The cardiac interferon response to reovirus infection

心脏干扰素对呼肠孤病毒感染的反应

• 批准号: 7056053
• 负责人: BARBARA SHERRY
• 金额: $ 28.23万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-15 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7056053
• 关键词: Reoviridae; animal tissue; cardiac myocytes; cell population study; cytoprotection; fibroblasts; gene induction /repression; genetically modified animals; immune response; interferon beta; interferon inducers; laboratory mouse; myocarditis; plaque assay; polymerase chain reaction; terminal nick end labeling; tissue /cell culture; virus cytopathogenic effect; virus diseases; virus replication

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.

描述（由申请人提供）：许多病毒感染心脏，并且>5%的人群经历过某种形式的病毒性心肌炎。 不幸的是，心肌细胞得不到补充。 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，直到可以部署免疫防御。 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（IRF），其诱导IFN-β表达。分泌的IFN-β然后诱导大量的干扰素刺激基因（ISG）。 有些ISG具有抗病毒作用，有些是IRF，它们既可以进一步诱导IFN-β，也可以直接诱导ISG。 以前，我们证明了由一组呼肠孤病毒诱导的小鼠心脏损伤的变化与原代心肌细胞培养物（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PCMCs、原代心脏成纤维细胞培养物（PCFCs）和骨骼肌细胞之间存在显著差异，表明IFN-β反应的细胞类型特异性差异。 此外，这些差异是病毒复制和致细胞病变效应的细胞类型特异性变异的决定因素。 重要的是，多条证据表明IRFs，IFN-β和ISGs在心脏细胞中发挥独特的功能。因此，我们推测，细胞类型特异性反应病毒感染有关的IFN-β决定病毒复制和心脏细胞和心脏的损害。在我们的第一个目标中，我们将确定IFN-β和ISG表达的细胞类型特异性差异，并确定这些变化的分子基础。 结果将确定心脏特异性，肌肉特异性，和其他差异的组成性和诱导IFN-β和ISG的表达;并将确定细胞类型特异性变化的基础调控因子。 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中作用的细胞类型特异性差异，并确定这些变化的分子基础。 结果将确定IFN-β反应的组分在病毒复制、致细胞病变效应和心脏细胞损伤中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相关的反应，这对预防心肌炎至关重要，可能为心脏病毒感染的干预提供新的途径。