Candidiasis now represents the third most frequent nosocomial infection in hospitals both in the US and worldwide, and C. albicans remains the most frequent causative agent of candidiasis. Unfortunately these infections carry unacceptably high mortality rates. Candidiasis is often associated with biofilm formation and once established, biofilms have the potential to initiate or prolong infections by providing a safe sanctuary from which organisms can invade local tissue, seed new infection sites and resist eradication efforts. Biofilm accumulation results from the balance of attachment, growth, and dispersion processes. Without any question, of these phenomena, the least understood is biofilm dispersion. In the case of C. albicans this is particularly worrisome because biofilm dispersion is the step that represents the main culprit associated with life-threatening clinical infections in susceptible patients: it is precisely the detached cells that are responsible for septicemia and for dissemination to target organs prior to the establishment of invasive disease. Importantly, both of these clinical manifestations (candidemia and systemic invasive candidiasis) are associated with the high morbidity and mortality rates. Therefore, the main objective of the proposed studies is to examine the process of biofilm dispersion. To this end we will: i) identify the environmental signals associated with C. albicans biofilm dispersion, ii) identify the molecular mechanisms involved in biofilm dispersion and iii) analyze the phenotypes of yeast cells dispersed from the biofilm, with special emphasis on adhesive properties, drug resistance and virulence. The proposed research is innovative since it studies biofilms, one of the major paradigms of modern microbiology. Moreover, it focuses on a process, biofilm dispersion, that has largely been ignored in the past by C. albicans investigators.

Public Health Relevance

Biofilm formation has severe consequences for human health. The main idea behind this study is that we need to better understand how C. albicans cells detach or separate from biofilms, since these cells are responsible for the subsequent establishment of infections in different organs. If we prevent this critical step, it may lead to a substantial reduction in morbidity, mortality and extended hospital stay, while simultaneously reducing healthcare costs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI080930-02
Application #
7847613
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Duncan, Rory A
Project Start
2009-05-22
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
2
Fiscal Year
2010
Total Cost
$180,625
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
Uppuluri, Priya; Lopez-Ribot, Jose L (2016) Go Forth and Colonize: Dispersal from Clinically Important Microbial Biofilms. PLoS Pathog 12:e1005397
Banerjee, Mohua; Uppuluri, Priya; Zhao, Xiang R et al. (2013) Expression of UME6, a key regulator of Candida albicans hyphal development, enhances biofilm formation via Hgc1- and Sun41-dependent mechanisms. Eukaryot Cell 12:224-32
Martins, Margarida; Henriques, Mariana; Lopez-Ribot, Jose L et al. (2012) Addition of DNase improves the in vitro activity of antifungal drugs against Candida albicans biofilms. Mycoses 55:80-5
Martins, Margarida; Lazzell, Anna L; Lopez-Ribot, Jose L et al. (2012) Effect of exogenous administration of Candida albicans autoregulatory alcohols in a murine model of hematogenously disseminated candidiasis. J Basic Microbiol 52:487-91
Robbins, Nicole; Uppuluri, Priya; Nett, Jeniel et al. (2011) Hsp90 governs dispersion and drug resistance of fungal biofilms. PLoS Pathog 7:e1002257
Uppuluri, Priya; Srinivasan, Anand; Ramasubramanian, Anand et al. (2011) Effects of fluconazole, amphotericin B, and caspofungin on Candida albicans biofilms under conditions of flow and on biofilm dispersion. Antimicrob Agents Chemother 55:3591-3
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
Uppuluri, Priya; Chaturvedi, Ashok K; Srinivasan, Anand et al. (2010) Dispersion as an important step in the Candida albicans biofilm developmental cycle. PLoS Pathog 6:e1000828
Martins, Margarida; Uppuluri, Priya; Thomas, Derek P et al. (2010) Presence of extracellular DNA in the Candida albicans biofilm matrix and its contribution to biofilms. Mycopathologia 169:323-31
Pierce, Christopher G; Uppuluri, Priya; Tummala, Sushma et al. (2010) A 96 well microtiter plate-based method for monitoring formation and antifungal susceptibility testing of Candida albicans biofilms. J Vis Exp :

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