Candida parapsilosis produces prostaglandins from exogenous arachidonic acid and OLE2 is not required for their synthesis

Abstract

Prostaglandins are C20 fatty acid metabolites with diverse biological functions. In mammalian cells, prostaglandins are produced from arachidonic acid (AA) via cyclooxygenases (COX1 and COX2). Although fungi do not possess cyclooxygenase homologues, several pathogenic species are able to produce prostaglandins from host-derived arachidonic acid. In this study, we characterized the prostaglandin profile of the emerging human pathogen Candida parapsilosis with HPLC-MS and compared it to that of C. albicans. We found that both species synthesized prostaglandins (mainly PGD 2 and PGE 2 ) from exogenous AA. Furthermore, as OLE2 has been associated with prostaglandin synthesis in C. albicans, we generated homozygous OLE2 deletion mutants in C. parapsilosis and examined their PGE 2 production. However, the PGE 2 production of the OLE2 KO strain was similar to that of wild type (WT), indicating that OLE2 is not required for prostaglandin synthesis in C. parapsilosis. Interestingly, analyses of the fatty acid composition of WT and OLE2 KO cells by gas chromatography (GC) highlighted the accumulation of palmitoleic and oleic acid in the OLE2 deletion mutant. The OLE2 KO cells were killed more efficiently by human monocytes-derived macrophages (MDMs) as well as induced higher interleukin-10 (IL-10) secretion, indicating that OLE2 affects the virulence of C. parapsilosis. Taken together, these results contribute to the better understanding of fatty acid biosynthesis pathways in C. parapsilosis.

Eicosanoid biosynthesis influences the virulence of Candida parapsilosis

“…As the incidence of this species has increased over the past two decades and the patient group at risk includes immunosuppressed children and adults as well as neonates, understanding the pathogenesis of C. parapsilosis has gained increased attention [16,28]. Preliminary studies have started to elucidate the prostaglandin profile of this species [17], however, the involved biosynthetic pathways and the presence or role of other fungal eicosanoids remained elusive. Previously, we have shown that in the presence of exogenous arachidonic acid, C. parapsilosis is capable of producing fungal prostaglandins, although OLE2 is not involved in the synthetic mechanisms, leaving the corresponding biosynthetic processes unexplored [17].…”

“…Preliminary studies have started to elucidate the prostaglandin profile of this species [17], however, the involved biosynthetic pathways and the presence or role of other fungal eicosanoids remained elusive. Previously, we have shown that in the presence of exogenous arachidonic acid, C. parapsilosis is capable of producing fungal prostaglandins, although OLE2 is not involved in the synthetic mechanisms, leaving the corresponding biosynthetic processes unexplored [17]. …”

“…Previously, we demonstrated that C. parapsilosis is also able to produce immunomodulatory prostaglandins from exogenous arachidonic acid. Although, in contrast with C. albicans , the fatty acid desaturase OLE2 is not involved in the process; hence, the molecular mechanisms behind eicosanoid biosynthesis remain to be elucidated [17]. …”

Candida parapsilosis Secreted Lipase as an Important Virulence Factor

“…Both C. albicans and C. parapsilosis assimilate exogenic arachidonic acid in order to produce human prostaglandin-like molecules (PGE 2 and PGD 2 ) [47,48]. Fungal prostaglandins were shown to modulate host immune responses via a variety of mechanisms to promote host colonization [49].…”

“…These cytokines include interleukin -1 (IL-1), interleukin -6 (IL-6) and tumor necrosis factor alpha (TNFα) as major inducers of inflammatory reactions; IL-8 as a neutrophil chemotactic factor and other chemokines to recruit leukocytes to the infection site [57,58]. Cyclooxygenase 2 (COX-2) is essential for the synthesis of the biologically active inflammation inducer prostaglandin E2 [48]. Toth A. et al and Nagy and Filkor et al reported that both DCs and PBMC-DMs released IL-1, IL-6 and TNFα pro-inflammatory cytokines at a markedly increased level in the presence Cp ΔΔlip1-ΔΔlip2 cells compared to that occurring in the presence of wild type yeast cells and an elevated level of IL-8 was detected after DCs were challenged with Cp ΔΔlip1-ΔΔlip2 compared to wild type cells [55].…”