Early inhibition of hepatocyte innate responses by hepatitis B virus

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• 作者：Souphalone Luangsay¹ ; ² ; ^&dagger ; ; Marion Gruffaz¹ ; ² ; ^&dagger ; ; Nathalie Isorce¹ ; ² ; Barbara Testoni¹ ; ² ; Maud Michelet¹ ; ² ; Suzanne Faure-Dupuy¹ ; ² ; Sarah Maadadi¹ ; ² ; Malika Ait-Goughoulte¹ ; ² ; Romain Parent¹ ; ² ; Michel Rivoire³ ; ⁴ ; Hassan Javanbakht⁵ ; Julie Lucifora¹ ; ² ; David Durantel¹ ; ² ; ^&Dagger ; ; ^{david.durantel@inserm.fr" class="auth_mail" title="E-mail the corresponding author} ; Fabien Zoulim¹ ; ² ; ⁶ ; ⁷ ; ^&Dagger ; ; ^{fabien.zoulim@inserm.fr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Bac ; baculovirus ; DMSO ; dimethyl sulfoxyde ; GFP ; green fluorescent protein ; HBV ; hepatitis B virus ; HCV ; hepatitis C virus ; IFN ; interferon ; ISG ; interferon stimulated genes ; KC ; Kupffer cells ; LSEC ; liver sinusoidal endothelial cells ; MDA ; melanoma differentiation-associated gene ; MOI ; multiplicity of infection ; NLR ; NOD-like receptor ; PEG ; polyethylene glycol ; PHH ; primary human hepatocytes ; PRR ; pathogen recognition receptor ; RIG ; retinoic-acid-inducible protein ; RLR ; RIG-like receptor ; SV ; S
• 刊名：Journal of Hepatology
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：63
• 期：6
• 页码：1314-1322
• 全文大小：960 K

文摘

The outcome of hepatitis B virus (HBV) infection may be influenced by early interactions between the virus and hepatocyte innate immune responses. To date, the study of such interactions during the very early step of infection has not been adequately investigated.

Methods

We used the HepaRG cell line, as well as primary human hepatocytes to analyze, within 24 h of exposure to HBV, either delivered by a physiologic route or baculovirus vector (Bac-HBV), the early modulation of the expression of selected antiviral/pro-inflammatory cytokines and interferon stimulated genes. Experiments were also performed in the presence or absence of innate receptor agonists to investigate early HBV-induced blockade of innate responses.

Results

We show that hepatocytes themselves could detect HBV, and express innate genes when exposed to either HBV virions or Bac-HBV. Whereas Bac-HBV triggered a strong antiviral cytokine secretion followed by the clearance of replicative intermediates, a physiologic HBV exposure led to an abortive response. The early inhibition of innate response by HBV was mainly evidenced on Toll-like receptor 3 and RIG-I/MDA5 signaling pathways upon engagement with exogenous agonist, leading to a decreased expression of several pro-inflammatory and antiviral cytokine genes. Finally, we demonstrate that this early inhibition of dsRNA-mediated response is due to factor(s) present in the HBV inoculum, but not being HBsAg or HBeAg themselves, and does not require de novo viral protein synthesis and replication.

Conclusions

Our data provide strong evidence that HBV viral particles themselves can readily inhibit host innate immune responses upon virion/cell interactions, and may explain, at least partially, the “stealthy” character of HBV.