Coxsackie Myocarditis and Viral Persistence in the Heart

描述（由申请人提供）：柯萨奇B3病毒引起心肌炎、胰腺炎和脑膜炎脑炎，但尽管导致人类发病率和死亡率，但目前尚无治疗方法和疫苗。我的实验室已经证明，宿主细胞的代谢状态在决定CVB3感染的结果方面起着关键作用，在之前的支持期间，我们确定干细胞是CVB3感染的早期目标。在本次续期申请中，我提出了4个具体目标，主要围绕以下主题：1.续期申请；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。我们将识别和鉴定受感染的骨髓细胞；并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CVB3感染中的作用。我们将使用各种方法来问：增殖细胞是靶向的吗？心肌干细胞是感染的首选部位吗？先前的心肌损伤是否改变了病毒在心脏中的复制，这是否加剧了病毒性心肌炎？3. 一般来说，对小核糖核酸病毒的先天免疫反应，特别是对肠道病毒的先天免疫反应，人们知之甚少。我们将研究淋巴组织（脾脏和淋巴结）对CVB3感染的先天反应。安装了哪些响应？许多天生的分子传感器中涉及哪一个？先天系统的激活如何影响后续CVB3感染的结果？4. 许多病毒感染诱导非常强烈的T细胞反应，但CVB3似乎没有这样做；在wtCVB3感染期间，CD4+和CD8+ T细胞都没有被强烈激活。我们将使用新的方法，从动力学和解剖学的角度来绘制CVB3编码的MHC I类和II类表位，并将探讨对CVB3感染的先天反应如何影响适应性T细胞免疫的后续发展。公共卫生相关性：

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Coxsackieviruses infect millions of people each year in the USA. In most cases, the infections cause little harm, but in some cases - especially in very young children - the diseases can be serious, and sometimes fatal. This research will help us understand how these viruses cause disease, and will provide clues about how to prevent or treat these dangerous infections.