The cardiac interferon response to reovirus infection

描述（由申请人提供）：许多病毒感染心脏，大约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，直到免疫防御能够部署。干扰素- β (ifn - 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（IRFs），从而诱导ifn - β的表达。分泌的ifn - β随后诱导大量干扰素刺激基因（isg）。一些isg具有抗病毒功能，一些是irf，它们既可以进一步诱导ifn - β，也可以直接诱导isg。先前，我们证明了呼肠孤病毒组诱导小鼠心脏损伤的变化与原代心肌细胞培养（PCMCs）中ifn - β的病毒诱导和敏感性相关。然而，我们发现，ifn - β的保护作用在pcmc、原代心脏成纤维细胞培养物（pcfc）和骨骼肌细胞之间存在显著差异，表明ifn - β反应在细胞类型上存在特异性差异。此外，这些差异是病毒复制和细胞致病作用中细胞类型特异性变异的决定因素。重要的是，多项证据表明，irf、ifn - β和isg在心脏细胞中发挥着独特的作用。因此，我们假设细胞对与ifn - β相关的病毒感染的类型特异性反应决定了病毒在心脏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ifn - β和ISGs表达的细胞类型特异性差异，并确定这些差异的分子基础。结果将确定心脏特异性、肌肉特异性和其他组成型和诱导型ifn - β和ISG表达的差异；并将确定潜在调节因子中细胞类型特异性的变化。在我们的第二个目标中，我们将确定ifn - β在防止病毒复制和细胞损伤方面作用的细胞类型特异性差异，并确定这些差异的分子基础。结果将确定ifn - β反应成分在病毒复制、细胞致病作用和心脏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ifn - β的因子在预防心肌炎中的作用。总之，研究结果将确定细胞类型特异性ifn - β相关反应，这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.