Cleavage of the T Cell Protein Tyrosine Phosphatase by the Hepatitis C Virus Nonstructural 3/4A Protease Induces a Th1 to Th2 Shift Reversible by Ribavirin Therapy
Cleavage of the T Cell Protein Tyrosine Phosphatase by the Hepatitis C Virus Nonstructural 3/4A Protease Induces a Th1 to Th2 Shift Reversible by Ribavirin Therapy
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DOI：
10.4049/jimmunol.1301077
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发表时间：
2014-02-15
影响因子：
4.4
通讯作者：
Saellberg, Matti
中科院分区：
文献类型：
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作者：
Brenndoerfer, Erwin Daniel;Brass, Anette;Saellberg, Matti
利巴韦林已被证明是丙型肝炎治疗的关键组成部分，包括IFN和新的直接作用的抗病毒药物。丙型肝炎病毒介导的干扰肝内免疫的线粒体抗病毒信号蛋白（MAVS）和T细胞蛋白酪氨酸磷酸酶（TCPTP）的切割表明，化合物，可能会抵消这些影响的途径。因此，我们研究了利巴韦林，有或没有抑制非结构（NS）3/4A蛋白酶，对肝内免疫的影响。通过Western blot、ELISA、流式细胞术和存活分析来测定野生型和NS3/4A转基因小鼠的肝内免疫。流体动力学地注射各种MAVS或TCPTP构建体以研究它们的相关性。在表达功能性或抑制性NS3/4A蛋白酶的小鼠中进行利巴韦林预处理，以分析其对NS3/4A介导的变化的影响。肝内NS3/4A表达使小鼠对TNF-α诱导的肝损伤具有抵抗力，并导致肝内细胞因子（IFN-γ和IL-10）和趋化因子（CCL3、CCL17、CCL22、CXCL9和CXCL11）谱向抗炎状态改变。与此一致，在NS3/4A转基因小鼠中，肝内Th1细胞和IFN-γ（+）T细胞的数量减少，而Th2细胞的数量增加。这些作用可以通过注射不可裂解的TCPTP而不是不可裂解的MAVS来逆转，并且在表达非功能性NS3/4A蛋白酶的小鼠中不存在。重要的是，NS3/4A介导的作用被利巴韦林治疗逆转。因此，通过NS3/4A切割TCPTP诱导肝内免疫应答向非抗病毒Th2主导的免疫转变。这些作用被利巴韦林逆转，支持利巴韦林作为免疫调节化合物补充直接作用抗病毒药的作用。
Ribavirin has proven to be a key component of hepatitis C therapies both involving IFNs and new direct-acting antivirals. The hepatitis C virus-mediated interference with intrahepatic immunity by cleavage of mitochondrial antiviral signaling protein (MAVS) and T cell protein tyrosine phosphatase (TCPTP) suggests an avenue for compounds that may counteract these effects. We therefore studied the effects of ribavirin, with or without inhibition of the nonstructural (NS)3/4A protease, on intrahepatic immunity. The intrahepatic immunity of wild-type and NS3/4A-transgenic mice was determined by Western blot, ELISA, flow cytometry, and survival analysis. Various MAVS or TCPTP constructs were injected hydrodynamically to study their relevance. Ribavirin pretreatment was performed in mice expressing a functional or inhibited NS3/4A protease to analyze its effect on NS3/4A-mediated changes. Intrahepatic NS3/4A expression made mice resistant to TNF-alpha-induced liver damage and caused an alteration of the intrahepatic cytokine (IFN-gamma and IL-10) and chemokine (CCL3, CCL17, CCL22, CXCL9, and CXCL11) profiles toward an anti-inflammatory state. Consistent with this, the number of intrahepatic Th1 cells and IFN-gamma(+) T cells in NS3/4A-transgenic mice decreased, whereas the amount of Th2 cells increased. These effects could be reversed by injection of uncleavable TCPTP but not uncleavable MAVS and were absent in a mouse expressing a nonfunctional NS3/4A protease. Importantly, the NS3/4A-mediated effects were reversed by ribavirin treatment. Thus, cleavage of TCPTP by NS3/4A induces a shift of the intrahepatic immune response toward a nonantiviral Th2-dominated immunity. These effects are reversed by ribavirin, supporting that ribavirin complements the effects of direct-acting antivirals as an immunomodulatory compound.