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DOI: 10.1055/s-0036-1597516
Hepatitis B virus activates toll-like receptor 2 signaling in primary human hepatocytes
Publikationsverlauf
Publikationsdatum:
19. Dezember 2016 (online)
Background: Chronic infection with the hepatitis B virus (HBV) is a major cause of liver-related morbidity and mortality world-wide. Little is known about the initial cellular response in hepatocytes upon HBV infection. Here, we analyzed the responses of primary human hepatocytes (PHH) infected with HBV in vitro.
Methods: PHH were isolated after perfusion and digestion of liver tissue obtained after tumor resections or transplantations. Cells were infected with cell culture-derived HBV particles and cultured for ten days. Infection was monitored by the release of HBsAg and HBeAg, HBV DNA, and immunohistochemistry staining. Cellular responses in PHH were analyzed by microarray and quantitative RT-PCR. TLR ligands and neutralizing antibodies were used to characterize the initial immune response of PHH
Results: PHH could be efficiently infected with cell culture-derived HBV particles. The secretion of viral antigens and expression of viral RNAs in PHH could be inhibited by UV irradiation of viral particles. The HBV exposure dose-dependently induced a gene expression profile in PHH that is comparable to a TLR2-mediated response after Pam3Cys stimulation, leading to the induction of inflammatory and chemoattractant cytokines. The induction of interferons or interferon-stimulated genes in PHH was not detected neither initially nor at later time points after HBV infection. Furthermore, HBV-induced gene expression could be neutralized by TLR2-specific antibodies. Interestingly, PHH isolated from HBV-infected patients revealed a higher responsiveness to TLR2 stimulation compared to uninfected resection or transplantation controls, indicated by elevated induction of cytokine gene expression.
Conclusions: The present data demonstrate that TLR2 may be involved in recognition of HBV during the infection process and activate cellular responses in PHH. Consistently, recent data suggest that TLR2 might be involved in antiviral responses during hepadnaviral infection and play an important role in the pathogenesis of chronic HBV infection.