Liver Fibrosis Is Enhanced by a Higher Egg Burden in Younger Mice Infected with <i>S. mansoni</i>
Heike Müller,
Jan K. Straßmann,
Anne S. Baier,
Verena von Bülow,
Frederik Stettler,
Maximilian J. Hagen,
Fabian P. Schmidt,
Annette Tschuschner,
Andreas R. Schmid,
Daniel Zahner,
Kernt Köhler,
Jörn Pons-Kühnemann,
Daniel Leufkens,
Dieter Glebe,
Surmeet Kaur,
Max F. Möscheid,
Simone Haeberlein,
Christoph G. Grevelding,
Ralf Weiskirchen,
Mohamed El-Kassas,
Khaled Zalata,
Elke Roeb,
Martin Roderfeld
Affiliations
Heike Müller
Department of Gastroenterology, Justus Liebig University, 35392 Giessen, Germany
Jan K. Straßmann
Department of Gastroenterology, Justus Liebig University, 35392 Giessen, Germany
Anne S. Baier
Department of Gastroenterology, Justus Liebig University, 35392 Giessen, Germany
Verena von Bülow
Department of Gastroenterology, Justus Liebig University, 35392 Giessen, Germany
Frederik Stettler
Department of Gastroenterology, Justus Liebig University, 35392 Giessen, Germany
Maximilian J. Hagen
Department of Gastroenterology, Justus Liebig University, 35392 Giessen, Germany
Fabian P. Schmidt
Department of Gastroenterology, Justus Liebig University, 35392 Giessen, Germany
Annette Tschuschner
Department of Gastroenterology, Justus Liebig University, 35392 Giessen, Germany
Andreas R. Schmid
Department of Internal Medicine III, Justus Liebig University, 35392 Giessen, Germany
Daniel Zahner
Central Laboratory Animal Facility, Justus Liebig University, 35392 Giessen, Germany
Kernt Köhler
Institute of Veterinary Pathology, Justus Liebig University, 35392, Germany
Jörn Pons-Kühnemann
Institute of Medical Informatics, Justus Liebig University, 35392, Germany
Daniel Leufkens
Institute of Medical Informatics, Justus Liebig University, 35392, Germany
Dieter Glebe
Institute of Medical Virology, National Reference Center for Hepatitis B Viruses and Hepatitis D Viruses, German Center for Infection Research (DZIF; Partner Site Giessen-Marburg-Langen), Justus Liebig University, 35392 Giessen, Germany
Surmeet Kaur
Institute of Medical Virology, National Reference Center for Hepatitis B Viruses and Hepatitis D Viruses, German Center for Infection Research (DZIF; Partner Site Giessen-Marburg-Langen), Justus Liebig University, 35392 Giessen, Germany
Max F. Möscheid
Institute of Parasitology, BFS, Justus Liebig University, 35392 Giessen, Germany
Simone Haeberlein
Institute of Parasitology, BFS, Justus Liebig University, 35392 Giessen, Germany
Christoph G. Grevelding
Institute of Parasitology, BFS, Justus Liebig University, 35392 Giessen, Germany
Ralf Weiskirchen
Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, 52074 Aachen, Germany
Mohamed El-Kassas
Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo 11795, Egypt
Khaled Zalata
Pathology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
Elke Roeb
Department of Gastroenterology, Justus Liebig University, 35392 Giessen, Germany
Martin Roderfeld
Department of Gastroenterology, Justus Liebig University, 35392 Giessen, Germany
Schistosomiasis affects over 250 million people worldwide, with the highest prevalence at the age of 10–14 years. The influence of the host’s age on the severity of liver damage is unclear. We infected male 8, 14, and 20-week-old mice with S. mansoni. Hepatic damage, inflammation, fibrosis, and metabolism were analyzed by RT-qPCR, Western blotting, ELISA, immunohistochemistry, and mechanistic transwell chamber experiments using S. mansoni eggs and human hepatic stellate cells (HSCs) or primary mouse hepatocytes. Major results were validated in human biopsies. We found that hepatosplenomegaly, granuloma size, egg load, inflammation, fibrosis, and glycogen stores all improved with the increasing age of the host. However, serum alanine transaminase (ALT) levels were lowest in young mice infected with S. mansoni. Hepatic carbohydrate exploitation was characterized by a shift towards Warburg-like glycolysis in S. mansoni-infected animals. Notably, S. mansoni eggs stimulated hepatic stellate cells to an alternatively activated phenotype (GFAP+/desmin+/αSMA−) that secretes IL-6 and MCP-1. The reduction of fibrosis in older age likely depends on the fine-tuning of regulatory and inflammatory cytokines, alternative HSC activation, and the age-dependent preservation of hepatic energy stores. The current results emphasize the significance of investigations on the clinical relevance of host age-dependent liver damage in patients with schistosomiasis.
