Farnesol is a virulence factor in a mouse model of disseminated candidiasis.

摘要

Farnesol is the first identified fungal and eukaryotic quorum sensing molecule that was discovered in the Nickerson laboratory at University of Nebraska Lincoln. This fascinating molecule is responsible for the regulation of yeast to mycelium conversion in the dimorphic fungus Candida albicans. C. albicans is the number one opportunistic fungal pathogen and is a commensal of humans. Their natural habitat is the mucosal surfaces of warm blooded animals. Therefore farnesol should have a probable in vivo role in fungal biology and investigation of its in vivo role is highly warranted. We addressed this issue systematically to understand the role of farnesol in a mouse model of disseminated candidiasis. First we have shown that exogenous farnesol administered to mice infected with C. albicans enhanced virulence of the organism. Second we addressed the impact of intrinsic farnesol production capability in disease pathogenesis. To do this study, we created a mutant which had only 10% of farnesol production capacity and then investigated its impact on disseminated candidiasis. We found that the virulence of this mutant strain (KWN2) had reduced significantly compared to the wild type (SN152). Third, we developed a strategy of programming Candida cells to secrete more farnesol by treating them with sublethal levels of Fluconazole. Then we tested the virulence of those cells in comparison to untreated cells. We found the cells programmed to secrete more farnesol were significantly more virulent than untreated C. albicans. With these findings, we concluded that the fungal quorum sensing molecule farnesol is a virulence attribute in candidiasis. Thereafter we investigated farnesol's mode of action as a virulence factor. We observed that farnesol altered the normal cytokine expression pattern in mice in a fashion favoring disease progression. Finally we resolved one of the reasons why kidneys are targeted in systemic candidiasis; we discovered that chlamydospores, the only known spores in C. albicans, are produced in kidneys in vivo. By combining in vivo and in vitro experiments, we showed that C. albicans capitalizes on urea rich kidneys to induce chlamydospores, a resistant body needed to face the acute immune onslaught. All these novel findings will have a great impact on complete understanding of C. albicans biology and should help in the design of effective future antifungals as there is still a severe shortage of safe and effective antifungal drugs.