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Hepatitis B Virus Particles Activate Toll-Like Receptor 2 Signaling Initially Upon Infection of Primary Human Hepatocytes

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Hepatitis B Virus Particles Activate Toll-Like Receptor 2 Signaling Initially Upon Infection of Primary Human Hepatocytes. / Zhang, Zhenhua; Trippler, Martin; Real, Catherine I; Werner, Melanie; Luo, Xufeng; Schefczyk, Stefan; Kemper, Thekla; Anastasiou, Olympia E; Ladiges, Yvonne; Treckmann, Juergen; Paul, Andreas; Baba, Hideo A; Allweiss, Lena; Dandri, Maura; Gerken, Guido; Wedemeyer, Heiner; Schlaak, Joerg F; Lu, Mengji; Broering, Ruth.

In: HEPATOLOGY, Vol. 72, No. 3, 09.2020, p. 829-844.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Zhang, Z, Trippler, M, Real, CI, Werner, M, Luo, X, Schefczyk, S, Kemper, T, Anastasiou, OE, Ladiges, Y, Treckmann, J, Paul, A, Baba, HA, Allweiss, L, Dandri, M, Gerken, G, Wedemeyer, H, Schlaak, JF, Lu, M & Broering, R 2020, 'Hepatitis B Virus Particles Activate Toll-Like Receptor 2 Signaling Initially Upon Infection of Primary Human Hepatocytes', HEPATOLOGY, vol. 72, no. 3, pp. 829-844. https://doi.org/10.1002/hep.31112

APA

Zhang, Z., Trippler, M., Real, C. I., Werner, M., Luo, X., Schefczyk, S., Kemper, T., Anastasiou, O. E., Ladiges, Y., Treckmann, J., Paul, A., Baba, H. A., Allweiss, L., Dandri, M., Gerken, G., Wedemeyer, H., Schlaak, J. F., Lu, M., & Broering, R. (2020). Hepatitis B Virus Particles Activate Toll-Like Receptor 2 Signaling Initially Upon Infection of Primary Human Hepatocytes. HEPATOLOGY, 72(3), 829-844. https://doi.org/10.1002/hep.31112

Vancouver

Zhang Z, Trippler M, Real CI, Werner M, Luo X, Schefczyk S et al. Hepatitis B Virus Particles Activate Toll-Like Receptor 2 Signaling Initially Upon Infection of Primary Human Hepatocytes. HEPATOLOGY. 2020 Sep;72(3):829-844. https://doi.org/10.1002/hep.31112

Bibtex

@article{23242ec97c6c430ba73a6e3c4ce737e4,
title = "Hepatitis B Virus Particles Activate Toll-Like Receptor 2 Signaling Initially Upon Infection of Primary Human Hepatocytes",
abstract = "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.",
author = "Zhenhua Zhang and Martin Trippler and Real, {Catherine I} and Melanie Werner and Xufeng Luo and Stefan Schefczyk and Thekla Kemper and Anastasiou, {Olympia E} and Yvonne Ladiges and Juergen Treckmann and Andreas Paul and Baba, {Hideo A} and Lena Allweiss and Maura Dandri and Guido Gerken and Heiner Wedemeyer and Schlaak, {Joerg F} and Mengji Lu and Ruth Broering",
note = "{\textcopyright} 2020 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.",
year = "2020",
month = sep,
doi = "10.1002/hep.31112",
language = "English",
volume = "72",
pages = "829--844",
journal = "HEPATOLOGY",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "3",

}

RIS

TY - JOUR

T1 - Hepatitis B Virus Particles Activate Toll-Like Receptor 2 Signaling Initially Upon Infection of Primary Human Hepatocytes

AU - Zhang, Zhenhua

AU - Trippler, Martin

AU - Real, Catherine I

AU - Werner, Melanie

AU - Luo, Xufeng

AU - Schefczyk, Stefan

AU - Kemper, Thekla

AU - Anastasiou, Olympia E

AU - Ladiges, Yvonne

AU - Treckmann, Juergen

AU - Paul, Andreas

AU - Baba, Hideo A

AU - Allweiss, Lena

AU - Dandri, Maura

AU - Gerken, Guido

AU - Wedemeyer, Heiner

AU - Schlaak, Joerg F

AU - Lu, Mengji

AU - Broering, Ruth

N1 - © 2020 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.

PY - 2020/9

Y1 - 2020/9

N2 - 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.

AB - 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.

U2 - 10.1002/hep.31112

DO - 10.1002/hep.31112

M3 - SCORING: Journal article

C2 - 31925967

VL - 72

SP - 829

EP - 844

JO - HEPATOLOGY

JF - HEPATOLOGY

SN - 0270-9139

IS - 3

ER -