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Innate and adaptive immunity associated with resolution of acute woodchuck hepatitis virus infection in adult woodchucks.
PLoS Pathogens ( IF 5.5 ) Pub Date : 2019-12-23 , DOI: 10.1371/journal.ppat.1008248 Manasa Suresh 1 , Stefanie Czerwinski 1 , Marta G Murreddu 1 , Bhaskar V Kallakury 2 , Ashika Ramesh 3 , Severin O Gudima 4 , Stephan Menne 1
PLoS Pathogens ( IF 5.5 ) Pub Date : 2019-12-23 , DOI: 10.1371/journal.ppat.1008248 Manasa Suresh 1 , Stefanie Czerwinski 1 , Marta G Murreddu 1 , Bhaskar V Kallakury 2 , Ashika Ramesh 3 , Severin O Gudima 4 , Stephan Menne 1
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Viral and/or host factors that are directly responsible for the acute versus chronic outcome of hepatitis B virus (HBV) infection have not been identified yet. Information on immune response during the early stages of HBV infection in humans is mainly derived from blood samples of patients with acute hepatitis B (AHB), which are usually obtained after the onset of clinical symptoms. Features of intrahepatic immune response in these patients are less studied due to the difficulty of obtaining multiple liver biopsies. Woodchuck hepatitis virus (WHV) infection in woodchucks is a model for HBV infection in humans. In the present study, five adult woodchucks were experimentally infected with WHV and then followed for 18 weeks. Blood and liver tissues were frequently collected for assaying markers of WHV replication and innate and adaptive immune responses. Liver tissues were further analyzed for pathological changes and stained for important immune cell subsets and cytokines. The increase and subsequent decline of viral replication markers in serum and liver, the elicitation of antibodies against viral proteins, and the induction of virus-specific T-cell responses indicated eventual resolution of acute WHV infection in all animals. Intrahepatic innate immune makers stayed unchanged immediately after the infection, but increased markedly during resolution, as determined by changes in transcript levels. The presence of interferon-gamma and expression of natural killer (NK) cell markers suggested that a non-cytolytic response mechanism is involved in the initial viral control in liver. This was followed by the expression of T-cell markers and cytolytic effector molecules, indicating the induction of a cytolytic response mechanism. Parallel increases in regulatory T-cell markers suggested that this cell subset participates in the overall immune cell infiltration in liver and/or has a role in regulating AHB induced by the cytolytic response mechanism. Since the transcript levels of immune cell markers in blood, when detectable, were lower than in liver, and the kinetics, except for NK-cells and interferon-gamma, did not correlate well with their intrahepatic expression, this further indicated enrichment of immune cells within liver. Conclusion: The coordinated interplay of innate and adaptive immunity mediates viral clearance in the woodchuck animal model of HBV infection. The initial presence of NK-cell associated interferon-gamma response points to an important role of this cytokine in HBV resolution.
中文翻译：
先天性和适应性免疫与成年土拨鼠急性土拨鼠肝炎病毒感染的解决相关。
尚未确定直接导致乙型肝炎病毒 (HBV) 感染的急性与慢性结果的病毒和/或宿主因素。人类感染乙肝病毒早期的免疫反应信息主要来自急性乙型肝炎（AHB）患者的血液样本，这些样本通常是在临床症状出现后获得的。由于难以获得多次肝活检，因此对这些患者肝内免疫反应特征的研究较少。土拨鼠肝炎病毒（WHV）感染土拨鼠是人类乙型肝炎病毒感染的模型。在本研究中，五只成年土拨鼠通过实验感染了 WHV，然后进行了 18 周的随访。经常收集血液和肝组织来分析 WHV 复制以及先天性和适应性免疫反应的标记物。进一步分析肝组织的病理变化，并对重要的免疫细胞亚群和细胞因子进行染色。血清和肝脏中病毒复制标记物的增加和随后的下降、针对病毒蛋白的抗体的引发以及病毒特异性T细胞反应的诱导表明所有动物的急性WHV感染最终得到解决。肝内先天免疫标记物在感染后立即保持不变，但在消退过程中显着增加，这是根据转录水平的变化确定的。干扰素-γ的存在和自然杀伤（NK）细胞标记物的表达表明非溶细胞反应机制参与了肝脏的初始病毒控制。随后是 T 细胞标记物和溶细胞效应分子的表达，表明溶细胞反应机制的诱导。 调节性 T 细胞标记物的平行增加表明该细胞亚群参与肝脏中的整体免疫细胞浸润和/或在调节由细胞溶解反应机制诱导的 AHB 中发挥作用。由于血液中免疫细胞标记物的转录水平（当可检测到时）低于肝脏中的转录水平，并且除了 NK 细胞和干扰素-γ 之外，其动力学与其肝内表达没有很好的相关性，这进一步表明免疫细胞的富集肝脏内。结论：先天免疫和适应性免疫的协调相互作用介导了 HBV 感染土拨鼠动物模型中的病毒清除。 NK 细胞相关的干扰素-γ 反应的最初存在表明该细胞因子在 HBV 消退中发挥着重要作用。
更新日期：2019-12-25
中文翻译：
先天性和适应性免疫与成年土拨鼠急性土拨鼠肝炎病毒感染的解决相关。
尚未确定直接导致乙型肝炎病毒 (HBV) 感染的急性与慢性结果的病毒和/或宿主因素。人类感染乙肝病毒早期的免疫反应信息主要来自急性乙型肝炎（AHB）患者的血液样本，这些样本通常是在临床症状出现后获得的。由于难以获得多次肝活检，因此对这些患者肝内免疫反应特征的研究较少。土拨鼠肝炎病毒（WHV）感染土拨鼠是人类乙型肝炎病毒感染的模型。在本研究中，五只成年土拨鼠通过实验感染了 WHV，然后进行了 18 周的随访。经常收集血液和肝组织来分析 WHV 复制以及先天性和适应性免疫反应的标记物。进一步分析肝组织的病理变化，并对重要的免疫细胞亚群和细胞因子进行染色。血清和肝脏中病毒复制标记物的增加和随后的下降、针对病毒蛋白的抗体的引发以及病毒特异性T细胞反应的诱导表明所有动物的急性WHV感染最终得到解决。肝内先天免疫标记物在感染后立即保持不变，但在消退过程中显着增加，这是根据转录水平的变化确定的。干扰素-γ的存在和自然杀伤（NK）细胞标记物的表达表明非溶细胞反应机制参与了肝脏的初始病毒控制。随后是 T 细胞标记物和溶细胞效应分子的表达，表明溶细胞反应机制的诱导。 调节性 T 细胞标记物的平行增加表明该细胞亚群参与肝脏中的整体免疫细胞浸润和/或在调节由细胞溶解反应机制诱导的 AHB 中发挥作用。由于血液中免疫细胞标记物的转录水平（当可检测到时）低于肝脏中的转录水平，并且除了 NK 细胞和干扰素-γ 之外，其动力学与其肝内表达没有很好的相关性，这进一步表明免疫细胞的富集肝脏内。结论：先天免疫和适应性免疫的协调相互作用介导了 HBV 感染土拨鼠动物模型中的病毒清除。 NK 细胞相关的干扰素-γ 反应的最初存在表明该细胞因子在 HBV 消退中发挥着重要作用。
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