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.
Highlights
Alveolar echinococcosis (AE) is a rare, but severe zoonotic helminthic disease due to the proliferation of the larval stage of cestode Echinococcus multilocularis (E. multilocularis) [1]
Despite the major potential role attributed to transforming growth factor-b (TGF-b) in the tolerance and the fibrosis processes in AE, only one study until now reported that TGF-b was expressed in the periparasitic infiltrate in liver biopsies from a patient with AE [14]; quantified expression of TGF-b protein and mRNA was never studied, and neither the presence of TGF-b receptors nor that of components of the TGF-b metabolic pathway were ever looked for in E. multilocularis-infected livers
Phenotypic study of cells within the periparasitic granuloma confirmed that CD4+ T cells represented the major population of T cells at the beginning of the infection and that this sub-population was progressively replaced by CD8+ T cells [9], and this change of CD4/CD8 ratios could contribute to maintain TGF-b1 secretion
Summary
Alveolar echinococcosis (AE) is a rare, but severe zoonotic helminthic disease due to the proliferation of the larval stage of cestode Echinococcus multilocularis (E. multilocularis) [1]. Accidental intermediate hosts, the severity of this disease results from both a continuous asexual proliferation of the metacestode and an intense inflammatory granulomatous infiltration around the parasite which causes pathological damages in the liver. Studies performed in the 1980s– 1990s showed that dense and irreversible fibrosis composed of thick concentric bundles of heavily cross-linked type I and type III collagens surrounded the parasitic vesicles, and that a-smooth muscle actin (a-SMA)-expressing myofibroblasts (MFB) derived from the hepatic stellate cells (HSC) could play an important role in fibrosis development [3,4,5,6,7]. The diffusion of the fibrotic process even far from the parasitic lesions strongly suggested that cytokines produced in the periparasitic area could be involved in collagen synthesis, locally in the lesions and in the liver distant from the lesions; it was suggested that cytokines might be involved in the cross-linking of the collagen bundles. Little evidence has been given until now on how E. multilocularis metacestode interacts with its host to promote fibrosis and especially on the nature and role of cytokines in fibrosis development in AE
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