Coxsackie Myocarditis and Viral Persistence in the Heart

柯萨奇病毒B3引起心肌炎，胰腺炎和脑膜脑炎，但尽管 导致人类发病率和死亡率，既没有治疗方法，也没有疫苗。我的实验室 表明宿主细胞的代谢状态在决定CVB 3的结果中起关键作用 感染，在前一阶段的支持，我们确定干细胞作为CVB 3的早期目标， 感染在这次更新申请中，我提出了4个具体目标，重点关注以下主题： 1.骨髓是成人干细胞的主要储存库，我们在此表明，CVB 在体内自然感染约1%的骨髓细胞。我们将鉴定和描述骨髓 被感染的细胞;并将评估这种感染的生物学意义。 2.我们将确定细胞活化在调节心脏中CVB 3感染中的作用。我们将 用各种方法问：增殖细胞是靶向的吗？心肌干细胞是首选吗 感染部位？先前的心肌损伤是否会改变心脏中的病毒复制， 会加重病毒性心肌炎吗 3.一般来说，对小核糖核酸病毒，特别是对肠道病毒的先天免疫应答， 不太了解。我们将研究淋巴组织对CVB 3感染的先天性反应 （脾和淋巴结）。安装了哪些响应？在众多的先天分子传感器中 有关系吗先天系统的激活如何影响随后的CVB 3的结果 感染？ 4.许多病毒感染诱导非常强的T细胞反应，但CVB 3似乎没有这样做; CD 4+或CD 8 + T细胞在wtCVB 3感染期间被强烈激活。我们将使用新方法， 从动力学和解剖学上绘制CVB 3编码的MHC I类和II类表位的呈递， 并将询问对CVB 3感染的先天反应如何影响随后的发展， 适应性T细胞免疫

Coxsackievirus B3 causes myocarditis, pancreatitis and meningo-encephalitis but, despite the resulting human morbidity and mortality, neither a treatment, nor a vaccine, is available. My lab has shown that the metabolic status of the host cell plays a key role in determining the outcome of CVB3 infection and, in the previous period of support, we identified stem cells as early targets of CVB3 infection. In this renewal application, I propose 4 Specific Aims, focusing on the following topics : 1. Bone marrow is the main repository of stem cells in the adult, and we show herein that CVB naturally infects ~1% of bone marrow cells in vivo. We shall identify and characterize the bone marrow cells that become infected; and will evaluate the biological implications of this infection. 2. We shall determine the role of cellular activation in regulating CVB3 infection in the heart. We shall use a variety of methods to ask: are proliferating cells targeted? Are myocardial stem cells a preferred site of infection? Does prior myocardial damage alter viral replication in the heart, and does this exacerbate the viral myocarditis? 3. The innate immune response to picornaviruses in general, and to enteroviruses in particular, is poorly understood. We shall investigate the innate responses to CVB3 infection in lymphoid tissues (spleen & lymph nodes). What responses are mounted? Which of the many innate molecular sensors are involved? How does activation of the innate system affect the outcome of subsequent CVB3 infection? 4. Many virus infections induce very strong T cell responses, but CVB3 appears not to do so; neither CD4+ nor CD8+ T cells are strongly activated during wtCVB3 infection. We shall use novel methods to map, kinetically and anatomically, the presentation of CVB3-encoded MHC class I & class II epitopes, and will ask how the innate responses to CVB3 infection affect the subsequent development of adaptive T cell immunity.