Farnesol Biosynthesis in
            <i>Candida albicans</i>
            : Cellular Response to Sterol Inhibition by Zaragozic Acid B

Hornby, Jacob M.; Kebaara, Bessie W.; Nickerson, Kenneth W.

doi:10.1128/aac.47.7.2366-2369.2003

Cited by 108 publications

(78 citation statements)

References 12 publications

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“…albicans strain and growth conditions. Candida albicans strain A72 (ATCC MYA-2430) is a well-characterized farnesol-producing and farnesol-responsive strain that has been used in previous in vitro studies (12,13,27,45). This strain was originally isolated from a patient by Antonio Cassone (Rome, Italy).…”

Section: Methodsmentioning

confidence: 99%

Effect of Farnesol on a Mouse Model of Systemic Candidiasis, Determined by Use of a DPP3 Knockout Mutant of Candida albicans

Hornby²,

et al. 2007

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This work extends our previous observation that the fungus Candida albicans secretes micromolar levels of farnesol and that accumulation of farnesol in vitro prevents the yeast-to-mycelium conversion in a quorumsensing manner. What does farnesol do in vivo? The purpose of this study was to determine the role of farnesol during infection with a well-established mouse model of systemic candidiasis with C. albicans A72 administered by tail vein injection. This question was addressed by altering both endogenous and exogenous farnesol. For endogenous farnesol, we created a knockout mutation in DPP3, the gene encoding a phosphatase which converts farnesyl pyrophosphate to farnesol. This mutant (KWN2) produced six times less farnesol and was ca. 4.2 times less pathogenic than its SN152 parent. The strain with DPP3 reconstituted (KWN4) regained both its farnesol production levels and pathogenicity. These mutants (KWN1 to KWN4) retained their full dimorphic capability. With regard to exogenous farnesol, farnesol was administered either intraperitoneally (i.p.) or orally in the drinking water. Mice receiving C. albicans intravenously and farnesol (20 mM) orally had enhanced mortality (P < 0.03). Similarly, mice (n ‫؍‬ 40) injected with 1.0 ml of 20 mM farnesol i.p. had enhanced mortality (P < 0.03), and the onset of mortality was 30 h sooner than for mice which received a control injection without farnesol. The effect of i.p. farnesol was more pronounced (P < 0.04) when mice were inoculated with a sublethal dose of C. albicans. These mice started to die 4 days earlier, and the percent survival on day 6 postinoculation (p.i.) was five times lower than for mice receiving C. albicans with control i.p. injections. In all experiments, mice administered farnesol alone or Tween 80 alone remained normal throughout a 14-day observation period. Finally, beginning at 12 h p.i., higher numbers of C. albicans cells were detected in kidneys from mice receiving i.p. farnesol than in those from mice receiving control i.p. injections. Thus, reduced endogenous farnesol decreased virulence, while providing exogenous farnesol increased virulence. Taken together, these data suggest that farnesol may play a role in disease pathogenesis, either directly or indirectly, and thus may represent a newly identified virulence factor.Candida albicans is a dimorphic commensal fungus which is localized primarily in the gastrointestinal tract (20). It is a medically important opportunistic pathogen, particularly for immunocompromised individuals (16), and can invade a wide range of organ systems during systemic infections. For healthy, immunocompetent individuals, it is an opportunistic pathogen only. However, Calderone and Gow (6), Navarro-Garcia et al. (33) have detailed the contributions of virulence factors in candidiasis. These virulence factors could either promote Candida invasion or affect host defense mechanisms. It is likely that the virulence of C. albicans is multifactorial. Therefore, pathogenesis is the sum of the attributes of the fungus, ...

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Section: Methodsmentioning

confidence: 99%

Effect of Farnesol on a Mouse Model of Systemic Candidiasis, Determined by Use of a DPP3 Knockout Mutant of Candida albicans

Hornby²,

et al. 2007

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“…Quorum sensing in C. albicans was established based on the observation that dense cultures display a reduced propensity for the yeast-to-hypha switch (Hornby et al 2001). The inhibitory activity is caused by the accumulation of a sesquiterpine alcohol, farnesol (Hornby et al 2001), formed from an intermediate of the sterol biosynthesis pathway (Hornby et al 2003). Therefore, farnesol is a quorum-sensing molecule secreted to the medium by C. albicans cells as a cell density signal (Hornby et al 2001).…”

Section: Quorum Sensingmentioning

confidence: 99%

Fungal Morphogenesis

Lin

Alspaugh

Liu

et al. 2014

Cold Spring Harbor Perspectives in Medicine

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Morphogenesis in fungi is often induced by extracellular factors and executed by fungal genetic factors. Cell surface changes and alterations of the microenvironment often accompany morphogenetic changes in fungi. In this review, we will first discuss the general traits of yeast and hyphal morphotypes and how morphogenesis affects development and adaptation by fungi to their native niches, including host niches. Then we will focus on the molecular machinery responsible for the two most fundamental growth forms, yeast and hyphae. Last, we will describe how fungi incorporate exogenous environmental and host signals together with genetic factors to determine their morphotype and how morphogenesis, in turn, shapes the fungal microenvironment. PROPERTIES OF MORPHOGENESIS IN FUNGAL CELLS

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“…Hornby et al (30) showed that C. albicans extracts possess an enzyme capable of producing farnesol from farnesyl pyrophosphate and that farnesol production increases upon zaragozic acid B-mediated inhibition of squalene synthase, an enzyme involved in ergosterol biosynthesis. Disruption of ergosterol biosynthesis by the addition of azole-derived antifungal compounds, including fluconazole, clotrimazole, ketoconazole, and miconazole, also leads to increased farnesol production by C. albicans cultures, perhaps by causing an accumulation of the farnesyl pyrophosphate precursor (31,59).…”

Section: Albicans and Autoregulationmentioning

confidence: 99%

Talking to Themselves: Autoregulation and Quorum Sensing in Fungi

2006

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Extracellular autoinducing compounds in the supernatants of microbial cultures were first recognized for their roles in the induction of genetic competence in gram-positive bacteria (17,94) and in the regulation of light production in marine vibrios (60). In 1994, this form of population-level regulation in microbes was dubbed "quorum sensing" since it enabled bacterial cells to chemically measure the density of the surrounding population (18). Subsequently, many examples of cell densitydependent regulation by extracellular factors have been found in diverse microorganisms. The widespread incidence of diverse quorum-sensing systems strongly suggests that regulation in accordance with cell density is important for the success of microbes in many environments (see references 25 and 95 for reviews).Cell density-dependent regulatory networks in microorganisms generally control processes that involve cell-cell interactions, such as group motility (10, 37) and the formation of multicellular structures (67,93,95). In a wide array of environmental and medically relevant bacteria, the development, maintenance, and dispersion of multicellular, surface-associated biofilms are in part controlled by quorum-sensing regulatory pathways (for reviews, see references 67 and 93). The uptake of extracellular DNA is often regulated in accordance with cell density presumably to enhance the chances of taking up DNA from closely related strains. For some bacteria, a link between the competence and biofilm formation has been established (69, 93). Both pathogens and symbionts that live in association with plant or animal hosts often use quorum sensing to regulate factors involved in microbe-host interactions (20,86,96). Quorum-sensing regulation may allow host-associated microbes to delay detection until an effective population has formed in the appropriate niche within the host.Recently, it has become apparent that fungi, like bacteria, also use quorum regulation to affect population-level behaviors such as biofilm formation and pathogenesis. Considering the extent to which quorum-sensing regulation controls important processes in many distantly related bacterial genera, it is not surprising that cell density-dependent regulation also appears to be prevalent in diverse fungal species. Because fungal quorum sensing has been most extensively studied in Candida albicans, a dimorphic opportunistic pathogen, the majority of this review focuses on the details of quorum-sensing regulation in this fungus. A discussion of other fungi that appear to use quorum-sensing regulation and the identities of other known fungal signaling molecules are presented, and potential connections between mating in fungi and cell density-dependent regulation are explored. The review will conclude with points relating to the ecology of quorum sensing and a discussion of quorum-sensing networks as potential targets for antifungal therapies.

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Farnesol Biosynthesis in Candida albicans : Cellular Response to Sterol Inhibition by Zaragozic Acid B

Cited by 108 publications

References 12 publications

Effect of Farnesol on a Mouse Model of Systemic Candidiasis, Determined by Use of a DPP3 Knockout Mutant of Candida albicans

Effect of Farnesol on a Mouse Model of Systemic Candidiasis, Determined by Use of a DPP3 Knockout Mutant of Candida albicans

Fungal Morphogenesis

Talking to Themselves: Autoregulation and Quorum Sensing in Fungi

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