| Summary: | Reactive sulfur species (RSS) like hydrogen sulfide (H<sub>2</sub>S) and cysteine persulfide (Cys-SSH) emerged as key signaling molecules with diverse physiological roles in the body, depending on their concentration and the cellular environment. While it is known that H<sub>2</sub>S and Cys-SSH are produced by both colonocytes and by the gut microbiota through sulfur metabolism, it remains unknown how these RSS affect amebiasis caused by <i>Entamoeba histolytica</i>, a parasitic protozoan that can be present in the human gastrointestinal tract. This study investigates H<sub>2</sub>S and Cys-SSH’s impact on <i>E. histolytica</i> physiology and explores potential therapeutic implications. Exposing trophozoites to the H<sub>2</sub>S donor, sodium sulfide (Na<sub>2</sub>S), or to Cys-SSH led to rapid cytotoxicity. A proteomic analysis of Cys-SSH-challenged trophozoites resulted in the identification of >500 S-sulfurated proteins, which are involved in diverse cellular processes. Functional assessments revealed inhibited protein synthesis, altered cytoskeletal dynamics, and reduced motility in trophozoites treated with Cys-SSH. Notably, cysteine proteases (CPs) were significantly inhibited by S-sulfuration, affecting their bacterial biofilm degradation capacity. Immunofluorescence microscopy confirmed alterations in actin dynamics, corroborating the proteomic findings. Thus, our study reveals how RSS perturbs critical cellular functions in <i>E. histolytica</i>, potentially influencing its pathogenicity and interactions within the gut microbiota. Understanding these molecular mechanisms offers novel insights into amebiasis pathogenesis and unveils potential therapeutic avenues targeting RSS-mediated modifications in parasitic infections.
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