title: Hemozoin induces hepatic inflammation in mice and is differentially associated with liver pathology depending on the Plasmodium strain.
abstract: Malaria is a global disease that clinically affects more than two hundred million people annually. Despite the availability of effective antimalarials, mortality rates associated with severe complications are high. Hepatopathy is frequently observed in patients with severe malarial disease and its pathogenesis is poorly understood. Previously, we observed high amounts of hemozoin or malaria pigment in livers from infected mice. In this study, we investigated whether hemozoin is associated with liver injury in different mouse malaria models. C57BL/6J mice infected with the rodent parasites Plasmodium berghei ANKA, P. berghei NK65 or P. chabaudi AS had elevated serum liver enzymes without severe histological changes in the liver, in line with the observations in most patients. Furthermore, liver enzymes were significantly higher in serum of P. chabaudi AS-infected mice compared to mice infected with the P. berghei parasite strains and a strong positive correlation was found between hepatic hemozoin levels, hepatocyte damage and inflammation in the liver with P. chabaudi AS. The observed liver injury was only marginally influenced by the genetic background of the host, since similar serum liver enzyme levels were measured in infected C57BL/6J and BALB/c mice. Intravenous injection of P. falciparum-derived hemozoin in malaria-free C57BL/6J mice induced inflammatory gene transcription in the liver, suggesting that hemozoin may be involved in the pathogenesis of malaria hepatopathy by inducing inflammation.
authors.affiliation: Department of Microbiology & Immunology, Laboratory of Immunobiology, Rega Institute for Medical Research, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: Deroost
authors.affiliation: Department of Microbiology & Immunology, Laboratory of Immunobiology, Rega Institute for Medical Research, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Natacha
authors.initials: N
authors.lastname: Lays
authors.affiliation: Department of Microbiology & Immunology, Laboratory of Immunobiology, Rega Institute for Medical Research, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Thao-Thy
authors.initials: TT
authors.lastname: Pham
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy; Department of Biology, Tor Vergata Rome University, Rome, Italy.
authors.forename: Denisa
authors.initials: D
authors.lastname: Baci
authors.affiliation: Translational Cell & Tissue Research, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Van den Eynde
authors.affiliation: Translational Cell & Tissue Research, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Mina
authors.initials: M
authors.lastname: Komuta
authors.affiliation: Department of Neuroscience, University of Torino, Torino, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Prato
authors.affiliation: Translational Cell & Tissue Research, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Tania
authors.initials: T
authors.lastname: Roskams
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy; Department of Genetics, Biology, and Biochemistry, University of Torino, Torino, Italy.
authors.forename: Evelin
authors.initials: E
authors.lastname: Schwarzer
authors.affiliation: Department of Microbiology & Immunology, Laboratory of Immunobiology, Rega Institute for Medical Research, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Ghislain
authors.initials: G
authors.lastname: Opdenakker
authors.affiliation: Department of Microbiology & Immunology, Laboratory of Immunobiology, Rega Institute for Medical Research, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Philippe E
authors.initials: PE
authors.lastname: Van den Steen
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000469:parasitology; D016207:Cytokines / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006420:Hemeproteins / Q000378:metabolism / Q000633:toxicity*; D006790:Host-Parasite Interactions; D008099:Liver / Q000469:parasitology / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism; D008288:Malaria / Q000150:complications* / Q000469:parasitology; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000145:classification / Q000502:physiology; D016788:Plasmodium chabaudi / Q000502:physiology; D010963:Plasmodium falciparum / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D013045:Species Specificity
chemical_list: D016207:Cytokines; D006420:Hemeproteins; C020753:hemozoin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase