Hepatitis B Virus Particles Activate Toll-Like Receptor 2 Signaling Initially Upon Infection of Primary Human Hepatocytes
| Autor: | Martin Trippler, Yvonne Ladiges, Ruth Broering, Guido Gerken, Heiner Wedemeyer, Maura Dandri, Xufeng Luo, Zhenhua Zhang, CI Real, Joerg F. Schlaak, Juergen Treckmann, M Werner, Olympia E. Anastasiou, Andreas Paul, Hideo A. Baba, Stefan Schefczyk, Thekla Kemper, Lena Allweiss, Mengji Lu |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Hepatitis B virus MAP Kinase Signaling System Lipoproteins p38 mitogen-activated protein kinases Interleukin-1beta Medizin medicine.disease_cause p38 Mitogen-Activated Protein Kinases Proinflammatory cytokine Mice 03 medical and health sciences 0302 clinical medicine Immune system medicine Animals Humans Phosphorylation Toll-like receptor Hepatology Interleukin-6 Tumor Necrosis Factor-alpha Chemistry NF-kappa B virus diseases Hepatitis B Antibodies Neutralizing Molecular biology Immunity Innate Toll-Like Receptor 2 digestive system diseases TLR2 030104 developmental biology TLR3 Hepatocytes 030211 gastroenterology & hepatology Tumor necrosis factor alpha Transcriptome |
| Popis: | Background and aims To date, conflicting data exist as to whether hepatitis B virus (HBV) has the ability to induce innate immune responses. Here, we investigated cellular changes after the first contact between HBV and primary human hepatocytes (PHH) in vitro and in vivo. Approach and results The exposure of PHH to HBV particles resulted in nuclear translocation of NFκB, followed by the expression and secretion of inflammatory cytokines (IL [interleukin] 1B, IL6, and TNF [tumor necrosis factor]). Ultraviolet irradiation of viral particles suppressed HBV infectivity but not the induction of cytokines in PHH, suggesting that the inoculum contains the immune-inducing agent. Purified HBV particles on the whole, which were prepared from HBV DNA-positive and protein-rich fractions after heparin column separation, still had immune-inducing capacity in PHH. The HBV-induced gene expression profile was similar to that induced by toll-like receptor 2 (TLR2) ligand Pam3Cys, but different from those induced by the viral sensors TLR3 or TLR7-9. Treatment of PHH with both HBV particles and Pam3Cys led to phosphorylation of ERK (extracellular signal-regulated kinase), JNK, and p38 mitogen-activated protein kinases as well as NFκB (nuclear factor kappa B). Finally, HBV-induced gene expression could be neutralized by TLR2-specific antibodies. Of note, pretreatment with an HBV entry inhibitor attenuated the TLR2-mediated response to HBV, suggesting a receptor binding-related mechanism. In liver-humanized uPA/severe combined immunodeficient (SCID)/beige mice challenged with HBV in vivo, immune induction could only marginally be seen. Conclusions PHHs are able to sense HBV particles through TLR2, leading to an activation of anti-HBV immune responses in vitro. These findings challenge the previously described stealth properties of HBV. |
| Databáze: | OpenAIRE |
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