) Expression levels of a filament-specific transcriptional regulator are sufficient to determine Candida albicans morphology and virulence. Proc Natl Acad Sci U S A 106:599-604
Saville, Stephen P; Lazzell, Anna L; Chaturvedi, Ashok K et al. (2009) Efficacy of a genetically engineered Candida albicans tet-NRG1 strain as an experimental live attenuated vaccine against hematogenously disseminated candidiasis. Clin Vaccine Immunol 16:430-2
Saville, Stephen P; Lazzell, Anna L; Chaturvedi, Ashok K et al. (2008) Use of a genetically engineered strain to evaluate the pathogenic potential of yeast cell and filamentous forms during Candida albicans systemic infection in immunodeficient mice. Infect Immun 76:97-102
Banerjee, Mohua; Thompson, Delma S; Lazzell, Anna et al. (2008) UME6, a novel filament-specific regulator of Candida albicans hyphal extension and virulence. Mol Biol Cell 19:1354-65