Coxsackie Myocarditis and Viral Persistence in the Heart

柯萨奇病毒B3会引起心肌炎、胰腺炎和脑膜脑炎，但尽管 由此导致的人类发病率和死亡率，既没有治疗方法，也没有疫苗。我的实验室有 表明宿主细胞的代谢状态在决定CVB3的结果中起着关键作用 在之前的支持阶段，我们将干细胞确定为CVB3的早期靶点 感染。在本次续费申请中，我提出了4个具体目标，重点围绕以下主题： 1.骨髓是成人干细胞的主要储存库，我们在这里证明了CVB 在体内自然感染~1%的骨髓细胞。我们将对骨髓进行鉴定和鉴定 被感染的细胞；并将评估这种感染的生物学影响。 2.我们将确定细胞激活在调节心脏中CVB3感染中的作用。我们会 用各种方法问：增殖细胞是目标细胞吗？心肌干细胞是首选吗？ 感染的地方？先前的心肌损伤是否会改变心脏中的病毒复制，并做到这一点 加重病毒性心肌炎？ 3.对小核糖核酸病毒，特别是对肠道病毒的先天免疫反应是 人们对此知之甚少。我们将研究淋巴组织中CVB3感染的先天反应。 (脾和淋巴结)。采取了哪些应对措施？在众多与生俱来的分子传感器中 有牵连吗？先天系统的激活如何影响随后的CVB3的结果 感染？ 4.许多病毒感染会引起非常强烈的T细胞反应，但CVB3似乎不会；也不会 在wtCVB3感染过程中，CD4+Nor CD8+T细胞被强烈激活。我们将使用新的方法来 绘制了CVB3编码的MHC I类和II类表位的运动学和解剖学图谱， 并将询问对CVB3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.