Oral thrush, a mucosal biofilm infection, continues to afflict an unacceptably high percentage of immunocompromised individuals, particularly neonates and patients on immunosuppressive medications. Although C. albicans is the primary etiologic pathogen, the microbial ecology of this infection is complex since it contains members of the endogenous bacterial flora. Candida forms mixed biofilms with streptococci in the oral cavities of humans but the role of these biofilms during the course of mucosa-associated or invasive infections is unknown. In the proposed work C. albicans and S. oralis will be used as model organisms to study the mucosal disease-promoting interactions of the non-pathogenic oral bacterial flora with opportunistic fungi that have established virulence, such as C. albicans. Our studies rely upon a systematic and comprehensive approach to characterize both host- and pathogen-mediated aspects of the pathogenesis of mixed opportunistic mucosal infections. We hypothesize that enhanced proinflammatory host responses and increased Candida virulence mediate a pathogenic synergy of these microorganisms in the oral and esophageal mucosa.
In aim I we will characterize the influence of streptococci on the TLR2/4-mediated host response to mixed infection and test the hypothesis that the exaggerated proinflammatory and neutrophilic response to mixed Candida-streptococcal biofilms leads to increased pathology.
In aim II we will examine mechanisms of mixed microbial community assembly and virulence. The role of streptococcal glucosyltransferases, major enzymes contributing to the extracellular slime that promotes biofilms, will be examined. In C. albicans we will identify the transcription factor(s) tht control dual community assembly. We will also test the hypothesis that S. oralis increases the virulence of C. albicans by modulating several Rim101-dependent virulence genes, important in oral mucosal invasion, using a mouse oral co-infection model. An understanding of the effects of oral streptococci on Candida virulence and the mucosal inflammatory response will provide important novel insights into the pathogenesis of fungal infection within the oral and esophageal host niche. More importantly, the discovery of a synergistic role for oral bacteria in pathogenesis may have important clinical implications in the treatment of oral thrush which is currently based solely on antifungals.

Public Health Relevance

Oral thrush (also known as candidiasis) is still the most prevalent form of infection in patients with weakened or immature immune systems such as HIV+ children, neonates and patients with malignancies. We propose that certain oral bacteria cooperate with the principal fungal species responsible for this infection, Candida albicans, to trigger inflammatory mucosal lesions that are a cause for severe morbidity in millions of individuals worldwide. Defining the mechanism of microbial synergy in mucosal polymicrobial infections is important, because these infections are notoriously resistant to antimicrobials and thus there is an urgent need for the development of new prevention and treatment strategies.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01DE013986-11A1
Application #
8697320
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030
Xu, H; Jenkinson, H F; Dongari-Bagtzoglou, A (2014) Innocent until proven guilty: mechanisms and roles of Streptococcus-Candida interactions in oral health and disease. Mol Oral Microbiol 29:99-116
Xu, H; Sobue, T; Thompson, A et al. (2014) Streptococcal co-infection augments Candida pathogenicity by amplifying the mucosal inflammatory response. Cell Microbiol 16:214-31
Diaz, Patricia I; Strausbaugh, Linda D; Dongari-Bagtzoglou, Anna (2014) Fungal-bacterial interactions and their relevance to oral health: linking the clinic and the bench. Front Cell Infect Microbiol 4:101
Xu, Hongbin; Nobile, Clarissa J; Dongari-Bagtzoglou, Anna (2013) Glucanase Induces Filamentation of the Fungal Pathogen Candida albicans. PLoS One 8:e63736
Diaz, Patricia I; Xie, Zhihong; Sobue, Takanori et al. (2012) Synergistic interaction between Candida albicans and commensal oral streptococci in a novel in vitro mucosal model. Infect Immun 80:620-32
Xie, Zhihong; Thompson, Angela; Kashleva, Helena et al. (2011) A quantitative real-time RT-PCR assay for mature C. albicans biofilms. BMC Microbiol 11:93
Dwivedi, Prabhat; Thompson, Angela; Xie, Zhihong et al. (2011) Role of Bcr1-activated genes Hwp1 and Hyr1 in Candida albicans oral mucosal biofilms and neutrophil evasion. PLoS One 6:e16218
Sun, Jianing N; Solis, Norma V; Phan, Quynh T et al. (2010) Host cell invasion and virulence mediated by Candida albicans Ssa1. PLoS Pathog 6:e1001181
Dongari-Bagtzoglou, Anna; Kashleva, Helena; Dwivedi, Prabhat et al. (2009) Characterization of mucosal Candida albicans biofilms. PLoS One 4:e7967
Dwivedi, P P; Mallya, S; Dongari-Bagtzoglou, A (2009) A novel immunocompetent murine model for Candida albicans-promoted oral epithelial dysplasia. Med Mycol 47:157-67

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