Intrahepatic Transcriptional Signature Associated with Response to Interferon-α Treatment in the Woodchuck Model of Chronic Hepatitis B.
Intrahepatic Transcriptional Signature Associated with Response to Interferon-α Treatment in the Woodchuck Model of Chronic Hepatitis B.
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DOI：
10.1371/journal.ppat.1005103
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发表时间：
2015-09
期刊：
影响因子：
6.7
通讯作者：
Menne S
中科院分区：
文献类型：
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作者：
Fletcher SP;Chin DJ;Gruenbaum L;Bitter H;Rasmussen E;Ravindran P;Swinney DC;Birzele F;Schmucki R;Lorenz SH;Kopetzki E;Carter J;Triyatni M;Thampi LM;Yang J;AlDeghaither D;Murreddu MG;Cote P;Menne S
重组干扰素-α（IFN-α）是一种被批准用于治疗慢性B型肝炎（CH B）的药物，但治疗反应的分子基础仍有待确定。慢性B型肝炎病毒（HBV）感染的土拨鼠模型显示了许多人类疾病的特征，并已被广泛用于评估抗病毒治疗。在这项研究中，慢性土拨鼠肝炎病毒（WHV）感染的土拨鼠用重组土拨鼠IFN-α（wIFN-α）或安慰剂（n = 12/组）治疗15周。wIFN-α给药显著降低了一部分动物血清和肝脏中的病毒标志物，通常在停止给药后观察到病毒反弹。为了确定对wIFN-α的抗病毒应答的肝内细胞和分子特征，我们在研究期间的不同时间对取自动物（n = 8-12/组）的肝活检的转录谱进行了表征。出乎意料的是，这表明对治疗的抗病毒应答与wIFN-α对大多数IFN刺激基因（ISG）的肝内诱导无关。相反，治疗反应与肝脏中NK/T细胞特征的诱导以及肝内IFN-γ转录反应和肝损伤生物标志物的升高相关。总的来说，这些数据表明NK/T细胞溶细胞和非溶细胞机制介导了对wIFN-α治疗的抗病毒应答。总之，通过在完全免疫活性的CHB动物模型中研究重组IFN-α，我们确定了这种多效性细胞因子的免疫调节作用而非直接抗病毒活性与治疗反应最密切相关。这对于合理设计治疗CHB的新疗法具有重要意义。大约有2.5亿人慢性感染HBV，每年有超过50万人死于相关的肝脏疾病。干扰素-α已用于治疗慢性乙型肝炎病毒感染患者20多年，但目前尚不清楚为什么有些患者对治疗有反应，而另一些患者则没有反应。在很大程度上，这是因为无法获得肝脏样本来表征不同治疗结局患者对IFN-α的肝内反应。在这项研究中，我们使用慢性HBV感染的土拨鼠模型来研究IFN-α在治疗过程中如何改变肝脏中的基因表达模式。令人惊讶的是，我们发现治疗反应与抗病毒效应基因的表达无关，这些基因先前已被证明介导IFN-α在体外的直接抗病毒作用。相反，我们发现对IFN-α治疗的反应与肝脏中选择的免疫细胞（自然杀伤细胞和T细胞）的存在有关。我们的工作还表明，这些免疫细胞通过杀死受感染的细胞以及不需要杀死肝细胞的方式来抑制病毒。总之，我们的研究表明，刺激肝脏中这些免疫细胞的新疗法可能有望治疗慢性HBV感染。
Recombinant interferon-alpha (IFN-α) is an approved therapy for chronic hepatitis B (CHB), but the molecular basis of treatment response remains to be determined. The woodchuck model of chronic hepatitis B virus (HBV) infection displays many characteristics of human disease and has been extensively used to evaluate antiviral therapeutics. In this study, woodchucks with chronic woodchuck hepatitis virus (WHV) infection were treated with recombinant woodchuck IFN-α (wIFN-α) or placebo (n = 12/group) for 15 weeks. Treatment with wIFN-α strongly reduced viral markers in the serum and liver in a subset of animals, with viral rebound typically being observed following cessation of treatment. To define the intrahepatic cellular and molecular characteristics of the antiviral response to wIFN-α, we characterized the transcriptional profiles of liver biopsies taken from animals (n = 8–12/group) at various times during the study. Unexpectedly, this revealed that the antiviral response to treatment did not correlate with intrahepatic induction of the majority of IFN-stimulated genes (ISGs) by wIFN-α. Instead, treatment response was associated with the induction of an NK/T cell signature in the liver, as well as an intrahepatic IFN-γ transcriptional response and elevation of liver injury biomarkers. Collectively, these data suggest that NK/T cell cytolytic and non-cytolytic mechanisms mediate the antiviral response to wIFN-α treatment. In summary, by studying recombinant IFN-α in a fully immunocompetent animal model of CHB, we determined that the immunomodulatory effects, but not the direct antiviral activity, of this pleiotropic cytokine are most closely correlated with treatment response. This has important implications for the rational design of new therapeutics for the treatment of CHB. Approximately 250 million people are chronically infected with HBV, and over 500,000 people die every year because of associated liver diseases. IFN-α has been used to treat patients with chronic HBV infection for over 20 years, but it is not well understood why some patients respond to treatment and others do not. In large part, this is because it is not practicable to obtain liver samples to characterize the intrahepatic response to IFN-α in patients with different treatment outcomes. In this study we used the woodchuck model of chronic HBV infection to study how IFN-α changes gene expression patterns in the liver during treatment. Surprisingly, we found that the treatment response did not correlate with the expression of antiviral effector genes that have previously been shown to mediate the direct antiviral effects of IFN-α in vitro. Instead, we found that the response to IFN-α treatment was associated with the presence of select immune cells (natural killer cells and T cells) in the liver. Our work also indicates that these immune cells inhibit the virus by killing infected cells, as well as in ways that do not require killing of liver cells. Altogether, our study suggests that new therapies that stimulate these immune cells in the liver may hold promise for the treatment of chronic HBV infection.