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Dive into the research topics where Stéphanie Pascarella is active.

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Featured researches published by Stéphanie Pascarella.


Liver International | 2011

Hepatitis D virus: an update

Stéphanie Pascarella; Francesco Negro

Hepatitis D virus (HDV) infection involves a distinct subgroup of individuals simultaneously infected with the hepatitis B virus (HBV) and characterized by an often severe chronic liver disease. HDV is a defective RNA agent needing the presence of HBV for its life cycle. HDV is present worldwide, but the distribution pattern is not uniform. Different strains are classified into eight genotypes represented in specific regions and associated with peculiar disease outcome. Two major specific patterns of infection can occur, i.e. co‐infection with HDV and HBV or HDV superinfection of a chronic HBV carrier. Co‐infection often leads to eradication of both agents, whereas superinfection mostly evolves to HDV chronicity. HDV‐associated chronic liver disease (chronic hepatitis D) is characterized by necro‐inflammation and relentless deposition of fibrosis, which may, over decades, result in the development of cirrhosis. HDV has a single‐stranded, circular RNA genome. The virion is composed of an envelope, provided by the helper HBV and surrounding the RNA genome and the HDV antigen (HDAg). Replication occurs in the hepatocyte nucleus using cellular polymerases and via a rolling circle process, during which the RNA genome is copied into a full‐length, complementary RNA. HDV infection can be diagnosed by the presence of antibodies directed against HDAg (anti‐HD) and HDV RNA in serum. Treatment involves the administration of pegylated interferon‐α and is effective in only about 20% of patients. Liver transplantation is indicated in case of liver failure.


Hepatology | 2011

Down‐regulation of phosphatase and tensin homolog by hepatitis C virus core 3a in hepatocytes triggers the formation of large lipid droplets

Sophie Clément; Marion Peyrou; Andrea Sanchez-Pareja; Lucie Bourgoin; Pierluigi Ramadori; David M. Suter; Manlio Vinciguerra; Kévin Guilloux; Stéphanie Pascarella; Laura Rubbia-Brandt; Francesco Negro; Michelangelo Foti

Hepatitis C virus (HCV) perturbs the hosts lipid metabolism and often results in hepatic steatosis. In nonalcoholic fatty liver disease, the intrahepatic down‐regulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a critical mechanism leading to steatosis and its progression toward fibrosis and hepatocellular carcinoma. However, whether an HCV infection triggers the formation of large lipid droplets through PTEN‐dependent mechanisms is unknown. We assessed PTEN expression in the livers of patients infected with HCV genotype 1 or 3 with or without steatosis. The role of PTEN in the HCV‐induced biogenesis of lipid droplets was further investigated in vitro with hepatoma cells transduced with the HCV core protein of genotype 1b or 3a. Our data indicate that PTEN expression was down‐regulated at the posttranscriptional level in steatotic patients infected with genotype 3a. Similarly, the in vitro expression of the HCV genotype 3a core protein (but not 1b), typically leading to the appearance of large lipid droplets, down‐regulated PTEN expression by a mechanism involving a microRNA‐dependent blockade of PTEN messenger RNA translation. PTEN down‐regulation promoted in turn a reduction of insulin receptor substrate 1 (IRS1) expression. Interestingly, either PTEN or IRS1 overexpression prevented the development of large lipid droplets, and this indicates that the down‐regulation of both PTEN and IRS1 is required to affect the biogenesis of lipid droplets. However, IRS1 knockdown per se did not alter the morphology of lipid droplets, and this suggests that other PTEN‐dependent mechanisms are involved in this process. Conclusion: The down‐regulation of PTEN and IRS1 is a critical event leading to the HCV genotype 3a–induced formation of large lipid droplets in hepatocytes. (HEPATOLOGY 2011;)


Journal of Hepatology | 2010

The hepatitis C virus core protein indirectly induces alpha-smooth muscle actin expression in hepatic stellate cells via interleukin-8

Sophie Clément; Stéphanie Pascarella; Stéphanie Conzelmann; Carmen Gonelle-Gispert; Kévin Guilloux; Francesco Negro

BACKGROUND & AIMS Progressive deposition of liver fibrosis is a common feature of chronic hepatitis associated with hepatitis C virus (HCV) infection, and it may eventually lead to cirrhosis and liver failure. Although this fibrogenic process appears to be linked to HCV protein expression and replication via indirect mechanisms, i.e., to be mediated by virally-driven inflammation, a direct role of HCV in inducing fibrosis deposition has never been entirely excluded. METHODS We established an in vitro system in which the human hepatic stellate cell line LX-2 was cultured in the presence of conditioned medium from human hepatoma Huh-7 cells transduced with a lentiviral vector expressing HCV core proteins of different genotypes. RESULTS Treatment of LX-2 cells, with conditioned medium from Huh-7 cells expressing HCV core protein, led to the activation of alpha-smooth muscle actin expression. Among the chemokines secreted by cells transduced with HCV core, interleukin-8 was identified as the strongest inducer of alpha-smooth muscle actin expression in LX-2 and primary hepatic stellate cells. This effect was accompanied by a decrease in cell migration and increased focal contact organisation. CONCLUSIONS The expression of the HCV core in hepatocytes may contribute to the establishment of a profibrogenic microenvironment.


Viruses | 2009

Hepatitis C virus infection: molecular pathways to steatosis, insulin resistance and oxidative stress

Sophie Clément; Stéphanie Pascarella; Francesco Negro

The persistent infection with hepatitis C virus is a major cause of chronic liver disease worldwide. However, the morbidity associated with hepatitis C virus widely varies and depends on several host-related cofactors, such as age, gender, alcohol consumption, body weight, and co-infections. The objective of this review is to discuss three of these cofactors: steatosis, insulin resistance and oxidative stress. Although all may occur independently of HCV, a direct role of HCV infection in their pathogenesis has been reported. This review summarizes the current understanding and potential molecular pathways by which HCV contributes to their development.


Liver International | 2009

Gene expression profile of Huh-7 cells expressing hepatitis C virus genotype 1b or 3a core proteins.

Valerio Pazienza; Sophie Clément; Paolo Pugnale; Stéphanie Conzelmann; Stéphanie Pascarella; Alessandra Mangia; Francesco Negro

Background: The liver disease expression in chronic hepatitis C patients is variable and may partially depend on the sequence of the infecting viral genotype.


Journal of Medical Virology | 2011

Effects of hepatitis C virus on suppressor of cytokine signaling mRNA levels: comparison between different genotypes and core protein sequence analysis

Stéphanie Pascarella; Sophie Clément; Kévin Guilloux; Stéphanie Conzelmann; François Penin; Francesco Negro

Glucose metabolism disturbances, including insulin resistance and type 2 diabetes, are frequent and important cofactors of hepatitis C. Increasing epidemiological and experimental data suggest that all major genotypes of hepatitis C virus (HCV), albeit to a different extent, cause insulin resistance. The HCV core protein has been shown to be sufficient to impair insulin signaling in vitro through several post‐receptorial mechanisms, mostly via the activation of suppressor of cytokine signaling (SOCS) family members and the consequent decrease of insulin receptor substrate‐1 (IRS‐1). The levels of IRS‐1 and SOCS were investigated upon expression of the core protein of HCV genotypes 1–4. Furthermore, the core protein sequences were analyzed to identify the amino acid residues responsible for IRS‐1 decrease, with particular regard to SOCS mRNA deregulation. The results suggest that the activation of SOCS family members is a general mechanism associated with the common HCV genotypes. A rare genotype 1b variant, however, failed to activate any of the SOCS tested: this allowed to analyze in detail the distinct amino acid sequences responsible for SOCS deregulation. By combining approaches using intergenotypic chimeras and site‐directed mutagenesis, genetic evidence was provided in favor of a role of amino acids 49 and 131 of the HCV core‐encoding sequence in mediating SOCS transactivation. J. Med. Virol. 83:1005–1015, 2011.


PLOS ONE | 2014

Clinical significance of the CCR5delta32 allele in hepatitis C.

Isabelle Morard; Sophie Clément; Alexandra Calmy; Alessandra Mangia; Andrea Cerny; Andrea De Gottardi; Meri Gorgievski; Markus H. Heim; Raffaele Malinverni; Darius Moradpour; Beat Müllhaupt; David Semela; Stéphanie Pascarella; Pierre-Yves Bochud; Franco Negro

Background The CCR5 receptor, expressed on Th1 cells, may influence clinical outcomes of HCV infection. We explored a possible link between a CCR5 32-base deletion (CCR5delta32), resulting in the expression of a non-functioning receptor, and clinical outcomes of HCV infection. Methods CCR5 and HCV-related phenotypes were analysed in 1,290 chronically infected patients and 160 patients with spontaneous clearance. Results Carriage of the CCR5delta32 allele was observed in 11% of spontaneous clearers compared to 17% of chronically infected patients (OR = 0.59, 95% CI interval 0.35–0.99, P = 0.047). Carriage of this allele also tended to be observed more frequently among patients with liver inflammation (19%) compared to those without inflammation (15%, OR = 1.38, 95% CI interval 0.99–1.95, P = 0.06). The CCR5delta32 was not associated with sustained virological response (P = 0.6), fibrosis stage (P = 0.8), or fibrosis progression rate (P = 0.4). Conclusions The CCR5delta32 allele appears to be associated with a decreased rate of spontaneous HCV eradication, but not with hepatitis progression or response to antiviral therapy.


Liver International | 2013

Intrahepatic mRNA levels of SOCS1 and SOCS3 are associated with cirrhosis but do not predict virological response to therapy in chronic hepatitis C.

Stéphanie Pascarella; Sophie Clément; Michael T. Dill; Stéphanie Conzelmann; Martin Lagging; Gabriele Missale; Avidan U. Neumann; Jean-Michel Pawlotsky; Stefan Zeuzem; Laura Rubbia-Brandt; Pierre-Yves Bochud; Francesco Negro

Antiviral treatment of chronic hepatitis C is not invariably successful, costly and associated with serious side‐effects, and therefore should be indicated only when the chances of benefitting patients exceed the potential risks. The suppressor of cytokine signalling (SOCS) family members have been suggested to affect the rate of virological response to therapy, but the published evidence is conflicting.


Journal of Hepatology | 2011

773 HEPATITIS C VIRUS AND LIPID DROPLETS: ROLE OF SEIPIN IN LIPID DROPLET MATURATION AND VIRAL LIFE CYCLE

Sophie Clément; C. Fauvelle; Stéphanie Pascarella; Stéphanie Conzelmann; V. Kaddai; K. Minehira; Francesco Negro


Journal of Hepatology | 2012

885 INTRAHEPATIC MRNA LEVELS OF THE SUPPRESSORS OF CYTOKINE SIGNALLING 1 AND 3 ARE ASSOCIATED WITH CIRRHOSIS BUT NOT WITH TREATMENT RESPONSE IN CHRONIC HEPATITIS C

Sophie Clément; Stéphanie Pascarella; Michael T. Dill; Stéphanie Conzelmann; M. Lagging; Gabriele Missale; Avidan U. Neumann; Jean-Michel Pawlotsky; Stefan Zeuzem; Pierre-Yves Bochud; Francesco Negro

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