Cardiac SOCS Proteins: A Role in Enterovirus Infection

描述(申请人提供)：心脏的柯萨奇病毒感染是导致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固有信号机制知之甚少。对这些机制的更好理解可能有助于设计新的病毒性心脏病治疗策略。最近，我们发现SOCS-1的表达抑制了心肌细胞JAK信号转导和转录激活因子(STAT)的表达，对病毒复制和病毒介导的细胞病变有显著影响。干扰素α/β受体的破坏对心脏早期病毒复制没有影响，干扰素-伽马受体的破坏对早期病毒复制的影响很小。因此，我们假设其他非干扰素介导的先天性免疫机制在心肌细胞内对抗病毒感染是重要的。这些可能包括通过糖蛋白(GP)130发出的信号，该信号也能激活JAK-STAT信号。因此，我们提出了以下具体目标：1)在CVB3感染的小鼠中，确定gp130信号和/或干扰素-γ信号对于a)在心脏中诱导JAK-STAT-SoCs信号和b)针对病毒感染的先天性免疫防御是重要的。2)明确病毒感染和复制的相关机制，通过在心肌细胞中强制表达SOCS1来诱导CVB3感染后显著的细胞病变效应，并确定转基因SOCS3表达是否也会以类似于SOCS1转基因小鼠的方式影响先天免疫反应。3)确定心脏特异的SOCS1和SOCS3基因敲除对心肌细胞JAK-STAT信号的影响以及与CVB3感染相关的心肌病。这些目的将为心肌细胞内JAK-STAT-SOC激活调节先天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.