Liver Fibrosis Is Enhanced by a Higher Egg Burden in Younger Mice Infected with S. mansoni

Cells, vol. 13, pp. 1643

Abstract

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.

Authors 22

1. Heike Müller

   Justus-Liebig-Universität Gießen

   Affiliation as printed

   Department of Gastroenterology, Justus Liebig University, 35392 Giessen, Germany

2. Jan K. Straßmann

   Justus-Liebig-Universität Gießen

   Affiliation as printed

   Department of Gastroenterology, Justus Liebig University, 35392 Giessen, Germany

3. A Baier

   Justus-Liebig-Universität Gießen

   Affiliation as printed

   Department of Gastroenterology, Justus Liebig University, 35392 Giessen, Germany

4. Verena von Bülow

   Justus-Liebig-Universität Gießen

   Affiliation as printed

   Department of Gastroenterology, Justus Liebig University, 35392 Giessen, Germany

5. Frederik Stettler

   Justus-Liebig-Universität Gießen

   Affiliation as printed

   Department of Gastroenterology, Justus Liebig University, 35392 Giessen, Germany

6. Maximilian Hagen

   Justus-Liebig-Universität Gießen

   Affiliation as printed

   Department of Gastroenterology, Justus Liebig University, 35392 Giessen, Germany

7. Annette Tschuschner

   Justus-Liebig-Universität Gießen

   Affiliation as printed

   Department of Gastroenterology, Justus Liebig University, 35392 Giessen, Germany

8. Andreas Schmid

   Justus-Liebig-Universität Gießen

   Affiliation as printed

   Department of Internal Medicine III, Justus Liebig University, 35392 Giessen, Germany

9. Daniel Zahner

   Justus-Liebig-Universität Gießen

   Affiliation as printed

   Central Laboratory Animal Facility, Justus Liebig University, 35392 Giessen, Germany

10. Kernt Köhler

    Justus-Liebig-Universität Gießen

    Affiliation as printed

    Institute of Veterinary Pathology, Justus Liebig University, 35392, Germany

11. Jörn Pons‐Kühnemann

    Justus-Liebig-Universität Gießen

    Affiliation as printed

    Institute of Medical Informatics, Justus Liebig University, 35392, Germany

12. Daniel Leufkens

    Justus-Liebig-Universität Gießen

    Affiliation as printed

    Institute of Medical Informatics, Justus Liebig University, 35392, Germany

13. Dieter Glebe

    German Center for Infection Research · Justus-Liebig-Universität Gießen

    Affiliation as printed

    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

14. Surmeet Kaur

    German Center for Infection Research · Justus-Liebig-Universität Gießen

    Affiliation as printed

    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

15. Max F. Moescheid

    Justus-Liebig-Universität Gießen

    Affiliation as printed

    Institute of Parasitology, BFS, Justus Liebig University, 35392 Giessen, Germany

16. Simone Haeberlein

    Justus-Liebig-Universität Gießen

    Affiliation as printed

    Institute of Parasitology, BFS, Justus Liebig University, 35392 Giessen, Germany

17. Christoph Gero Grevelding

    Justus-Liebig-Universität Gießen

    Affiliation as printed

    Institute of Parasitology, BFS, Justus Liebig University, 35392 Giessen, Germany

18. Ralf Weiskirchen Aachen Institute of Molecular Pathobiochemistry Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC)

    RWTH Aachen University · Universitätsklinikum Aachen

    Affiliation as printed

    Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, 52074 Aachen, Germany

19. Mohamed El‐Kassas

    Helwan University

    Affiliation as printed

    Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo 11795, Egypt

20. Khaled Refaat Zalata

    Mansoura University

    Affiliation as printed

    Pathology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt

21. Elke Roeb

    Justus-Liebig-Universität Gießen

    Affiliation as printed

    Department of Gastroenterology, Justus Liebig University, 35392 Giessen, Germany

22. M Roderfeld corresponding

    Justus-Liebig-Universität Gießen

    Affiliation as printed

    Department of Gastroenterology, Justus Liebig University, 35392 Giessen, Germany