Candida albicans modulates host defense by biosynthesizing the pro-resolving mediator resolvin E1 - PubMed (original) (raw)

Candida albicans modulates host defense by biosynthesizing the pro-resolving mediator resolvin E1

Eric J Haas-Stapleton et al. PLoS One. 2007.

Abstract

Candida albicans is an opportunistic fungal pathogen of humans that resides commensally on epithelial surfaces, but can cause inflammation when pathogenic. Resolvins are a class of anti-inflammatory lipids derived from omega-3 polyunsaturated fatty acids (PUFA) that attenuate neutrophil migration during the resolution phase of inflammation. In this report we demonstrate that C. albicans biosynthesizes resolvins that are chemically identical to those produced by human cells. In contrast to the trans-cellular biosynthesis of human Resolvin E1 (RvE1), RvE1 biosynthesis in C. albicans occurs in the absence of other cellular partners. C. albicans biosynthesis of RvE1 is sensitive to lipoxygenase and cytochrome P450 monoxygenase inhibitors. We show that 10nM RvE1 reduces neutrophil chemotaxis in response to IL-8; 1nM RvE1 enhanced phagocytosis of Candida by human neutrophils, as well as intracellular ROS generation and killing, while having no direct affect on neutrophil motility. In a mouse model of systemic candidiasis, RvE1 stimulated clearance of the fungus from circulating blood. These results reveal an inter-species chemical signaling system that modulates host immune functions and may play a role in balancing host carriage of commensal and pathogenic C. albicans.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. C. albicans produces a tri-hydroxy derivative of EPA that is structurally identical to the human anti-inflammatory lipid mediator RvE1.

The MS/MS spectra of biogenic RvE1 (1A) and 18-HEPE (1B) produced by C. albicans cultured in liquid media supplemented with EPA. (1C) C. albicans, cultured in the presence of EPA the LO inhibitors esculetin or zileuton (100 µM) as well as the CYP450 inhibitor, 17-ODA, reduced RvE1 biosynthesis (squares). LO inhibitors, but not the CYP450 inhibitor, reduced biosynthesis of 5-HEPE (circles), 12-HEPE (diamonds), and 18-HEPE (triangles).

Figure 2

Figure 2. RvE1 blocks IL-8-stimulated neutrophil chemotaxis.

IL-8-directed chemotaxis of neutrophils was significantly inhibited by 10 and 100 nM RvE1 (Asterisks indicate significant differences from vehicle-treated controls; ANOVA: p<0.001).

Figure 3

Figure 3. RvE1 enhances the effector functions of neutrophils.

(3AB) Neutrophil phagocytosis of FITC-stained heat-killed opsonized (HKO) C. albicans. (3B) Significantly more FITC-stained HKO C. albicans were phagocytosed by adherent human neutrophils treated with RvE1 (yellow bars) relative to vehicle-treated cells (open bar; asterisks indicate significant differences from vehicle-treated controls; ANOVA: p<0.001). Neutrophils treated with the non-hydrolyzable cAMP analog 8-bromo-cAMP were less likely to phagocytose the yeast (black bar). (3A) Representative images of isolated neutrophils phagocytosing FITC-stained HKO C. albicans in the presence of 10 nM RvE1, 1 nM RvE1 or vehicle and trypan blue. Green fluorescence (right panels) correspond to FITC-stained HKO C. albicans phagocytosed by neutrophils (3C) Neutrophils exposed to RvE1 exhibited a positive dose-dependent increase in their ability to kill opsonized C. albicans (yellow bars). Twice as many C. albicans were killed by neutrophils treated with 1nM RvE1 and over three times as many yeast were killed by neutrophils treated with 10 nM RvE1 relative to vehicle-treated neutrophils. Asterisks indicate significant differences from vehicle-treated controls (ANOVA: p<0.001). (3D) RvE1 had no effect on hydroxy-radical produced by neutrophils exposed to HKO C. albicans (red, orange, and yellow circles vs blue diamonds). (3E) 100 nM RvE1 increased neutrophil super-oxide production in neutrophils exposed to HKO C. albicans relative to neutrophils exposed to vehicle and HKO C. albicans (red circles vs blue diamonds) while lower concentrations of RvE1 (orange and yellow circles) did not increase neutrophil super-oxide relative to cells exposed to vehicle and HKO C. albicans (blue diamonds). 100nM RvE1 alone did not increase the amount of ROS produced by neutrophils relative to vehicle controls (3DE: black circles).

Figure 4

Figure 4. RvE1 reduces C. albicans concentrations in the blood.

To evaluate the actions of RvE1 on the virulence of C albicans, 8–10 week old female BALB/c mice were injected via the tail vein with RvE1 (8 ng g−1 mouse) or vehicle and C. albicans (5×104 yeast cells g−1 mouse). After 24 h, and blood and organs were collected, homogenized, serially diluted and plated. There was a 10-fold reduction in C. albicans circulating in the blood of mice injected with RvE1 compared to those injected with vehicle (circles vs triangles). In contrast, RvE1 and vehicle-treated mice showed similar levels of organ colonization.

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