MOLECULAR BASIS OF VIRULENCE FACTORS OF ORAL FUNGAL SP.

Summary

Principal Investigator: M Romagnoli
Abstract: [unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] This is a Revision of a K22 Scholar Development and Faculty Transition Award application, submitted on behalf of Mary Ann Jabra-Rizk who is currently a Post-Doctoral Fellow in the Department of Diagnostic Sciences and Pathology at the U of MD Dental School. A 2 year Scholar Development phase and three years of Faculty Transition win be centered at U of MD involving co-mentors and consultants at Johns Hopkins, the U of VA and the U of Wurzburg and will establish Dr. Jabra-Rizk as an independent expert in oral fungal diseases. An Advisory Committee at the U of MD will evaluate her progress and aid in the Faculty Transition. The hypothesis to be tested during the Scholar Development is that C. dubliniensis is a species that exhibits constant cell surface hydrophobicity, possessing a homologue to the C. albicans CSHl gene which encodes a hydrophobic cell wall protein involved in cell adherence but differs in the expression of the MNN mannosylation family of genes and other putative virulence genes. Two aims are planned: 1. (a) Determine the presence of the C. albicans CSHl and CaMNN9 genes or homologues of the genes in C. dubliniensis using PCR primers designed based on the C albicans CSIII and CaMNN9 gene sequences. These will be subsequently amplified and cloned using C. dubliniensis CDS6 genomic DNA and probe hybridization. A C. dubliniensis knockout of the CSH 1 homologue gene will be generated using the latest technique (ura3 amxotrophic C. dubliniensis mutants in the URA-blaster) in gene disruption technique (b) Determine the effect of the disruption of the CdCShl gene on adherence by assessing the C. dubliniensis knockout clone for cell surface hydrophobicity7 adhesion to fibronectin, adherence to Fusobacterium nucleatum and pooled human buccal epithelial cells, in comparison to the wild type (c) Determine differences in the ability of macrophages to phagocytize 37C-grown C. albicans, 37C grown CdCSH1 mutant and wild type C. dubliniensis and the C. albicans mnn9 mutant in order to determine the effect of structural changes in the side chains of cell wall mannan on the ability of C. dubliniensis and C. albicans to evade host cell phagocytosis. 2. Based on cDNA microarray sequences of genes in the C. albicans genome, we will determine levels of differential expression of the CSHl and CaMNN9 genes between hydrophilic (37C-grown C. albicans) and hydrophobic (250C-grown C. albicans, 25 and 37C-grown C. dubliniensis and C. albicans mutants, A9V10 and Camnn9) yeast cells, as well as the C. dubliniensis CdCSHl mutant generated in Aim 1. Dr. Jabra-Rizic will subsequently utilize the information and mutants generated to investigate whole genome differences between C. dubliniensis and C. albicans in the Faculty Transition phase using DNA microarrays. She will also analyze differences in the levels of expression of hsp90 gene and other glycosylation and heat shock proteins genes in C. dubliniensis. In addition, a hsp90 knock out mutant of C. albicans will be generated and assessed for thermotolerance and phagcytosis by macrophages. Long range plans include using the mutants generated to study Candida mannoprotein-specific host immunomodulation, such as stimulation of cytokines and chemokines.
Funding Period: 2002-09-01 - 2008-06-30
more information: NIH RePORT

Top Publications

  1. pmc Protection of the oral mucosa by salivary histatin-5 against Candida albicans in an ex vivo murine model of oral infection
    Brian M Peters
    Graduate Program in Life Sciences, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
    FEMS Yeast Res 10:597-604. 2010
  2. pmc Farnesol-induced apoptosis in Candida albicans
    Mark E Shirtliff
    Department of Microbial Pathogenesis, Dental School, University of Maryland, Baltimore, MD 21201, USA
    Antimicrob Agents Chemother 53:2392-401. 2009
  3. pmc A novel immune evasion strategy of candida albicans: proteolytic cleavage of a salivary antimicrobial peptide
    Timothy F Meiller
    Department of Oncology and Diagnostic Sciences, University of Maryland Baltimore, Baltimore, Maryland, United States of America
    PLoS ONE 4:e5039. 2009
  4. ncbi Prevalence of oral Candida species ina North American pediatric population
    Mary Ann Jabra Rizk
    Department of Diagnostic Sciences and Pathology, Dental School, University of Maryland, Baltimore, MD 21201, USA
    J Clin Pediatr Dent 31:260-3. 2007
  5. ncbi Salivary histatin-5 and oral fungal colonisation in HIV+ individuals
    Sandra R Torres
    Department of Diagnostic Sciences and Pathology, Dental School, University of Maryland, Baltimore, MD 21201, USA
    Mycoses 52:11-5. 2009
  6. pmc Farnesol, a fungal quorum-sensing molecule triggers apoptosis in human oral squamous carcinoma cells
    Mark A Scheper
    Department of Diagnostic Sciences and Pathology, University of Maryland, Baltimore, MD 21201, USA
    Neoplasia 10:954-63. 2008
  7. ncbi Effect of farnesol on Candida dubliniensis biofilm formation and fluconazole resistance
    Mary Ann Jabra-Rizk
    Department of Diagnostic Sciences and Pathology, Dental School, University of Maryland, Baltimore, MD 21201, USA
    FEMS Yeast Res 6:1063-73. 2006
  8. pmc Effect of farnesol on Staphylococcus aureus biofilm formation and antimicrobial susceptibility
    M A Jabra-Rizk
    Department of Diagnostic Sciences and Pathology, Dental School, University of Maryland Baltimore, 666 W Baltimore Street, Room 4G11, Baltimore, MD 21201, USA
    Antimicrob Agents Chemother 50:1463-9. 2006
  9. ncbi Prevalence of Candida dubliniensis fungemia at a large teaching hospital
    Mary Ann Jabra-Rizk
    Department of Diagnostic Sciences and Pathology, Dental School, University of Maryland, Baltimore, MD 21201, USA
    Clin Infect Dis 41:1064-7. 2005

Scientific Experts

  • M Romagnoli
  • Mary Ann Jabra-Rizk
  • Timothy F Meiller
  • Mark A Scheper
  • Brian M Peters
  • Mark E Shirtliff
  • Sandra R Torres
  • Jingsong Zhu
  • Mary Ann Jabra Rizk
  • M A Jabra-Rizk
  • Sara El Shaye
  • Paul L Fidel
  • William Hackett
  • Roelien A M Meijering
  • Alfredo Garzino-Demo
  • Robert Winkler
  • Bernhard Hube
  • Amy Ton
  • Lydia Schild
  • Bastiaan P Krom
  • Valli Meeks
  • Megan L Harris
  • Isabel Rambob
  • Lindsey K Grossman
  • Glenn Minah
  • M E Shirtliff
  • Timothy Meiller
  • C E James
  • T F Meiller
  • Mark Shirtliff
  • Cathy James
  • Richard A Venezia
  • Graeme Forrest
  • Kristina Mankes
  • Jennifer K Johnson

Detail Information

Publications10

  1. pmc Protection of the oral mucosa by salivary histatin-5 against Candida albicans in an ex vivo murine model of oral infection
    Brian M Peters
    Graduate Program in Life Sciences, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
    FEMS Yeast Res 10:597-604. 2010
    ..Combined, the findings from this study demonstrate for the first time the efficacy of salivary Hst-5 in protecting host oral tissue against C. albicans infection, thereby affirming the therapeutic potential of this natural host peptide...
  2. pmc Farnesol-induced apoptosis in Candida albicans
    Mark E Shirtliff
    Department of Microbial Pathogenesis, Dental School, University of Maryland, Baltimore, MD 21201, USA
    Antimicrob Agents Chemother 53:2392-401. 2009
    ..albicans through caspase activation, implying an important physiological role for farnesol in the fungal cell life cycle with important implications for adaptation and survival...
  3. pmc A novel immune evasion strategy of candida albicans: proteolytic cleavage of a salivary antimicrobial peptide
    Timothy F Meiller
    Department of Oncology and Diagnostic Sciences, University of Maryland Baltimore, Baltimore, Maryland, United States of America
    PLoS ONE 4:e5039. 2009
    ..This report characterizes the first defined mechanism behind the enhanced susceptibility of HIV+ individuals to oral candidiasis since the emergence of HIV...
  4. ncbi Prevalence of oral Candida species ina North American pediatric population
    Mary Ann Jabra Rizk
    Department of Diagnostic Sciences and Pathology, Dental School, University of Maryland, Baltimore, MD 21201, USA
    J Clin Pediatr Dent 31:260-3. 2007
    ..Intrinsic differences in the pediatric population may favor the presence of yeast species other than C. albicans...
  5. ncbi Salivary histatin-5 and oral fungal colonisation in HIV+ individuals
    Sandra R Torres
    Department of Diagnostic Sciences and Pathology, Dental School, University of Maryland, Baltimore, MD 21201, USA
    Mycoses 52:11-5. 2009
    ....
  6. pmc Farnesol, a fungal quorum-sensing molecule triggers apoptosis in human oral squamous carcinoma cells
    Mark A Scheper
    Department of Diagnostic Sciences and Pathology, University of Maryland, Baltimore, MD 21201, USA
    Neoplasia 10:954-63. 2008
    ..The capability of farnesol to trigger apoptosis in cancer cells makes it a potential tool for studying tumor progression and an attractive candidate as a therapeutic agent...
  7. ncbi Effect of farnesol on Candida dubliniensis biofilm formation and fluconazole resistance
    Mary Ann Jabra-Rizk
    Department of Diagnostic Sciences and Pathology, Dental School, University of Maryland, Baltimore, MD 21201, USA
    FEMS Yeast Res 6:1063-73. 2006
    ..Synergy testing of farnesol and fluconazole in resistant strains resulted in reversal of fluconazole resistance, indicating a potential application for farnesol as an adjuvant therapeutic agent...
  8. pmc Effect of farnesol on Staphylococcus aureus biofilm formation and antimicrobial susceptibility
    M A Jabra-Rizk
    Department of Diagnostic Sciences and Pathology, Dental School, University of Maryland Baltimore, 666 W Baltimore Street, Room 4G11, Baltimore, MD 21201, USA
    Antimicrob Agents Chemother 50:1463-9. 2006
    ....
  9. ncbi Prevalence of Candida dubliniensis fungemia at a large teaching hospital
    Mary Ann Jabra-Rizk
    Department of Diagnostic Sciences and Pathology, Dental School, University of Maryland, Baltimore, MD 21201, USA
    Clin Infect Dis 41:1064-7. 2005
    ..Peptide nucleic acid fluorescent in situ hybridization analysis was used as a rapid and reliable test for differentiating C. dubliniensis from Candida albicans, making it feasible to determine the prevalence of C. dubliniensis fungemia...