The Candida albicans quorum-sensing molecule, farnesol, remodels the peritoneal cavity microenvironment to promote innate inflammatory responses in mice.

Abstract

Abstract Candida albicans is a polymorphic fungus that causes mucosal candidiasis and life threatening, systemic and intra-abdominal disease in immunocompromised and transplant patients. In normal healthy adults, C albicans is maintained as a commensal mainly through the actions of innate cells. Secretion of the quorum-sensing molecule, farnesol, acts as a virulence factor for C. albicans during systemic infection, but is protective in oral models of infection. Despite the clinical importance of intra-abdominal candidiasis with a mortality rate as high as 65%, the role of farnesol in its pathogenesis has not been studied. In ongoing experiments, we found that introduction of farnesol into the peritoneal cavity (PC) of mice remodels the peritoneal microenvironment to promote innate inflammatory responses. Early following intraperitoneal injection, farnesol stimulates the rapid depletion of B cells followed by recruitment of inflammatory macrophages and neutrophils into the PC compared to thioglycollate and control mice. Kinetic analyses of the transcriptional profile of farnesol-elicited cells reveal an early increase in chemokines followed by increased proinflammatory cytokines consistent with macrophage recruitment and activation. In addition, farnesol-elicited macrophages and dendritic cells demonstrate hallmarks of innate immune activation through high surface expression of class II and co-stimulatory molecules. Current experiments aim to determine the impact of this innate immune recruitment on antifungal defenses and clearance in the PC. Defining the immunostimulatory properties of farnesol will inform development of more appropriate therapeutic strategies for treatment of intra-abdominal Candida infection.