Cardiac SOCS Proteins: A Role in Enterovirus Infection

描述（由申请人提供）：心脏的柯萨奇病毒感染是儿童和成人心肌病的重要原因。然而，对心肌细胞内控制病毒感染的先天信号传导机制知之甚少。更好地理解这些机制可能有助于设计新的病毒性心脏病治疗策略。最近，我们已经表明，通过表达SOCS 1抑制心肌细胞中的Janus激酶（JAK）信号转导子和转录激活子（STAT）对病毒复制和病毒介导的细胞病变效应具有显著影响。干扰素α/β受体的破坏没有影响，干扰素γ受体的破坏对心脏中的早期病毒复制的影响极小。因此，我们假设其他非干扰素介导的先天免疫机制在心肌细胞内对抗病毒感染是重要的。这些可以包括通过糖蛋白（gp）130的信号传导，糖蛋白130也激活JAK-STAT信号传导。因此，我们提出以下具体目标：1）在CVB 3感染的小鼠中确定gp 130、IFN-γ信号传导或两者对于a）心脏中JAK-STAT-SOCS信号传导的诱导和B）针对病毒感染的先天免疫防御是否重要。2)确定与病毒感染和复制相关的机制，通过该机制，心肌细胞中SOCS 1的强制表达在CVB 3感染后诱导显著的细胞病变效应，并确定转基因SOCS 3表达是否也会以类似于在SOCS 1转基因小鼠中观察到的方式影响先天免疫应答。3)确定心脏特异性敲除SOCS 1和SOCS 3对心肌细胞中JAK-STAT信号传导和与CVB 3感染相关的心肌病的影响。这些目标将为心肌细胞内JAK-STAT-SOCS激活调节先天性抗病毒反应的机制提供新的见解。

DESCRIPTION (provided by applicant): Coxsackieviral infection of the heart is an important cause of cardiomyopathy in children and adults. However, little is known of the innate signaling mechanisms within the cardiac myocytes that control viral infection. A better understanding of these mechanisms may allow design of novel therapeutic strategies for viral heart disease. Recently, we have shown that inhibition of Janus kinase (JAK)- signaling transducer and activator of transcription (STAT) in the cardiac myocyte by expression of SOCS 1 has a marked effect on viral replication and viral-mediated cytopathic effects. Disruption of interferon alpha/beta receptors had no effect and disruption of interferon-gamma receptors had minimal effect on early viral replication in the heart. We, therefore, hypothesize that other, non-interferon mediated innate immune mechanisms are important within the cardiac myocyte to combat viral infection. These could include signaling through the glycoprotein (gp) 130 that also activates JAK-STAT signaling. We, therefore, propose the following specific aims: 1) Determine in CVB3 infected mice whether gp130, IFN-gamma signaling, or both are important for a) the induction of JAK-STAT-SOCS signaling in the heart and b) the innate immune defense against viral infection. 2) Identify mechanisms related to viral infection and replication by which forced expression of SOCS1 in the cardiac myocyte induces a marked cytopathic effect following CVB3 infection and determine whether transgenic SOCS3 expression will also affect the innate immune response in a manner similar to that observed in SOCS1 transgenic mice. 3) Determine the effect of cardiac-specific knockout of SOCS1 and SOCS3 on JAK-STAT signaling in cardiac myocytes and the cardiomyopathy associated with CVB3 infection. These aims will provide a novel insight into the mechanisms by which JAK-STAT-SOCS activation within the cardiac myocyte regulates the innate anti-viral response.