Metabolic reprogramming of hepatocytes by Schistosoma mansoni eggs

Verena von Bülow; Sarah Gindner; Anne Baier; Laura Hehr; Nicola Buss; Lena Russ; Sarah Wrobel; Victoria Wirth; Kuscha Tabatabai; Thomas Quack; Simone Haeberlein; Patrik Kadesch; Stefanie Gerbig; Katja R Wiedemann; Bernhard Spengler; Annabel Mehl; Gertrud Morlock; Gabriele Schramm; Jörn Pons-Kühnemann; Franco H Falcone; R Alan Wilson; Katrin Bankov; Peter Wild; Christoph G Grevelding; Elke Roeb; Martin Roderfeld

doi:10.1016/j.jhepr.2022.100625

Metabolic reprogramming of hepatocytes by Schistosoma mansoni eggs

JHEP Rep. 2022 Nov 7;5(2):100625. doi: 10.1016/j.jhepr.2022.100625. eCollection 2023 Feb.

Authors

Verena von Bülow¹, Sarah Gindner¹, Anne Baier¹, Laura Hehr¹, Nicola Buss¹, Lena Russ¹, Sarah Wrobel¹, Victoria Wirth¹, Kuscha Tabatabai¹, Thomas Quack², Simone Haeberlein², Patrik Kadesch³, Stefanie Gerbig³, Katja R Wiedemann³, Bernhard Spengler³, Annabel Mehl⁴, Gertrud Morlock⁴, Gabriele Schramm⁵, Jörn Pons-Kühnemann⁶, Franco H Falcone², R Alan Wilson⁷, Katrin Bankov⁸, Peter Wild⁸, Christoph G Grevelding², Elke Roeb¹, Martin Roderfeld¹

Affiliations

¹ Department of Gastroenterology, Justus Liebig University, Klinikstr. 33, 35392 Giessen, Germany.
² Institute of Parasitology, BFS, Justus Liebig University, Schubertstr. 81, 35392 Giessen, Germany.
³ Institute of Inorganic and Analytical Chemistry, Justus Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen, Germany.
⁴ Institute of Nutritional Science, Food Science Department, and Interdisciplinary Research Center (iFZ), Justus Liebig University Giessen, Heinrich-Buff-Ring 26-32, 35392 Giessen, Germany.
⁵ Experimental Pneumology, Priority Research Area Asthma & Allergy, Research Center Borstel, Parkallee 1-40, 23845 Borstel, Germany.
⁶ Institute of Medical Informatics, Justus Liebig University, Rudolf-Buchheim-Str. 6. 35392 Giessen, Germany.
⁷ York Biomedical Research Institute, Department of Biology, University of York, York YO10 5DD, UK.
⁸ Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Frankfurt am Main, Germany.

Abstract

Background & aims: Schistosomiasis is a parasitic infection which affects more than 200 million people globally. Schistosome eggs, but not the adult worms, are mainly responsible for schistosomiasis-specific morbidity in the liver. It is unclear if S. mansoni eggs consume host metabolites, and how this compromises the host parenchyma.

Methods: Metabolic reprogramming was analyzed by matrix-assisted laser desorption/ionization mass spectrometry imaging, liquid chromatography with high-resolution mass spectrometry, metabolite quantification, confocal laser scanning microscopy, live cell imaging, quantitative real-time PCR, western blotting, assessment of DNA damage, and immunohistology in hamster models and functional experiments in human cell lines. Major results were validated in human biopsies.

Results: The infection with S. mansoni provokes hepatic exhaustion of neutral lipids and glycogen. Furthermore, the distribution of distinct lipid species and the regulation of rate-limiting metabolic enzymes is disrupted in the liver of S. mansoni infected animals. Notably, eggs mobilize, incorporate, and store host lipids, while the associated metabolic reprogramming causes oxidative stress-induced DNA damage in hepatocytes. Administration of reactive oxygen species scavengers ameliorates these deleterious effects.

Conclusions: Our findings indicate that S. mansoni eggs completely reprogram lipid and carbohydrate metabolism via soluble factors, which results in oxidative stress-induced cell damage in the host parenchyma.

Impact and implications: The authors demonstrate that soluble egg products of the parasite S. mansoni induce hepatocellular reprogramming, causing metabolic exhaustion and a strong redox imbalance. Notably, eggs mobilize, incorporate, and store host lipids, while the metabolic reprogramming causes oxidative stress-induced DNA damage in hepatocytes, independent of the host's immune response. S. mansoni eggs take advantage of the host environment through metabolic reprogramming of hepatocytes and enterocytes. By inducing DNA damage, this neglected tropical disease might promote hepatocellular damage and thus influence international health efforts.

Keywords: DMPE, dimethyl-phosphatidylethanolamine; DNA damage; GS, glycogen synthase; GSH, reduced L-glutathione; HCC, hepatocellular carcinoma; Lipid; MALDI-MSI, matrix assisted laser desorption/ionization mass spectrometry imaging; MDA, malondialdehyde; OA, oleic acid; Oxidative stress; PAS, periodic acid-Schiff; PC, phosphatidylcholine; PDH, pyruvate dehydrogenase; PE, phosphatidylethanolamine; PLIN2, perilipin 2; Parasite; ROS, reactive oxygen species; S. japonicum, Schistosoma japonicum; S. mansoni, Schistosoma mansoni; SEA, soluble egg antigens; Schistosomiasis; TG, triglyceride; bs, bisex; flOA, fluorescently labelled OA; hRF, retention factor ∗ 100; ms, monosex; ni, non-infected.