Dynamics of mixed candida species biofilms in response to antifungal treatment

Summary

Principal Investigator: Geethanjali Vipulanandan
Abstract: DESCRIPTION (provided by applicant): With a high attributable mortality rate of 40-50%, Candida species represent the fourth leading cause of hospital-acquired bloodstream infections in the United States. These fungal pathogens are normally found as commensals in mammalian mucosal niches, especially the oral cavity. In immunocompromised patients, Candida overgrowth leads to the formation of biofilms, which play an important role in the development of infection. Biofilms are complex microbial communities that adhere to a surface and are enclosed within an extracellular matrix. Many studies have shown that biofilms are generally more resistant to antimicrobial agents than single, planktonic cells. These biofilms are associated with the opportunistic yeast infection, oral candidiasis (oral thrush), found in newborns and many patients with AIDS, diabetes and cancer. Even though C. albicans is the predominant organism found in oral thrush, there is an increasing incidence of oral thrush isolates consisting of non-albicans Candida species (especially C. glabrata, C. dubliniensis and C. tropicalis). This finding is clinically relevant since conventional doses of antifungals are sometimes ineffective at clearing these oral infections. While single-species Candida biofilms have been well-studied, considerably less is known about the composition and interaction of Candida species in mixed biofilms in response to antifungal treatment. I have recently developed a highly accurate quantitative-PCR-based approach to determine the precise species composition of mixed Candida biofilms. Preliminary data shows that the proportion of C. glabrata in the mixed biofilm increases significantly upon treatment with fluconazole. My preliminary data also indicates that the metabolic activity of biofilms is altered when these four Candida species are mixed under different nutritional environments, suggesting that biofilm composition and dynamics have changed as well. Based on this data, my hypothesis is that the shift in mixed Candida species biofilm composition and spatial architecture following antifungal treatment favors non-albicans Candida species that are intrinsically resistant or rapidly develop drug resistance. In order to test this hypothesis, I will perform experiments to address the following specific aims: (1) To determine the precise composition of mixed Candida species biofilms generated from susceptible and drug-resistant strains in the presence vs. absence of antifungal treatment and (2) To determine the spatial architecture of Candida species in mixed biofilms generated in the presence and absence of antifungal treatment. Collectively, these innovative studies will have significant impact since they will provide new information about how mixed Candida species biofilms are associated with antifungal resistance. These studies will also test the efficacy of my quantitative-PCR assay to serve as a diagnostic tool for rapid composition determination of mixed Candida biofilms (i.e. oral thrush). Since mixed Candida species biofilms are encountered more frequently, these studies will pave the way for the development of more effective antifungals to improve patient outcomes. Moreover, successful completion of this project will provide exceptional training, advance my career development and prepare me to become a pediatric dental clinician scientist.
Funding Period: -----------------201 - ----------------2018
more information: NIH RePORT

Detail Information

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. The transcriptional circuitry controlling biofilm development in Candida albicans
    Alexander D Johnson; Fiscal Year: 2013
    ..C. albicans biofilms formed on implanted medical devices and are a major source of new infections. Understanding biofilms in more detail may lead to improvements in preventing and treating C. albicans infections. ..
  3. A Structural Approach for Treating Drug Resistant Fungal Pathogens
    Mitchell W Mutz; Fiscal Year: 2013
    ..4. Screen and select compounds against both C. albicans and non-albicans Candida strains. ..
  4. Pheromone Signaling, Sex, and Virulence in Candida albicans
    RICHARD JOHN BENNETT; Fiscal Year: 2013
    ....
  5. Phenotypic Plasticity and Inter-Species Communication in Candida Albicans
    STEPHEN KNOX JONES; Fiscal Year: 2013
    ..Understanding the white-opaque switch and inter-species signaling events will allow the development of new treatments for preventing the often debilitating, and sometimes even fatal, infections associated with this fungal pathogen. ..
  6. Discovering a Combination Therapeutic Approach to Use in the Treatment of Cryptoc
    Mitchell W Mutz; Fiscal Year: 2013
    ..Aim 3. Iterate library as needed to generate an additional 40 compounds based on the Aim 2 results to refocus library and perform more detailed pk and pd screens. ..
  7. Targeting virulence against oral candidiasis in HIV/AIDS
    Jose L Lopez-Ribot; Fiscal Year: 2013
    ....
  8. Investigate the multifunctional adhesins in Cryptococcus
    Xiaorong Lin; Fiscal Year: 2013
    ....
  9. Function And Genetic Control of Matrix Carbohydrates in Candida Biofilms
    Aaron P Mitchell; Fiscal Year: 2013
    ....
  10. Extracellular pH modulation by Candida albicans in vitro and in vivo
    Michael C Lorenz; Fiscal Year: 2013
    ..Finally, we will use live cell imaging to dissect the intracellular trafficking of C. albicans in the macrophage and determine the role of alkalinization and ammonia release in modulating endocytic maturation. ..
  11. Role of Ppg1 phosphatase in controlling Candida albicans morphology and virulence
    MOHAMMAD ALBATAINEH; Fiscal Year: 2013
    ..albicans filamentous growth and virulence will provide information that may eventually lead to the development of novel and more effective antifungal strategies to treat oral and systemic candidiasis. ..
  12. Role of phosphatidylethanolamine in regulating virulence in Candida albicans
    SARAH ELIZABETH DAVIS; Fiscal Year: 2013
    ..Rim101 pathway), 2) Determine if PS and PE play a role in evading the immune response 3) Discover if auxotrophy for ethanolamine, a known substrate of PE, affects virulence of the mutants in the host. ..
  13. Caloric Restricted Rodent Colony
    RICK MORIN; Fiscal Year: 2013
    ..The purpose of this project is to develop, maintain and distribute a standing colony ofaged, calorically restricted rodents ofdefined strains for use by investigators in studies of aging. ..
  14. CANDIDACIDAL MECHANISMS OF SALIVARY HISTATINS
    Mira Edgerton; Fiscal Year: 2013
    ..This approach will support our long-range goal to develop alternative peptide- based therapies for treatment of oral candidiasis, which is currently limited to a small group of antifungal drugs. ..
  15. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  16. Secreted Virulence Proteins and biofilm formation in Candida
    SAMUEL AUSTIN LEE; Fiscal Year: 2013
    ..abstract_text> ..
  17. Novel Azole Resistance Mechanisms in Candida albicans
    P David Rogers; Fiscal Year: 2013
    ..Our approach is innovative as it focuses on novel resistance mechanisms and employs creative strategies to achieve the proposed specific aims. ..
  18. Genetic Control of C. albicans Biofilm Formation
    Aaron P Mitchell; Fiscal Year: 2013
    ..Proposed studies will improve our understanding of mechanisms that permit Candida growth on implanted devices. The mechanistic understanding will permit longer-term development of new therapeutic and diagnostic strategies. ..
  19. Genome Integrity in Candida albicans
    Judith G Berman; Fiscal Year: 2013
    ....
  20. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  21. The role of Candida albicans biofilms in a novel rat model of denture stomatitis
    MAIRI NOVERR; Fiscal Year: 2013
    ..The third specific aim is to test the hypothesis that mixed species infection with C. albicans and C. glabrata accelerates disease progression in denture stomatitis. ..
  22. Candida-Bacteria Communication in Oral Biofilms
    Richard J Lamont; Fiscal Year: 2013
    ..Potential targets for inhibition of co-adhesion and community development can thus be identified, and these may ultimately prove a means for the control of infection by C. albicans. ..
  23. Dissecting triazole resistance and transcriptional regulation of ergosterol homeo
    Haoping Liu; Fiscal Year: 2013
    ..albicans. Identification of smal molecules and their targets will lead to the discovery of novel pathways and mechanisms that control ergosterol homeostasis and triazole resistance. ..
  24. Phosphoinositide-dependent kinase-1 as an antifungal drug target
    Damian J Krysan; Fiscal Year: 2013
    ..This focused research plan is designed to systematically evaluate the antifungal activity of human PDK1 inhibitor scaffolds and will hopefully lead to first-in-class antifungal molecules for additional development. ..
  25. Genetic and Evolutionary Basis of Fungal Drug Resistance
    Zhenglong Gu; Fiscal Year: 2013
    ..This work may improve diagnosis and treatment strategies for pathogenic fungal infection. ..
  26. Determination of morphology and virulence in Candida albicans
    David Kadosh; Fiscal Year: 2013
    ..Ultimately, these studies should provide information leading to the development of more effective treatments for yeast infections. ..