The cardiac interferon response to reovirus infection

描述(由申请人提供)：许多病毒感染心脏，5%的人经历过某种形式的病毒性心肌炎。不幸的是，心肌细胞没有得到补充。这种心脏脆弱性可能需要一种独特有效的心脏反应，以限制病毒通过心脏传播，直到部署免疫防御措施。干扰素-β(干扰素-β)可以提供这一关键的第一道防线。病毒诱导/激活干扰素调节因子，诱导干扰素-β的表达。分泌的干扰素-β可以诱导大量的干扰素刺激基因(ISGs)。有些ISGs具有抗病毒功能，有些是IRFs，它们既可以进一步诱导干扰素-β，也可以直接诱导ISGs。此前，我们证明了一组呼肠孤病毒引起的小鼠心脏损伤的变化与病毒诱导原代心肌细胞培养(PCMC)中干扰素-β的诱导和对其敏感性有关。然而，我们发现，在PCMC、原代心脏成纤维细胞培养(PCFC)和骨骼肌细胞之间，干扰素-β的保护作用显著不同，这表明细胞类型的不同在干扰素-β反应中存在差异。此外，这些差异是病毒复制和细胞病变效应中细胞类型特异性变异的决定因素。重要的是，多条证据表明，红外线、干扰素-β和胰岛素样生长因子在心肌细胞中具有独特的功能。因此，我们假设与干扰素-β相关的对病毒感染的细胞类型特异性反应决定了病毒在心肌细胞和心脏中的复制和损伤。在我们的第一个目标中，我们将确定细胞类型特异性的干扰素-β和ISGs表达的差异，并确定这些差异的分子基础。结果将确定心脏特异性、肌肉特异性和其他在组成性和诱导性干扰素-β和ISG表达方面的差异；并将确定潜在调节因子中细胞类型的特定变异。在我们的第二个目标中，我们将确定干扰素-β在保护病毒复制和细胞损伤方面的作用在细胞类型上的特定差异，并确定这些差异的分子基础。结果将确定干扰素-β反应的组成部分在病毒复制、细胞病变效应和心肌细胞损伤的细胞类型特异性差异中的作用。在我们的第三个目标中，我们将确定调节干扰素-β的因素在预防心肌炎中的作用。总而言之，结果将确定细胞类型特异性的干扰素-β相关反应，对预防心肌炎至关重要，可能为干预心脏病毒感染提供新的途径。

DESCRIPTION (provided by applicant): Many viruses infect the heart, and >5% of the human population has experienced some form of viral myocarditis. Unfortunately, cardiac myocytes are not replenished. This cardiac vulnerability likely necessitates a uniquely effective cardiac response, to limit virus spread through the heart until immune defenses can be deployed. Interferon-beta(IFN-beta) can provide this critical first line of defense. Viruses induce / activate interferon regulatory factors (IRFs), which induce IFN-beta expression. Secreted IFN-beta then induces a large number of interferon-stimulated genes (ISGs). Some ISGs have antiviral function and some are IRFs, which can both further induce IFN-beta and induce ISGs directly. Previously, we demonstrated that variations in cardiac damage induced by a panel of reoviruses in mice correlate with both viral induction of and sensitivity to IFN-beta in primary cardiac myocyte cultures (PCMCs). We found, however, that IFN-beta protection varied significantly between PCMCs, primary cardiac fibroblast cultures (PCFCs), and skeletal muscle cells, indicating cell type-specific differences in the IFN-beta response. Moreover, these differences were determinants of cell type-specific variations in viral replication and cytopathogenic effect. Importantly, multiple lines of evidence suggest that IRFs, IFN-beta, and ISGs function uniquely in cardiac cells. Therefore, we hypothesize that cell type-specific responses to viral infection relating to IFN-beta determine viral replication and damage in cardiac cells and the heart. In our first Aim, we will identify cell type-specific differences in expression of IFN-beta and ISGs, and determine the molecular basis for these variations. Results will identify cardiac-specific, muscle-specific, and other differences in constitutive and induced IFN-beta and ISG expression; and will identify cell type-specific variations in underlying regulatory factors. In our second Aim, we will identify cell type-specific differences in the role of IFN-beta in protection against viral replication and cell damage, and determine the molecular basis for these variations. Results will identify the role of components of the IFN-beta-response in cell type-specific differences in viral replication, cytopathogenic effect, and cardiac cell damage. In our third Aim, we will determine the role of factors that regulate IFN-beta in protection against myocarditis. In sum, results will identify cell type-specific IFN-beta-related responses critical for protection against myocarditis, potentially providing new avenues for intervention against viral infections of the heart.