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Abstract
The commensal fungus, Candida albicans, is a normal and life-long 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. Although, when normal immune responses are compromised, as is the case with immunocompromised and transplant patients, C. albicans can transition easily from a commensal to an opportunistic pathogen and disseminate throughout the body causing life-threatening disease via bloodstream and intra-abdominal infections. These invasive diseases are associated with mortality rates between 40-75%. With the incidence of invasive candidiasis on the rise as a result of increased drug resistance by Candida species and an ever-growing immunocompromised population, it is imperative to develop novel anti-fungal approaches to combat infection. For this reason, a sophisticated and holistic understanding of the interplay between host immune system and opportunistic pathogen during health (commensalism) and disease (virulence) is necessary. Fungal factors known to be important for virulence and commensalism are morphogenesis and secretion of the quorum-sensing molecule, farnesol. It is not known whether these two virulence factors are linked during interactions between the innate immune system and C. albicans, but they have the potential to influence early detection and elimination of pathogenic C. albicans. Here we show that C. albicans links farnesol secretion to the white-opaque switch modulating host-pathogen interactions to promote fungal survival within its host. Specifically, regulation of farnesol secretion by C. albicans stimulates host immune detection and recruitment towards white cells, while promoting host defense evasion by opaque cells. Additionally, in exploring the impact of farnesol on the immune response to C. albicans in the peritoneal cavity (a location often colonized by C. albicans following gastrointestinal tract perforations), we discovered a novel role for farnesol in remodeling the peritoneal cavity immune environment to promote inflammatory responses, which promote C. albicans virulence during intra-abdominal infection. Understanding farnesol’s role in modulating the innate immune response may one day lead to the development of an antifungal drug necessary to block systemic candidiasis. Most importantly, what we discover about the way C. albicans interacts with its host through secreted signaling molecules may help broaden our appreciation for small molecules in other opportunistic pathogen-host interactions.
