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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 fungus-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. Instead, fungal production of PGE2 was associated with enhanced fungal survival within phagocytes. Consequently, ablation of colonic phagocytes abrogated the intra-GI 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.

SUBMITTER: Tan TG

PROVIDER: S-EPMC6813641 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Fungal Symbionts Produce Prostaglandin E2 to Promote Their Intestinal Colonization.

Tan Tze Guan TG Lim Ying Shiang YS Tan Alrina A Leong Royston R Pavelka Norman N

Frontiers in cellular and infection microbiology 20191018

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 fungus-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< ...[more]

PMID: 31681635

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Project description:Background & aimsProstaglandin E2 (PGE2) promotes colorectal tumor formation and progression by unknown mechanisms. We sought to identify microRNAs (miRNAs) that might mediate the effects of PGE2 on colorectal cancer (CRC) development.MethodsWe incubated LS174T colorectal cancer cells with PGE2 or without (control) and used miRNA-sequencing technology to compare expression patterns of miRNAs. We knocked down levels of specific miRNAs or proteins in cells using small interfering RNAs or genome editing. Cells were analyzed by immunoblot, quantitative polymerase chain reaction, chromosome immunoprecipitation, cell invasion, and luciferase reporter assays; we measured gene expression, binding activity, cell migration and invasion, and transcriptional activity of transcription factors. NOD-scidIL-2Rg-/- mice were given injections of LS174T cells, and growth of primary tumors and numbers of liver and lung metastases were quantified and analyzed by histology. We used public databases to identify correlations in gene expression pattern with patient outcomes.ResultsWe identified miRNA 675-5p (miR675-5p) as the miRNA most highly up-regulated by incubation of colorectal cancer cells with PGE2. PGE2 increased expression of miR675-5p by activating expression of Myc, via activation of protein kinase B, also known as (AKT), nuclear factor ?B, and ?-catenin. PGE2 increased the invasive activities of cultured CRC cells. LS174T cells incubated with PGE2 formed more liver and lung metastases in mice than control LS174T cells. We identified a 3' untranslated region in the TP53 messenger RNA that bound miR675-5p; binding resulted in loss of the p53 protein. Expression of miR675-5p or its precursor RNA, H19, correlated with expression of cyclooxygenase-1 and cyclooxygenase-2 and shorter survival times of patients with CRC.ConclusionsWe found that treatment of mice with PGE2 increased CRC cells invasive activity and ability to form liver and lung metastases. PGE2 down-regulates expression of p53 by increasing expression of miR675-5p, which binds to and prevents translation of TP53 messenger RNA. These findings provide insight into the mechanisms by which PGE2 promotes tumor development and progression. Strategies to target PGE2 might be developed for treatment of CRC.

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Fungal Symbionts Produce Prostaglandin E2 to Promote Their Intestinal Colonization.

Publications

Fungal Symbionts Produce Prostaglandin E<sub>2</sub> to Promote Their Intestinal Colonization.

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