A Targeted Mass Spectrometric Analysis Reveals the Presence of a Reduced but Dynamic Sphingolipid Metabolic Pathway in an Ancient Protozoan, Giardia lamblia

Abstract

Giardia lamblia , a single-celled eukaryote, colonizes and thrives in the small intestine of humans. Because of its compact and reduced genome, Giardia has adapted a “minimalistic” life style, as it becomes dependent on available resources of the small intestine. Because Giardia expresses fewer sphingolipid (SL) genes—and glycosphingolipids are critical for encystation—we investigated the SL metabolic cycle in this parasite. A tandem mass spectrometry (MS/MS) analysis reveals that major SLs in Giardia include sphingomyelins, sphingoid bases, ceramides, and glycosylceramides. Many of these lipids are obtained by Giardia from the growth medium, remodeled at their fatty acyl chains and end up in the spent medium. For instance, ceramide-1-phosphate, a proinflammatory molecule that is not present in the culture medium, is generated from sphingosine (abundant in the culture medium) possibly by remodeling reactions. It is then subsequently released into the spent medium. Thus, the secretion of ceramide-1-phospate and other SL derivatives by Giardia could be associated with inflammatory bowel disease observed in acute giardiasis. Additionally, we found that the levels of SLs increase in encysting Giardia and are differentially regulated throughout the encystation cycle. We propose that SL metabolism is important for this parasite and, could serve as potential targets for developing novel anti-giardial agents.

Giardia duodenalis Induces Apoptosis in Intestinal Epithelial Cells via Reactive Oxygen Species-Mediated Mitochondrial Pathway In Vitro

“…Another piece of research confirmed the presence of ESPs in Caco-2 cells and indicated that the internalized ESPs could suppress inflammatory response via regulating NF-κB- and MAPK-signaling pathways [ 9 ]. In addition, the Giardia -secreted sphingolipid ceramide-1-phospate was depicted in association with IBD during acute infection [ 46 ]. Our future work will identify the molecular players, potentially ESPs, mediating Giardia -associated host cell death signaling and attempt to understand how they work.…”

Lipidome of extracellular vesicles from Giardia lamblia

“…It is well documented that Giardia has a limited ability to synthesize de novo its own lipid molecules and, therefore, depends on exogenous lipids for its growth and differentiation [22,23]. Therefore, many of these exogenous lipids undergo remodeling and/or base-exchange reactions before they are incorporated into giardial membranes [24].…”

“…Indeed, Giardia has evolved mechanisms to import exogenous lipids and cholesterol by receptor-mediated endocytosis and traffic via clathrin-mediated and actin/microtubule-dependent pathways [25]. The predominant sphingolipids (SLs) in Giardia are sphingoid bases (sphingosine and sphinganine), ceramides, GSLs and sphingomyelin SM [22]. The levels of SLs are differentially regulated during encystation and ceramide-1-phosphate (Cer-1-P) is a newly generated lipid in Giardia [22].…”

“…The predominant sphingolipids (SLs) in Giardia are sphingoid bases (sphingosine and sphinganine), ceramides, GSLs and sphingomyelin SM [22]. The levels of SLs are differentially regulated during encystation and ceramide-1-phosphate (Cer-1-P) is a newly generated lipid in Giardia [22]. It seems that the Cer-1-P is generated from sphingosine, possibly by remodeling reactions and subsequently is released.…”

Natural marine products as antiprotozoal agents against amitochondrial parasites

“…Additional to susceptibility, genetic variation of the giardia complex diversity suggests the possible apparition of virulent strains due to host adaptation and co-evolution. Current estimates indicate that nearly 184 million people get affected annually ( Argüello-García and Ortega-Pierres, 2021 ; Duarte et al, 2019 ).…”