Candida albicans Quorum Sensing Molecules Stimulate Mouse Macrophage Migration

Abstract

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...

Deciphering fungal dimorphism: Farnesol's unanswered questions

“…(). Farnesol is a known virulence factor for C. albicans (Navarathna et al ., ; Hargarten et al ., ). Lockhart et al .…”

“…This dilemma has been answered in part by the recent work of Hargarten et al . () who showed that C. albicans white cells secrete farnesol as a chemoattractive stimulant of macrophages, a phagocyte that they are able to survive within and escape from. Farnesol, which is secreted by white cells only (Dumitru et al ., ), is a potent stimulator of macrophage chemokinesis; it results in an 8.5‐fold increase in macrophage migration in vitro and a threefold increase in the peritoneal infiltration of macrophages in vivo (Hargarten et al ., ).…”

Quorum sensing in Candida albicans: farnesol versus farnesoic acid

“…Subsequently, Ghosh et al [18] showed that mouse macrophage cells produced ca. More recently [19] we showed that FOH stimulated the migration of mouse macrophages, induced the rapid depletion of B cells from the mouse peritoneal cavity, and recruited neutrophils, granulocytes, and small peritoneal macrophages to the mouse peritoneal cavity. Strain 10231 elicited only background levels of IL-6 expression.…”

“…The RAW264.7 mouse macrophage cells produced more IL-6, TLR2, and dectin1 mRNA by 100-, 2-, and 3fold, respectively, when exposed to a combination of FOH and zymosan than a combination of FA and zymosan [18]. More recently [19] we showed that FOH stimulated the migration of mouse macrophages, induced the rapid depletion of B cells from the mouse peritoneal cavity, and recruited neutrophils, granulocytes, and small peritoneal macrophages to the mouse peritoneal cavity. Unfortunately, this study did not include direct comparisons of FOH versus FA or of C. albicans 10231 versus A72 or SC5314.…”

Candida albicans morphology: still in focus

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