Background: hLF(1-11) exerts potent in vitro candidacidal activity. We investigated its efficacy against disseminated Candida albicans infections and the mechanisms underlying this activity. Methods: Neutropenic mice were i.v. infected with fluconazole-resistant C. albicans and 24 h later injected with hLF(1-11). 18 H after administration of the peptide, the number of viable yeasts in the kidneys was determined microbiologically; the size and number of infectious foci through pathohistology, and serum cytokine levels were measured. Results: Results revealed a U-shaped dose-effect curve for the antifungal activity of hLF(1-11). Although poor antifungal activity of high doses of hLF(1-11) (≥ 400 μg/kg) coincided with high levels of IL-10, a causal relationship could not be confirmed using IL-10 neutralizing mAb. As in control animals that were infected but left untreated with peptide, TNFα and IL-6 production was high. In contrast, effective doses of hLF(1-11) (8804;40 Âµg/kg) were accompanied by reduced TNF-α and IL-6 levels as compared to control mice. These mice did not show elevated IL-10 production. Histopathology of kidney tissue sections confirmed our microbiological data. Moreover, C. albicans infectious foci in effectively treated mice contained mainly blastoconidia whereas in control mice the virulent filamentous form was abundant. Microscopic analysis indicated that in vitro hLF(1-11) dose-dependently inhibited the phenotypic switching of C. albicans. Conclusions: Low doses of hLF(1-11) are effective against disseminated C. albicans infections. This antifungal activity involves effects of the peptide on Candida as well as host cells. Preclinical and clinical safety studies have been completed successfully and hLF1-11 has recently entered clinical phase II for prophylaxis and treatment of fungal infections in hematopoetic stem cell transplantation patients.
Full conference title:
46th Interscience Conference on Antimicrobial Agents and Chemotherapy
- ICAAC 46th