Analyzing the effects of type I interferons in the enterovirus-infected heart

分析 I 型干扰素对肠道病毒感染心脏的影响

• 批准号: 9198190
• 负责人: J. Lindsay Whitton
• 金额: $ 67.52万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198190
• 关键词: Ablation; Acute; Adaptive Immune System; Address; Affect; Antiviral Agents; Biological; Cardiac; Cardiac Myocytes; Cells; Coxsackie Viruses; Data; Dilated Cardiomyopathy; Disease; Enterovirus; Genes; Grant; Heart; Hematopoietic; Human; Immune response; Infection; Inflammation; Interferon Type I; Interferons; Knockout Mice; Mediating; Modeling; Mus; Mutation; Myocardial; Myocarditis; Myocardium; Natural Immunity; Organ; Outcome; Phase; Play; Predisposition; Production; Publishing; RNA; Resistance; Role; Signal Transduction; Source; TLR3 gene; Time; Variant; Viral; Virus; Virus Diseases; Virus Replication; Work; cell type; chronic myocarditis; in vivo; knockout gene; prevent; public health relevance; receptor; sensor; tissue culture; viral myocarditis

 DESCRIPTION (provided by applicant): Viral myocarditis is a relatively common, sometimes severe, and potentially fatal disorder, and one of the most frequent causes is the enterovirus coxsackievirus B3 (CVB3). CVB3 infection of the heart is highly focal, even in mice lacking an intact adaptive immune system, suggesting that innate immunity may hold the virus in check. Type I interferons (T1IFNs) are an obvious candidate, and are known to positively affect the outcome of enteroviral myocarditis. However, there is much that we do not know about how the effects of T1IFNs are mediated. For example, one very well-respected group has argued that T1IFNs may not even act within the heart, and that their cardioprotective effects may be indirect, resulting from the suppression of viral replication in other organs. We have generated mice in which the T1IFN receptor (T1IFNR) can be ablated in vivo specifically from cardiomyocytes, and our unpublished data show unequivocally that T1IFNs do, in fact, act directly on cardiomyocytes during CVB3 infection, and play a substantial role in viral titers and CVB-induced disease. But many questions remain. How do they do this - what genes are activated by T1IFNs in infected (and in uninfected) cardiomyocytes? We shall identify the cardiomyocyte genes that are directly responsive to T1IFN signals in vivo. CVB3 also causes chronic myocarditis and dilated cardiomyopathy, which are related to RNA persistence in the heart, and our inducible gene knockout model confers a key experimental advantage in this regard; we can establish persistent CVB3 infection in genetically-intact mice that do not develop disease, and afterwards ablate T1IFN signaling into cardiomyocytes, to ask: do these mice now develop disease, i.e. might resistance/susceptibility to chronic myocarditis / DCM be related to T1IFN signaling in cardiomyocytes? Our preliminary data indicate that the effects of T1IFN during CVB3 infection of the heart may be biphasic, and we hypothesize that the two temporal phases are defined by differing cellular sources of the T1IFNs. So, Aims 2 and 3 extend our focus to address the production of T1IFNs. What cells serve as the source of the T1IFNs? Plasmacytoid DCs (pDCs) are obvious candidates, but recent work has raised questions about their true in vivo role during viral infection, and also has shown that TLR3-dependent production of T1IFNs may be more important in controlling virus infection. The proposal has three Specific Aims Aim 1. To investigate the in vivo consequences of type 1 IFN signaling in cardiomyocytes during acute and persistent CVB3 infection. Aim 2. To evaluate the role of pDCs during CVB3 infection Aim 3. To determine why TLR3 plays a key role in CVB3-induced myocarditis.

 描述（由适用提供）：病毒心肌炎是一种相对常见的，有时是严重且可能致命的疾病，最常见的原因之一是肠肠病毒Coxsackievievirus B3（CVB3）。即使在缺乏完整的适应性免疫学系统的小鼠中，心脏的CVB3感染也是高度局灶性的，这表明先天免疫学可能会控制该病毒。 I型干扰素（T1IFN）是一个明显的候选者，众所周知会对肠病毒心肌炎的结果产生积极影响。但是，我们不知道如何介导T1IFN的效果。例如，一个非常受人尊敬的群体认为，T1IFN甚至可能无法在心脏内部起作用，并且其心脏保护作用可能是由于其他器官中病毒复制的抑制而导致的。我们已经产生了小鼠，其中T1IFN受体（T1IFNR）可以在体内特别是从心肌细胞中烧蚀，而我们未发表的数据明确表明，T1IFNS实际上表明，实际上，T1IFN在CVB3感染过程中直接作用于心肌细胞，在CVB3感染期间起着重大作用，并在病毒性滴定病中扮演CVB-Indies和CVB-Indive Inded。但是仍然存在许多问题。他们如何做到这一点 - 在感染（未感染）心肌细胞中T1IFN激活了哪些基因？我们将确定直接响应体内T1IFN信号的心肌细胞基因。 CVB3还会引起慢性心肌炎和扩张的心肌病，与心脏的RNA持久性有关，我们的诱导基因敲除模型在这方面赋予了一个关键的实验优势。我们可以在不发展疾病的普通小鼠中建立持久性的CVB3感染，然后消融T1IFN信号传导到心肌细胞中，以提出：这些小鼠现在是否患有疾病，即可能与慢性心肌 / DCM的耐药性 /易感性相关，与T1IFN信号与心脏手室内的T1IFN信号有关？我们的初步数据表明，心脏CVB3感染期间T1IFN的作用可能是双相，我们假设这两个临时相是由T1IFN的不同细胞来源定义的。因此，目标2和3扩大了我们的重点，以解决T1IFN的生产。哪些细胞是T1IFN的来源？血浆细胞类动物DC（PDC）是显而易见的候选者，但是最近的工作提出了有关其在病毒感染过程中的真实体内作用的问题，并且还表明，T1IFN的T1IFN产生T1IFN可能在控制病毒感染方面更为重要。该提案具有三个特定目的的目的1。研究在急性和持续性CVB3感染期间心肌细胞中1型IFN信号的体内后果。目的2。评估PDC在CVB3感染中的作用3。确定为什么TLR3在CVB3诱导的心肌炎中起关键作用。