TGF-β and TGF-β/Smad Signaling in the Interactions between Echinococcus multilocularis and Its Hosts

Abstract

Alveolar echinococcosis (AE) is characterized by the development of irreversible fibrosis and of immune tolerance towards Echinococcus multilocularis (E. multilocularis). Very little is known on the presence of transforming growth factor-β (TGF-β) and other components of TGF-β/Smad pathway in the liver, and on their possible influence on fibrosis, over the various stages of infection. Using Western Blot, qRT-PCR and immunohistochemistry, we measured the levels of TGF-β1, TGF-β receptors, and down-stream Smads activation, as well as fibrosis marker expression in both a murine AE model from day 2 to 360 post-infection (p.i.) and in AE patients. TGF-β1, its receptors, and down-stream Smads were markedly expressed in the periparasitic infiltrate and also in the hepatocytes, close to and distant from AE lesions. Fibrosis was significant at 180 days p.i. in the periparasitic infiltrate and was also present in the liver parenchyma, even distant from the lesions. Over the time course after infection TGF-β1 expression was correlated with CD4/CD8 T-cell ratio long described as a hallmark of AE severity. The time course of the various actors of the TGF-β/Smad system in the in vivo mouse model as well as down-regulation of Smad7 in liver areas close to the lesions in human cases highly suggest that TGF-β plays an important role in AE both in immune tolerance against the parasite and in liver fibrosis.

Susceptibility versus resistance in alveolar echinococcosis (larval infection with Echinococcus multilocularis)

“…Phosphorylated Smads translocate to the nucleus where they function as transcription factors, initiating target gene transcription (Banas et al, 2006). The relationship between the TGF-␤/Smad pathway, and especially the expression of Smad7, which may play a regulatory role in the system, and clinical and/or pathological features of AE in experimental models as well as in human AE has been exploratively addressed by Wang et al (2013) and recently also by Pang et al (2014). Other studies on the immunopathology of AE revealed that CD4+CD25+ Treg cells play a critical role in human AE by blunting immune responses to specific antigens, or by suppressing the secretion of proinflammatory cytokines, especially through IL-10 and TGF-␤1 (Hübner et al, 2006).…”

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

“…early, middle and late stages as defined previously [18], [19], and 2) to study the parasite and the host immune response in their usual context, the liver, in the experimental mouse model of hepatic secondary infection. Eighteen key-cytokines and -chemokines were measured both in the lesion, including the periparasitic infiltrate, and in the surrounding liver, close to the lesions, using qRT-PCR.…”

Echinococcosis

“…Immune-modulatory mechanisms by T-regs and macrophages operate in E. multilocularis infection of both human and mouse (Hubner et al 2006;Vuitton and Gottstein 2010). Finally, fibrosis formation, also induced by TGF-β, appears to be the major mechanism of host protection but also the main reason for clinical complications of AE in humans (Ricard-Blum et al 1996;Wang et al 2013).…”

“…The high rate of cross-reactivity (50-100 %) between CE and AE is a problem where the two infections are co-endemic (de la Rue et al 2010;HernandezGonzalez et al 2008;Li et al 2010;Poretti et al 1999;Schweiger et al 2012). The different band pattern in HCF IB may discriminate between the two species in about 75 % of cases (Liance et al 2000); however, more specific tests for AE should be applied in case of high suspicion such as serology based on Em2-Em18 antigens (15 % cross-reactions with CE) and microscopic/PCR analysis of parasitic material Wang et al 2013). …”