Time Course of Gene Expression Profiling in the Liver of Experimental Mice Infected with Echinococcus multilocularis

Abstract

BackgroundAlveolar echinococcosis (AE) is a severe chronic parasitic disease which behaves like a slow-growing liver cancer. Clinical observations suggest that the parasite, Echinococcus multilocularis (E. multilocularis) influences liver homeostasis and hepatic cell metabolism. However, this has never been analyzed during the time course of infection in the common model of secondary echinococcosis in experimental mice.Methodology/Principal FindingsGene expression profiles were assessed using DNA microarray analysis, 1, 2, 3 and 6 months after injection of E. multilocularis metacestode in the liver of susceptible mice. Data were collected at different time points to monitor the dynamic behavior of gene expression. 557 differentially expressed genes were identified at one or more time points, including 351 up-regulated and 228 down-regulated genes. Time-course analysis indicated, at the initial stage of E. multilocularis infection (month 1–2), that most of up-regulated pathways were related to immune processes and cell trafficking such as chemokine-, mitogen-activated protein kinase (MAPK) signaling, and down-regulated pathways were related to xenobiotic metabolism; at the middle stage (month 3), MAPK signaling pathway was maintained and peroxisome proliferator-activated receptor (PPAR) signaling pathway emerged; at the late stage (month 6), most of up-regulated pathways were related to PPAR signaling pathway, complement and coagulation cascades, while down-regulated pathways were related to metabolism of xenobiotics by cytochrome P450. Quantitative RT-PCR analysis of a random selection of 19 genes confirmed the reliability of the microarray data. Immunohistochemistry analysis showed that proliferating cell nuclear antigen (PCNA) was increased in the liver of E. multilocularis infected mice from 2 months to 6 months.Conclusions E. multilocularis metacestode definitely exerts a deep influence on liver homeostasis, by modifying a number of gene expression and metabolic pathways. It especially promotes hepatic cell proliferation, as evidenced by the increased PCNA constantly found in all the experimental time-points we studied and by an increased gene expression of key metabolic pathways.

Hepatocyte Proliferation/Growth Arrest Balance in the Liver of Mice during E. multilocularis Infection: A Coordinated 3-Stage Course

“…This suggested that, as shown in other models, activation of the ERK1/2 pathway increased hepatocyte DNA synthesis and was involved in the activation of cell cycle [39], [40], [41]. Increased expression of PCNA in the hepatic cells under the influence of E. multilocularis was constantly found in vivo , in previous studies [33], [34] and in this study as well. PCNA is a stable cell cycle-related 36 kDa nuclear protein which is increasingly expressed in late G1 and throughout S phase of the cell cycle.…”

Transcriptional Profiles of Cytokine/Chemokine Factors of Immune Cell-Homing to the Parasitic Lesions: A Comprehensive One-Year Course Study in the Liver of E. multilocularis-Infected Mice

“…IL-1β and IL-6 were then showing up, presumably to sustain the inflammatory response, with a ‘mirror’ image of their respective increase all along infection. The initial peak of IL-6 as early as 2 days post-infection may be related to the early activation of the acute phase protein genes in the hepatocytes, disclosed by previous microarray studies [21], [22]. Conversely, the absence of a significant increase of IL-6 at day 270 probably explains why, despite increased levels of haptoglobin, α-1 acid glycoprotein, C3 and C4, and ceruloplasmin in patients with AE, no increase of C-reactive protein (CRP) levels, typically associated with IL-6 stimulation, is usually observed, except in cases complicated by bacterial infection.…”

Cytoskeleton in Mast Cell Signaling

“…Phosphorylation of the γ-tubulin residue Tyr 445, which is invariably present in all γ-tubulins, was described and a mutation of this residue changed the microtubule dynamics (Vogel et al, 2001). Similarly phosphorylation of multiple serines on γ-tubulin can regulate microtubule organization (Lin et al, 2011). There are other data that point to an association of γ-tubulin with kinases.…”