The research in our laboratory focuses on the characterization of virulence factors in the opportunistic fungal pathogen Candida albicans and on analyzing the various factors and conditions that play a role in the transition between colonization and infection. Specifically, we are interested in studying host-pathogen interactions, polymicrobial biofilms and drug tolerance.
Our laboratory developed a murine model of oral candidiasis to study oral fungal-bacterial interactions in polymicrobial biofilms and specifically between C. albicans and the bacterial species Staphylococcus aureus. Our studies characterized a novel phenomenon whereby the development of oral candidiasis led to systemic bacterial infection with high mortality rate via adherence of the bacteria to the invasive hyphal elements of C. albicans. We are currently testing the implementation of antifungal treatment of oral candidiasis for prevention of development of systemic infection.
We are also using our mouse model to investigate the role of host oral innate immunity specifically salivary antimicrobial peptides in defense against colonization and infection by C. albicans. We recently identified the peptide histatin-5 to be the key anti-candidal salivary component. Importantly, we demonstrated significant decrease in the levels of this peptide in HIV-infected individuals characterizing a defined mechanism behind the enhanced prevalence of oral candidiasis in this population. We are currently performing prospective clinical studies to monitor the decline in host innate immune defenses during the progression of HIV disease. The importance of histatin-5 in the oral cavity led us to explore its potential application as a novel antifungal agent. We recently demonstrated the efficacy of histatin-5 in the animal model and based on these findings we developed a bioadhesive hydrogel-based delivery system for histatin-5. The formulation is currently being tested in the mouse model as well as in a rat model of Candida-associated denture stomatitis. The goal of these studies is to develop a pharmaceutically viable oral topical formulation for the prevention and/or treatment of oral infections in immunocompromised individuals. Our laboratory is also interested in understanding the dynamics of biofilm formation by C. albicans particularly as they relate to development of drug resistance. We are focusing on analyzing the role of the quorum sensing molecule, farnesol in orchestrating survival and drug tolerance of biofilm-associated C. albicans cell populations. We and others have demonstrated that exogenous farnesol has a significant inhibitory effect against Candida biofilm. We recently identified the mechanism of farnesol cytotoxicity in C. albicans to involve intracellular glutathione depletion leading to oxidative stress and apoptosis (cell death). Since fungal cells are eukaryotic cells similar to human cells, farnesol was also shown to trigger a classical apoptotic process in human cancer cells via a similar pathway. We are currently exploring the potential of farnesol as an anti-tumor agent using a xenograft mouse model of oral squamous carcinoma. Another project under development aims to study the role of the interaction between C. albicans and Streptococcus mutans (etiologic agent of dental caries) on the development and progression of caries.
Grants and Contracts: :
Belgian Interuniversity Attraction Poles (IAP) multi-institutional award (2013-2018).
Candida albicans and Staphylococcus aureus dual species biofilms: in vitro and in vivo studies. NIH/NIAID R01 (2010-2015). Principal Investigator
Therapeutic Potential of Histatin-5 against Experimental Oral Candidiasis (NIH/R21: submitted January 2013) (Principal Investigator)
Role of Oral Innate Immunity in the Predisposition to Candidiasis in HIV Disease (NIH/R21: submitted February 2013) (Principal Investigator)
Mark A. Scheper, Mark E. Shirtliff, Timothy F. Meiller, Brian Peters and Mary Ann Jabra-Rizk. Farnesol a Fungal Quorum Sensing Molecule Triggers Apoptosis in Human Oral Squamous Carcinoma Cells. Neoplasia 2008: 10(9): 954-963. PMID: 18714396.
Timothy F. Meiller, Bernhard Hube, Lydia Schild, Mark E. Shirtliff, Mark A. Scheper, Robert Winkler, Amy Ton and Mary Ann Jabra-Rizk. Novel Immune Evasion Strategy of Candida albicans: Proteolytic Cleavage of a Salivary Antimicrobial Peptide. PLoS ONE 2009 4(4): e5039, 1-9. PMID: 19352427A.
Mark E. Shirtliff, Bastiaan P. Krom, Roelien A.M. Meijering, Brian M. Peters, Jingsong Zhu and Mary Ann Jabra-Rizk. Farnesol-Induced Apoptosis in Candida albicans. Antimicrobial Agents and Chemotherapy 2009 April 53(6): 2392-2401. PMID: 19364863.
Brian M. Peters, Jingsong Zhu, Paul L. Fidel Jr, Mark A. Scheper, William Hackett, Sara El Shaye and Mary Ann Jabra-Rizk. Protection of the Oral Mucosa by Salivary Histatin-5 against Candida albicans in an Ex Vivo Murine Model of Oral Infection. FEMS Yeast Research 2010; 10(5): 597-604
Brian M. Peters, Mary Ann Jabra-Rizk, Jeff G. Leid, Jim W. Costerton and Mark E. Shirtliff. Microbial interactions and differential protein expression within Candida albicans-Staphylococcus aureus polymicrobial biofilms. FEMS Immunology and Medical Microbiology 2010; (59):494-503.
Brian M. Peters, Mark E. Shirtliff and Mary Ann Jabra-Rizk. Antimicrobial Peptides: Primeval molecules or novel drugs? PLoS Pathogens 2010: 6(10): e1001067).
Clinton C. Dawson, Chaidan Intapa and Mary Ann Jabra-Rizk. â?oPersistersâ?: Survival at the Cellular Level PLoS Pathogens 2011: 7(7): e1002121.
Jingsong Zhu, Bastiaan P. Krom, Dominique Sanglard, Chaidan Intapa, Clinton C. Dawson, Brian M. Peters, Mark E. Shirtliff and Mary Ann Jabra-Rizk. Farnesol-Induced Apoptosis in Candida albicans is Mediated by Cdr1-p Extrusion and Depletion of Intracellular Glutathione. PLoS ONE 2011: 6(12): e28830.
Brian M Peters, Mary Ann Jabra-Rizk, Graeme A Oâ?TMay, J. William Costerton and Mark E Shirtliff. Polymicrobial interactions in biofilms: impact on pathogenesis and human disease. Clinical Microbiology Reviews 2012: 25(1): 193-213.
Brian M Peters, Ekaterina Ovchinnikova, Lisa Marie Schlecht, Lois L. Hoyer, Henk J. Busscher, H.C. van der Mei, Bastiaan P Krom, Mary Ann Jabra-Rizk and Mark E Shirtliff. Staphylococcus aureus adherence to Candida albicans hyphae is mediated by the hyphal adhesin Als3p. Microbiology (August) 2012. PMID: 22918893.
Shariq A Khan, Paul L Fidel Jr, Awdah Al Thunayyan, Timothy F Meiller, Mary Ann Jabra-Rizk. Impaired histatin-5 level and salivary antimicrobial activity against C. albicans in HIV-infected individuals. J AIDS Clin Res 2013 (in press).
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