Role of Candida albicans and Candida glabrata interaction in Oropharyngeal Candidiasis and Candida glabrata's resistance towards Histatin 5
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Candida species are the eitiologic agents of oropharyngeal candidiasis (OPC), which is most commonly observed in immunocompromised patients, the elderly, or individuals taking steroids and broad-spectrum antibiotics. Candida albicans and Candida glabrata are the first and second most common causative agents of OPC. C. glabrata infections are difficult to treat because of its ability to readily acquire resistance to known antifungals. Many strains of C. glabrata are resistant to azoles, polyenes, and histatins. Human salivary histatins, importantly histatin 5 (Hst 5), are small cationic peptides that are the major source of fungicidal activity of saliva. Fungicidal activity of Hst 5 requires cell wall binding, energy dependent intracellular translocation, and accumulation to a threshold concentration for it to disrupt vital cellular processes. Previously, we identified and characterized the mechanism of Hst 5 uptake in C. albicans by polyamine transporters. C. glabrata is less sensitivite to Hst 5 as compared to C. albicans. Since Hst 5 requires binding to fungal cell wall components prior to intracellular translocation, we hypothesized that reduced Hst 5 binding to C. glabrata may be the reason for its insensitivity ( Chapter 1 ). Hst 5 binds to cell surface β-1,3-glucan and enters C. albicans cell through polyamine transporters CaDur3p and CaDur31p that are uncharacterized in C. glabrata. In this study, C. glabrata strains expressing CaDur3 and CaDur31, were constructed which showed two fold higher killing and uptake of Hst 5. Thus, β-1,3-glucan levels from either C. glabrata cell surface or biofilm matrix affected Hst 5 toxicity; rather the crucial rate limiting step was reduced uptake that was overcome by the expression of C. albicans Dur proteins in C. glabrata. Salivary histatins rapidly degrade in the oral cavity, which limits their efficacy as therapeutic agents despite their lack of toxicity. The fungicidal activity of a peptide prepared by conjugating active fragment of Hst 5 (Hst 5 4-15 ), and spermidine (Spd) towards C. albicans and C. glabrata were examined. The conjugate peptide was created based on the findings that C. albicans spermidine transporters are required for Hst 5 uptake and fungicidal activity ( Chapter 2 ). It was found that Hst 5 4-1 5-Spd conjugate was significantly more effective in killing both C. albicans and C. glabrata than Hst 5 alone in planktonic and biofilm growth and Hst 5 4-15 -Spd also retained high activity in both serum and saliva. Oropharyngeal candidiasis is predominantly associated with C. albicans and C. glabrata infection. C. albicans and C. glabrata are often co-isolated in OPC. The mechanism of interaction between C. albicans and C. glabrata adhesion was studied to understand the colonization strategy of C. glabrata in the host environment. C. glabrata adhered selectively to C. albicans hyphae and showed increased sedimentation in the presence of C. albicans hyphae. Dual species biofilm mass exhibited an increase compared to single species biofilms of C. albicans or C. glabrata alone. In vivo , OPC murine infection by C. glabrata infection alone negligibly colonized tongue tissues; however colonization increased upon co-infection with C. albicans. Pre-established C. albicans infection increased subsequent C. glabrata colonization showing the importance of C. albicans infection for C. glabrata colonization in vivo. Both in vitro and in vivo data suggest that C. glabrata adheres to C. albicans hyphal wall specific Als3 and Als1 adhesins ( Chapter 3 ). CgEPA8 , CgEPA19 , CgAWP2 , CgAWP7 , and CgF00181 adhesins of C. glabrata are required for adhesion to C. albicans and are induced in the presence of C. albicans. In vivo mixed infection showed a significant difference in colonization of CgDSY562 (high adherence strain) as compared to Cg90030 (low adherence strain) in the presence C. albicans. Furthermore, C. glabrata requires C. albicans for the initiation phase and for the maintenance of oral infection; as shown by eradication of C. albicans at respective infection phases in mixed infections using Fluconazole sensitive and resistant strains. In vivo OPC murine infection also shows that C. albicans is needed for C. glabrata colonization, suggesting that C. glabrata is a secondary colonize in human OPC.
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