Abstract
BackgroundAlveolar echinococcosis (AE) is characterized by the tumor-like growth of Echinococcus (E.) multilocularis. Very little is known on the influence of helminth parasites which develop in the liver on the proliferation/growth arrest metabolic pathways in the hepatocytes of the infected liver over the various stages of infection.Methodology/Principal FindingsUsing Western blot analysis, qPCR and immunohistochemistry, we measured the levels of MAPKs activation, Cyclins, PCNA, Gadd45β, Gadd45γ, p53 and p21 expression in the murine AE model, from day 2 to 360 post-infection. Within the early (day 2–60) and middle (day60–180) stages, CyclinB1 and CyclinD1 gene expression increased up to day30 and then returned to control level after day60; Gadd45β, CyclinA and PCNA increased all over the period; ERK1/2 was permanently activated. Meanwhile, p53, p21 and Gadd45γ gene expression, and caspase 3 activation, gradually increased in a time-dependent manner. In the late stage (day180–360), p53, p21 and Gadd45γ gene expression were significantly higher in infected mice; JNK and caspase 3 were activated. TUNEL analysis showed apoptosis of hepatocytes. No significant change in CyclinE, p53 mRNA and p-p38 expression were observed at any time.ConclusionsOur data support the concept of a sequential activation of metabolic pathways which 1) would first favor parasitic, liver and immune cell proliferation and survival, and thus promote metacestode fertility and tolerance by the host, and 2) would then favor liver damage/apoptosis, impairment in protein synthesis and xenobiotic metabolism, as well as promote immune deficiency, and thus contribute to the dissemination of the protoscoleces after metacestode fertility has been acquired. These findings give a rational explanation to the clinical observations of hepatomegaly and of unexpected survival of AE patients after major hepatic resections, and of chronic liver injury, necrosis and of hepatic failure at an advanced stage and in experimental animals.
Highlights
The larval stage of the fox-tapeworm Echinococcus (E.) multilocularis is the causative agent of alveolar echinococcosis (AE), one of the most dangerous parasitic disease of the northern hemisphere [1]
Our data support the concept of a sequential activation of metabolic pathways which 1) would first favor parasitic, liver and immune cell proliferation and survival, and promote metacestode fertility and tolerance by the host, and 2) would favor liver damage/apoptosis, impairment in protein synthesis and xenobiotic metabolism, as well as promote immune deficiency, and contribute to the dissemination of the protoscoleces after metacestode fertility has been acquired
The aims of the present study were in the secondary experimental murine model of Alveolar echinococcosis (AE), 1) to explore the influence of E. multilocularis metacestode on components of cell cycle regulation which characterize the host’s hepatic proliferation in the liver of mice infected with E. multilocularis over a time period of 1yr, i.e. from the date of E. multilocularis inoculation to the very late stage of infection; 2) to simultaneously explore the activation of inhibitory proteins involved in growth arrest/apoptosis metabolic pathways during the 3 stages of infection
Summary
The larval stage of the fox-tapeworm Echinococcus (E.) multilocularis is the causative agent of alveolar echinococcosis (AE), one of the most dangerous parasitic disease of the northern hemisphere [1]. AE is characterized by an infiltrative, destructive and tumorlike growth of the E. multilocularis metacestode, usually affecting the liver of natural intermediate hosts such as small rodents or the human liver [2]. In the experimental model of secondary E. multilocularis metacestode infection, which well mimics the natural infection [7,8], according to its clinical course AE is divided into 1) an early stage with tumor-like growth of the metacestode and mild hepatic enlargement, 2) a middle stage with invasive parasitic lesions and progressive hepatomegaly and 3) an advanced/terminal stage ( called ‘‘late stage’’) associated with invasion of other organs and/or metastases, fibrosis of the lesions and cholestasis, which may cause secondary liver cirrhosis with subsequent portal hypertension and eventually impaired liver function [9]. Very little is known on the influence of helminth parasites which develop in the liver on the proliferation/growth arrest metabolic pathways in the hepatocytes of the infected liver over the various stages of infection
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