Fungal symbionts produce prostaglandin E2 to promote their intestinal colonization

Abstract

Candida albicans is a ubiquitous fungal symbiont that resides on diverse human barrier surfaces. Both mammalian and fungal cells can convert arachidonic acid into the lipid mediator, prostaglandin E2 (PGE2), but the physiological significance of fungal-derived PGE2 remains elusive. Here we report that a C. albicans mutant deficient in PGE2 production suffered a loss of competitive fitness in the murine gastrointestinal (GI) tract and that PGE2 supplementation mitigated this fitness defect. Impaired fungal PGE2 production affected neither the in vitro fitness of C. albicans nor hyphal morphogenesis and virulence in either systemic or mucosal infection models. Fungus-derived PGE2 improved intra-GI fitness of C. albicans by diminishing the killing of C. albicans by phagocytes. Consequently, ablation of colonic phagocytes abrogated the fitness boost conferred by fungal PGE2. These observations suggest that C. albicans has evolved the capacity to produce PGE2 from arachidonic acid, a host-derived precursor, to promote its own colonization of the host gut. Analogous mechanisms might undergird host-microbe interactions of other symbiont fungi.\n\nAuthor SummaryCandida albicans is a symbiont fungus that resides in the gut of a majority of people without provoking disease. However, resident C. albicans can bloom and turn pathogenic in a subset of individuals who are immunocompromised due to infections or chemotherapy or who suffer a disruption of their intestinal microbial community due to antibiotic use. However, the fungal and host factors that regulate the fitness of C. albicans as a symbiont or an invasive pathogen remain poorly understood. Here we focused on the physiological role of fungus-derived prostaglandin E2 (PGE2) in the fitness of C. albicans using a PGE2-deficient C. albicans strain and mouse models of infections and intestinal symbiosis. We found that fungal PGE2, contrary to previously described functions of promoting virulence, played no role in fungal pathogenicity in vivo. Instead, fungal PGE2 specifically augmented the ability of C. albicans to colonize the gut, in part by reducing fungal killing by intestinal phagocytes. Our results suggest that fungal PGE2 synthetic pathways may be prophylactically targeted in individuals susceptible to invasive infections.