Hemozoin induces hepatic inflammation in mice and is differentially associated with liver pathology depending on the Plasmodium strain

Katrien Deroost; Natacha Lays; Thao-Thy Pham; Denisa Baci; Kathleen Van den Eynde; Mina Komuta; Mauro Prato; Tania Roskams; Evelin Schwarzer; Ghislain Opdenakker; Philippe E Van den Steen

doi:10.1371/journal.pone.0113519

Hemozoin induces hepatic inflammation in mice and is differentially associated with liver pathology depending on the Plasmodium strain

PLoS One. 2014 Nov 24;9(11):e113519. doi: 10.1371/journal.pone.0113519. eCollection 2014.

Affiliations

¹ Department of Microbiology & Immunology, Laboratory of Immunobiology, Rega Institute for Medical Research, KU Leuven - University of Leuven, Leuven, Belgium.
² Department of Oncology, University of Torino, Torino, Italy; Department of Biology, Tor Vergata Rome University, Rome, Italy.
³ Translational Cell & Tissue Research, KU Leuven - University of Leuven, Leuven, Belgium.
⁴ Department of Neuroscience, University of Torino, Torino, Italy.
⁵ Department of Oncology, University of Torino, Torino, Italy; Department of Genetics, Biology, and Biochemistry, University of Torino, Torino, Italy.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alanine Transaminase / blood
Animals
Aspartate Aminotransferases / blood
Chemical and Drug Induced Liver Injury / etiology*
Chemical and Drug Induced Liver Injury / parasitology
Cytokines / genetics
Female
Gene Expression / drug effects
Hemeproteins / metabolism
Hemeproteins / toxicity*
Host-Parasite Interactions
Liver / parasitology
Liver / pathology*
Macrophages / metabolism
Malaria / complications*
Malaria / parasitology
Male
Mice, Inbred BALB C
Mice, Inbred C57BL
Plasmodium berghei / classification
Plasmodium berghei / physiology
Plasmodium chabaudi / physiology
Plasmodium falciparum / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Severity of Illness Index
Species Specificity

Substances

Cytokines
Hemeproteins
hemozoin
Aspartate Aminotransferases
Alanine Transaminase

Grants and funding

This work was supported by a Ph.D. grant of the Agency for Innovation by Science and Technology (IWT) to Katrien Deroost, the “Geconcerteerde OnderzoeksActies” (GOA 2012/017 and GOA 2013/014) of the Research Fund of the KU Leuven, and the Fund for Scientific Research (F.W.O.-Vlaanderen). Philippe Van den Steen is a Research Professor of the KU Leuven. Evelin Schwarzer and Denisa Baci were supported by the European Virtual Institute dedicated to Malaria Research (EVIMALAR, FP7 Project No. 242095) and the Italian Ministry of Education, University and Research (MIUR, PRIN project 2010C2LKKJ). Mauro Prato holds a professorship granted by University of Torino and Azienda Sanitaria Locale-19 (ASL-19), along with Compagnia di San Paolo. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.