Exogenous Farnesol Interferes with the Normal Progression of Cytokine Expression during Candidiasis in a Mouse Model

Abstract

Candida albicans, a dimorphic fungus composed of yeast and mycelial forms, is the most common human fungal pathogen. Th1 cytokines such as interleukin-2 (IL-2), gamma interferon (IFN-␥), and tumor necrosis factor alpha (TNF-␣), which are induced by macrophage IL-12, are critical to resistance against systemic candidiasis, while Th2 cytokines such as IL-4 and IL-5 are less critical. Farnesol is a quorum-sensing molecule produced by C. albicans that controls the formation of mycelia but is also a virulence factor. To determine whether farnesol enhances the virulence of C. albicans by modulating the production of Th1 and Th2 cytokines, mice were pretreated with farnesol prior to intravenous infection with a sublethal dose of farnesol-producing C. albicans. Production of IL-2, IL-4, IL-5, TNF-␣, IFN-␥, and IL-12 was evaluated by bead-array flow cytometry and enzyme-linked immunosorbent assay. Mice exhibited an elevation in serum TNF-␣ levels at 48 h and an elevation in IFN-␥ and IL-12 levels at 6 to 12 h after infection with C. albicans. Pretreatment with farnesol significantly reduced the elevation of both IFN-␥ and IL-12 but not TNF-␣. In contrast, mice pretreated with farnesol exhibited an unexpected elevation in IL-5 levels. To determine whether farnesol has a direct effect on macrophage production of IL-12, peritoneal macrophages were pretreated with farnesol prior to stimulation with IFN-␥ plus lipopolysaccharide (LPS). Farnesol inhibited production of both IL-12 p40 and p70 from IFN-␥/LPS-stimulated macrophages. Therefore, the role of farnesol in systemic candidiasis is likely due to its ability to inhibit the critical Th1 cytokines IFN-␥ and IL-12 and perhaps to enhance a Th2 cytokine, IL-5.Candida albicans is a dimorphic commensal fungus and a medically important opportunistic pathogen, particularly in immunocompromised individuals (37). Previous work showed that yeast-mycelium dimorphism in C. albicans is regulated in part by secretion of a lipophilic molecule identified as farnesol (15). Farnesol prevents mycelial development in a quorumsensing or cell density-dependent manner, and it was the first quorum-sensing molecule (QSM) discovered in a eukaryotic organism. This work was recently reviewed by Nickerson et al. (33). However, all of the work on farnesol as a QSM has been done in vitro, leaving open the question of what role farnesol or farnesol analogs have in vivo. In this regard, Hornby et al. (15) proposed two competing hypotheses. The first was that the shift from yeast to mycelium was a critical step in pathogenesis and that exogenous farnesol could block this transition, thus acting in a therapeutic manner. The alternate hypothesis was that the lipophilic farnesol excreted during infection would interact with host cells in a manner that promoted virulence. The latter idea was supported by our work on the pathogenicity of C. albicans cells pretreated with subinhibitory concentrations (0.5 to 1 M) of fluconazole (29). These cells secreted 10 times more farnesol than did untreated cells, and they ...

Natural Isoprenoids are Able to Reduce Inflammation in a Mouse Model of Mevalonate Kinase Deficiency

“…Our data strengthened previous observations about an important role of isoprenoids in inflammation (8,(21)(22)(23)(24)(25), even if they do not explain how isoprenoids mediate this event. These compounds play an important role in different biological function, including protein prenylation and production of steroid hormones and biologically active terpenes.…”

Influence of heterocyclic and oxime-containing farnesol analogs on quorum sensing and pathogenicity in Candida albicans

“…We have shown that it blocks the yeast to mycelium transition in C. albicans, 3 acts as a virulence factor in a mouse model of systemic candidiasis, [10] and [11] probably by interfering with the normal progression of cytokine expression in their immune response, 12 and triggers apoptosis in the fungus Aspergillus nidulans. 22 Others have shown that farnesol alters circadian rhythms in Neurospora crassa and targets HMG CoA reductase for proteolysis in both Saccharomyces cerevisiae and Chinese hamster ovary cells.…”

“…In particular, the availability of molecules such as tetrazole 5 (a potent quorum-sensing molecule which enhances pathogenicity) and 10 (a potent quorum-sensing molecule which does not enhance pathogenicity) may provide a potent tool in understanding how farnesol functions as a virulence factor in interactions with cellular macrophages and CD4 T cells to alter adaptive immunity. 12 The analogs also provide a means of establishing differences and similarities between farnesol's effect on virulence and its ability to block both hyphal development and biofilm formation. [3] and [29] Along these lines, it is interesting to note that an analog of triazole 10 bearing five additional carbons has been reported to be a potent activator of protein kinase C. 20 Of course, the differences in the pathogenicity of C. albicans observed in the presence of farnesol, 5, and 10 could also be due to differing pharmacokinetics or their differing influence on mouse cytokine production.…”

“…19 A similar approach has been employed for synthesis of a thiotriazole from farnesyl chloride. 20 The substrates tested grafted a series of heterocyclic head groups onto a geranyl (3,7-dimethyl-2,6-octadienyl) tail: thio-1,2,3,4-tetrazole (9), thio-1,2,4-triazole (10), thio-1,2,3-triazole (11), and thioimidazole (12). We also investigated a carbon-linked 1,2,3-triazole (13) prepared through a dipolar cycloaddition (Eq.…”

“…We have subsequently discovered a potential basis for this behavior, in that farnesol interferes with the normal progression of cytokine induction in mice infected with C. albicans. 12 We are interested in the relationships between quorum sensing and virulence and, in particular, whether it is possible to decouple the two. Specifically, we were interested in the possibility of designing analogs that retain farnesol's ability to block hyphal development but lack farnesol's activity as a virulence factor.…”