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044
Activation and Induction of Immune Response Genes RIG-I, STING & NOD2 in the Antiviral Activity of SB 92000
in the Woodchuck Model of Chronic Hepatitis B
Manasa Suresh, M.S.1, Kyle Korolowicz, B.S.1, Stefanie Czerwinski, M.S.1, Robin Tucker, M.D.1, Stephan Menne, Ph.D.1, Radhakrishnan Iyer, Ph.D.2
, Seetharamaiyer Padmanabhan, Ph.D.2, Sreerupa Challa, Ph.D.2
, Shenghua Zhou, M.D., Ph.D.2
1Georgetown University, Washington D.C., District of Columbia, USA;
2Spring Bank Pharmaceuticals, Milford, Massachusetts, USA
INTRODUCTION:
SB 9200 is an orally bioavailable dinucleotide that activates the cellular viral sensors RIG-I and NOD2 causing the induction of IFN
signaling cascade for antiviral defense. In efficacy studies in WHV-infected woodchucks, SB 9200 was shown to cause significant reductions of viral DNA
and surface antigens in serum and liver (Menne, et al., EASL 2015). Reported here is the evaluation of the induction and expression of RIG-I, NOD2, and
STING, as well as, IRF3, IRF7 and antiviral cytokines associated with the antiviral activity of SB 9200.
METHODS:
Two groups of five chronically WHV-infected woodchucks were treated orally with SB 9200 at 15 and 30 mg/kg/day for 12 weeks. Both
groups were monitored for 8 weeks post-treatment. Immune responses associated with treatment were determined by changes in RNA transcript levels
of IFN-, , IP-10, IL-6, ISG15 and OAS1 in blood and liver using PCR. Samples from woodchucks were also analyzed for changes in expression levels of
innate immune response genes including RIG-I, NOD2, STING, IRF3, and IRF7 by RT-PCR and immunohistochemistry.
RESULTS:
SB 9200-treatment induced dose-dependent and long-lasting expression of type I IFNs and ISGs, and antiviral cytokines in blood and
liver of woodchucks. SB 9200 treatment also induced the expression of RIG-I, NOD2, STING, IRF3, and IRF7 in liver compared to pretreatment levels.
The expression of all genes was significantly induced during treatment and follow-up.
CONCLUSION:
Our studies demonstrate that anti-viral activity of SB 9200 in woodchucks is associated with activation and induction of the host-immune
response genes.
044
激活和免疫反应的基因RIG-I，STING与NOD2的诱导SB 92000的抗病毒活性
慢性乙型肝炎的土拨鼠模型
摩纳娑苏雷什，M.S.1，凯尔Korolowicz，B.S.1，孙燕姿Czerwinski，M.S.1，罗宾·塔克，M.D.1，斯蒂芬Menne，Ph.D.1，拉达克里希南艾耶，Ph.D.2
，Seetharamaiyer帕德马纳班，Ph.D.2，Sreerupa Challa，Ph.D.2
，周胜华，医学博士，Ph.D.2
1Georgetown大学，华盛顿，哥伦比亚特区，美国区;
2Spring银行制药，米尔福德，马萨诸塞州，美国
介绍：
SB 9200是一种口服生物可利用的二核苷酸激活蜂窝病毒传感器RIG-I和NOD2导致干扰素的诱导
信号级联的抗病毒防御。在WHV感染土拨鼠疗效研究，SB 9200被证明是导致病毒DNA显著减少
及血清和肝脏（Menne等人，EASL 2015）表面抗原。这里报告是诱导和RIG-I，NOD2的表达的评价，并
斯汀，以及，IRF3，IRF7并用SB 9200的抗病毒活性有关的抗病毒细胞因子。
方法：
五个慢性WHV感染旱獭两组在15和30mg / kg /天用SB 9200口服治疗12周。都
组8周治疗后进行了监测。与治疗相关的免疫应答通过在RNA转录水平的变化来确定
干扰素，，IP-10，IL-6，ISG15和OAS1在血液和肝脏的使用PCR。也分析了在表达水平的变化，从旱獭样品
先天免疫反应基因，包括RIG-I，NOD2，STING，IRF3和IRF7用RT-PCR和免疫组化。
结果：
SB 9200-处理诱导剂量依赖性和长效型的表达我干扰素和的ISG，并在血液的抗病毒细胞因子和
旱獭肝。 SB 9200治疗也诱导RIG-I，NOD2，刺痛，IRF3和IRF7的表达肝相比治疗前水平。
所有基因的表达治疗期间显著诱导和跟进。
结论：
我们的研究表明，在土拨鼠SB 9200的抗病毒活性与活化和诱导相关宿主免疫
反应基因。 |
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发表于 2016-6-13 13:00
NA heteroduplexes in Mn++. The endonucleolytic RNaseH activity required an DNA:RNA heteroduplex >14 basepairs long and had no sequence specificity or positional dependence within the RNA. The RNaseH could not cut substrates with a bulge or a gap in the DNA in the DNA trand, but it could cut when the DNA strand contained a nick. The enzyme cut the RNA at multiple positions within the minimal 14 nt heteroduplex, and the cleavage pattern implied that the enzyme may bind to the substrate in both possible orientations. The RNaseH was also found to have a processive 3’-5’ exoribonuclease activity. 
