Fungal symbionts produce prostaglandin E₂to promote their intestinal colonization

Abstract

1314 Candida albicans is a ubiquitous fungal symbiont that resides on diverse human barrier surfaces. Both 15 mammalian and fungal cells can convert arachidonic acid into the lipid mediator, prostaglandin E2 16 (PGE 2 ), but the physiological significance of fungal-derived PGE 2 remains elusive. Here we report 17 that a C. albicans mutant deficient in PGE 2 production suffered a loss of competitive fitness in the 18 murine gastrointestinal (GI) tract and that PGE 2 supplementation mitigated this fitness defect.19 Impaired fungal PGE 2 production affected neither the in vitro fitness of C. albicans nor hyphal 20 morphogenesis and virulence in either systemic or mucosal infection models. Fungus-derived PGE 2 21 improved intra-GI fitness of C. albicans by diminishing the killing of C. albicans by phagocytes.22 Consequently, ablation of colonic phagocytes abrogated the fitness boost conferred by fungal PGE 2 .23 These observations suggest that C. albicans has evolved the capacity to produce PGE 2 from 24 arachidonic acid, a host-derived precursor, to promote its own colonization of the host gut. Analogous 25 mechanisms might undergird host-microbe interactions of other symbiont fungi. 263 27 Author Summary 28 29 Candida albicans is a symbiont fungus that resides in the gut of a majority of people without 30 provoking disease. However, resident C. albicans can bloom and turn pathogenic in a subset of 31 individuals who are immunocompromised due to infections or chemotherapy or who suffer a disruption 32 of their intestinal microbial community due to antibiotic use. However, the fungal and host factors that 33 regulate the fitness of C. albicans as a symbiont or an invasive pathogen remain poorly understood.34 Here we focused on the physiological role of fungus-derived prostaglandin E2 (PGE 2 ) in the fitness of 35 C. albicans using a PGE 2 -deficient C. albicans strain and mouse models of infections and intestinal 36 symbiosis. We found that fungal PGE 2 , contrary to previously described functions of promoting 37 virulence, played no role in fungal pathogenicity in vivo. Instead, fungal PGE 2 specifically augmented 38 the ability of C. albicans to colonize the gut, in part by reducing fungal killing by intestinal phagocytes.39 Our results suggest that fungal PGE 2 synthetic pathways may be prophylactically targeted in 40 individuals susceptible to invasive infections.41 4 42 Introduction 43 44 Candida albicans is one of the most successful fungal symbionts in humans, colonizing 40-45 80% of individuals in industrialized nations and typically representing the predominant species within 46 the fungal microbiota [1, 2]. In healthy people, C. albicans dwells on diverse barrier sites of the body, 47 including the oral cavity, skin, female reproductive tract, and the intestines, where it does not cause 48 symptomatic disease [1, 2]. However, C. albicans can turn pathogenic and result in mucosal or life-49 threatening invasive bloodstream infections under a variety of conditions that compromise host 50 immunity, damage barr...

Therapeutic manipulation of gut microbiota by polysaccharides of Wolfiporia cocos reveals the contribution of the gut fungi-induced PGE2 to alcoholic hepatic steatosis

“…On the other hand, the production of PGE 2 by fungi is closely associated with fungal virulence and intestinal colonization. 36 , 37 PGE 2 was demonstrated to facilitate the growth of fungi by suppressing the interleukin-17 dependent anti-fungal immunity in mice. 38 In this work, the gut fungus M. guilliermondii enriched in mice with chronic ethanol feeding was found to produce PGE 2 on culturing with the exogenous arachidonic acid (Figure S3), which might facilitate its intestinal colonization, and contribute to the increase of PGE 2 in the liver of AHS mice.…”

A Modern-World View of Host–Microbiota–Pathogen Interactions

“…Commensal microbes produce chemicals at a diversity that rivals that of any other microbial ecosystem (112,113), a feature that attests to their vast potential in modulating host physiology, including susceptibility to infection. The molecules can either be produced directly by commensal microbes (i.e., microbial products) or result from microbe-mediated modification of host compounds (i.e., microbial metabolites).…”

Recognition of Candida albicans and Role of Innate Type 17 Immunity in Oral Candidiasis

“…Prostaglandins are potent lipid molecules playing a pivotal role in the modulation of immunity [ 56 , 57 ]. Intriguingly, C. albicans is able to produce prostaglandins itself de novo or via conversion of exogenous arachidonic acid, thereby amplifying downstream signaling [ 58 , 59 ]. It was shown that fungal prostaglandins can inhibit TNF-α and induce IL-10 production, which can enhance fungal-cell adhesion, germ-tube development, and biofilm formation by C. albicans [ 58 , 60 , 61 , 62 ].…”