The Fungal Quorum-Sensing Molecule Farnesol Activates Innate Immune Cells but Suppresses Cellular Adaptive Immunity

Leonhardt, Ines; Spielberg, Steffi; Weber, Michael; Albrecht-Eckardt, Daniela; Bläss, Markus F; Claus, Ralf A.; Barz, Dagmar; Scherlach, Kirstin; Hertweck, Christian; Löffler, Jürgen; Hünniger, Kerstin; Kurzai, Oliver

doi:10.1128/mbio.00143-15

Cited by 60 publications

(50 citation statements)

References 53 publications

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“…Farnesol is an appealing candidate because it is produced by white cells but not by opaque cells (26), and it is already a known virulence factor for C. albicans (3). Moreover, farnesol was previously found to activate neutrophils and stimulate proinflammatory cytokine production by monocytes, while dampening dendritic cell activity as antigen-presenting cells (21,22). We show here that the farnesol excreted by C. albicans stimulates macrophage migration by promoting chemokinesis rather than chemotaxis.…”

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confidence: 78%

“…This in vitro result is compatible with the importance of macrophages in vivo for the early elimination of C. albicans (19,20) because macrophages which have engulfed C. albicans secrete immunoregulatory cytokines including interleukin-6 (IL-6), IL-1␤, IL-10, and tumor necrosis factor alpha (TNF-␣) (21) prior to the escape of C. albicans. These cytokines presumably promote the development and chemotactic migration of other innate immune cells, including neutrophils, which are more capable of killing C. albicans (22). Even though evading host immunity is a common strategy used by pathogenic fungi (23)(24)(25), we hypothesize C. albicans white cells produce a chemoattractive stimulant(s) that promotes their engulfment by macrophages.…”

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Candida albicans Quorum Sensing Molecules Stimulate Mouse Macrophage Migration

et al. 2015

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The polymorphic commensal fungus Candida albicans causes life-threatening disease via bloodstream and intra-abdominal infections in immunocompromised and transplant patients. Although host immune evasion is a common strategy used by successful human fungal pathogens, C. albicans provokes recognition by host immune cells less capable of destroying it. To accomplish this, C. albicans white cells secrete a low-molecular-weight chemoattractive stimulant(s) of macrophages, a phagocyte that they are able to survive within and eventually escape from. C. albicans opaque cells do not secrete this chemoattractive stimulant(s). We report here a physiological mechanism that contributes to the differences in the interaction of C. albicans white and opaque cells with macrophages. E,E-Farnesol, which is secreted by white cells only, is a potent stimulator of macrophage chemokinesis, whose activity is enhanced by yeast cell wall components and aromatic alcohols. E,E-farnesol results in up to an 8.5-fold increase in macrophage migration in vitro and promotes a 3-fold increase in the peritoneal infiltration of macrophages in vivo. Therefore, modulation of farnesol secretion to stimulate host immune recognition by macrophages may help explain why this commensal is such a successful pathogen. Candida albicans is a serious fungal pathogen for humans (1). C. albicans is a dimorphic fungus and it has long been recognized that the ability to interconvert between the yeast and filamentous forms is essential for its pathogenicity. Thus, when we discovered that E,E-farnesol (referred to here as farnesol) is a quorum sensing molecule (QSM) for C. albicans which acts by blocking the conversion of yeasts to mycelia (2), we thought that farnesol would be an attractive lead compound in the design of novel antifungal drugs. However, this goal was not realized when we showed that farnesol itself acted as a virulence factor for C. albicans in a mouse intravenous infection model (3). These observations presented a dilemma: how can farnesol act as a virulence factor when part of its mode of action is to block the yeast-mycelium morphogenesis, which is necessary for its pathogenicity? We resolve this conundrum here by showing that farnesol is also a potent stimulator of macrophage migration both in vitro and in vivo.C. albicans is one of the best studied examples of an opportunistic fungal pathogen. It is a normal member of the human microbiota where it is found as a commensal primarily in the gastrointestinal and genitourinary tracts and on the skin of healthy individuals without causing significant disease. In healthy individuals, C. albicans commensals are controlled but tolerated while C. albicans pathogens are eliminated (reviewed in reference 4). The presence of innate immune phagocytes, which include both macrophages and neutrophils, is critical for early detection and elimination of C. albicans that have made the transition from commensal to an opportunistic pathogen (5-9; reviewed in reference 10). Thus, when normal immune responses are com...

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Candida albicans Quorum Sensing Molecules Stimulate Mouse Macrophage Migration

et al. 2015

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“…The chemical nature of QSM shows a great variety ranging from alcohols, peptides, lipids, acetaldehyde to volatile gas. Of note, human cells were also shown to respond to fungal QSM, such as farnesol (Decanis et al, 2009;Leonhardt et al, 2015), thus, quorum sensing (QS) seems to be used as a communication tool across the kingdoms. There is a lot more to learn about QS in fungi, with great potential to medically exploit these mechanisms for inhibition of biofilm formation, fungal resistance and pathogenicity.…”

Section: Quorum-sensing Moleculesmentioning

confidence: 99%

Fungal sensing of host environment

Braunsdorf

Mailänder-Sánchez²,

Schaller

2016

Cellular Microbiology

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Summary To survive inside a host, fungi have to adapt to a changing and often hostile environment and therefore need the ability to recognize what is going on around them. To adapt to different host niches, they need to sense external conditions such as temperature, pH and to recognize specific host factors. The ability to respond to physiological changes inside the host, independent of being in a commensal, pathogenic or even symbiotic context, implicates mechanisms for sensing of specific host factors. Because the cell wall is constantly in contact with the surrounding, fungi express receptors on the surface of their cell wall, such as pheromone receptors, which have important roles, besides mediating chemotropism for mating. We are not restricting the discussion to the human host because the receptors and mechanisms used by different fungal species to sense their environment are often similar even for plant pathogens. Furthermore, the natural habitat of opportunistic pathogenic fungi with the potential to cause infection in a human host is in soil and on plants. While the hosts' mechanisms of sensing fungal pathogens have been addressed in the literature, the focus of this review is to fill the gap, giving an overview on fungal sensing of a host‐(ile) environment. Expanding our knowledge on host–fungal interactions is extremely important to prevent and treat diseases of pathogenic fungi, which are important issues in human health and agriculture but also to understand the delicate balance of fungal symbionts in our ecosystem.

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“…[42]. Finally, recent evidence demonstrates that it negatively affects the host immune response [43,44], thereby reducing its suitability for therapeutic approaches.…”

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