The bacterial species Staphylococcus aureus and the human fungal pathogen Candida albicans are among the leading pathogens in bloodstream and hospital-acquired infections. Most infections caused by these diverse organisms are biofilm-associated due to their ability to adhere to a variety of surfaces causing persistent and chronic infections. More importantly, C. albicans and S. aureus are often co-isolated from wounds, mucosal surfaces and various sites in the host. Despite their prevalence and the clinical inferences of their co-existence in a host, studies exploring the implications of their interaction within the context of polymicrobial infections have been lacking. Based on extensive preliminary findings from in vitro and in vivo studies, this proposal was formulated to validate the hypothesis that these organisms interact in the host as they co-exist on mucosal surfaces with significant impact on their pathogenic potential and the infectious process. Specifically, using clinical strains of both species, this proposal aims to demonstrate infectious synergism and invasive systemic staphylococcal infection due to C. albicans and S. aureus dual species biofilms. To that end, a murine model of oral mucosal co-infection was developed in order to determine whether the penetration of the mouse oral mucosa by the highly invasive C. albicans hyphae leads to systemic infection by the normally non-invasive yet evasive S. aureus. In addition, as preliminary data seem to implicate the involvement of dual-species biofilm-induced protein expression in the co-infectious process in the animal model, global protein expression analyses are planned in order to profile the expression of specific virulence factors. Subsequently, the direct effect of the identified proteins on virulence enhancement will be elucidated using gene knockout studies. Combined, these novel preliminary findings warrant further in depth investigations into the intricate interaction between C. albicans and S. aureus as these common pathogens frequently co-infect critically-ill hospitalized patients causing significant morbidity and mortality. We expect the fulfillment of the aims of this proposal to serve as a paradigm to further the field of fungal- bacterial interactions and polymicrobial diseases in general. More importantly, the dissemination of the findings generated will aid in the design of novel therapeutic strategies aimed at combating fungal-bacterial polymicrobial infections.

Public Health Relevance

The bacterial species Staphylococcus aureus and the human fungal pathogen Candida albicans are capable of adhering on a variety of surfaces causing significant chronic biofilm-associated infections. These microbial species are also isolated together from various sites from infected patients. Yet despite their prevalence and pathogenesis, studies exploring the implications of their interaction within the context of polymicrobial or mixed infections have been lacking. To that end, using a mouse model of infection, we performed extensive preliminary studies which demonstrated enhanced virulence for these organisms when they co-exist in a host. In this application, we propose to perform additional in depth molecular and animal studies in order to confirm our preliminary findings and generate data to contribute to our understanding of the mechanisms leading to multi-microbial infections. We expect the findings generated from the accomplishment of this work to aid in the design of novel therapeutic strategies to combat polymicrobial infections.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DE020939-05
Application #
8689760
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lunsford, Dwayne
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Peters, Brian M; Jabra-Rizk, Mary Ann; O'May, Graeme A et al. (2012) Polymicrobial interactions: impact on pathogenesis and human disease. Clin Microbiol Rev 25:193-213
Prabhakara, Ranjani; Harro, Janette M; Leid, Jeff G et al. (2011) Suppression of the inflammatory immune response prevents the development of chronic biofilm infection due to methicillin-resistant Staphylococcus aureus. Infect Immun 79:5010-8
Peters, Brian M; Jabra-Rizk, Mary Ann; Scheper, Mark A et al. (2010) Microbial interactions and differential protein expression in Staphylococcus aureus -Candida albicans dual-species biofilms. FEMS Immunol Med Microbiol 59:493-503
Peters, Brian M; Zhu, Jingsong; Fidel Jr, Paul L et al. (2010) Protection of the oral mucosa by salivary histatin-5 against Candida albicans in an ex vivo murine model of oral infection. FEMS Yeast Res 10:597-604