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

Katrien Deroost,Thao-Thy Pham,Ghislain Opdenakker,Kathleen Van Den Eynde,Denisa Baci,Natacha Lays,Tania Roskams,Evelin Schwarzer,Mauro Prato,Mina Komuta,Philippe E Van Den Steen,Anne Charlotte Gruner

doi:10.1371/journal.pone.0113519

Katrien Deroost, Thao-Thy Pham + Show 10 more

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https://doi.org/10.1371/journal.pone.0113519

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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.

Highlights

Malaria-associated hepatocellular dysfunction is commonly observed in combination with other organ involvement, both in adult and pediatric patients [1, 2]
To investigate whether hepatic Hz levels correlate with liver pathology, parameters of liver injury were investigated in C57BL/6J mice infected with three different Plasmodium strains with a varying degree of virulence i.e. Plasmodium berghei ANKA (PbANKA), P. berghei NK65 (PbNK65) or P. chabaudi AS (PcAS)
Since host genetics are associated with differences in susceptibility to severe malaria, we investigated liver pathology in BALB/c mice, which are relatively resistant to severe complications such as cerebral malaria and malariaassociated acute respiratory distress syndrome (MA-ARDS) ([16] and data not shown)

Summary

Introduction

Malaria-associated hepatocellular dysfunction is commonly observed in combination with other organ involvement, both in adult and pediatric patients [1, 2]. It is a heterogeneous pathology with variable severity, as symptoms range from mild changes in liver function tests to severe liver failure, the latter is uncommon. The liver significantly contributes to phagocytosis of infected red blood cells (iRBC) and Hz, as evidenced by abundant pigment deposition on liver sections from patients [1, 2]. Liver damage is partly due to an imbalance in pro- and anti-inflammatory mediators in the liver, since restoring this balance diminishes pathology [8,9,10,11,12,13]

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