Coxsackie Myocarditis and Viral Persistence in the Heart

柯萨奇病毒（Coxsackieviruses，CVB）是重要的人类病原体，其引起心肌炎、脑膜炎和其他疾病。 可能致命的疾病，尤其是新生儿。该提案有五个具体目标，重点关注CVB 发病机制（目标1 - 3）和免疫（目标4、5）。 目标1. CVB在体内是否优先感染增殖细胞？我们已经在组织培养中证明， 细胞周期对CVB基因的表达和病毒的产生产生有显著的影响。在体内也是如此，在 心脏中枢神经系统还是免疫系统我们将鉴定这些组织中的增殖细胞， 并将确定他们是否更容易受到感染。如果心脏在体内受到损伤， 对随后的CVB感染的易感性？ 目标二。病毒的什么成分对宿主细胞周期有反应？接下来，我们将研究 方程式我们推测，内部核糖体进入位点可能是病毒的"反应元件"; 将在组织培养和体内进行评估。 目标3：提出的CVB受体在心脏和CNS的向性和发病机制中起什么作用？我们 应评估受体的表达水平。它们会随着年龄的增长而变化吗？感染后/组织 损伤时，邻近细胞中的受体是否上调？ 目标4。CD8 T细胞如何有助于控制CVB感染？我们已经证明，在CVB期间， 感染后，CD8 <$T细胞可以降低病毒滴度，并且这种作用不需要穿孔素。什么效应器 是否参与了抗病毒作用？这些效应器功能是否会导致组织损伤？ 目标5。CVB如何如此有效地避免诱导强烈的CD8 <$T细胞反应？大多数病毒感染 诱导高水平抗病毒CD8 + r1-细胞。CVB如何避免这种情况？我们能纠正这种情况吗？

Coxsackieviruses (CVB) are important human pathogens, causing myocarditis, meningitis, and other diseases which may be lethal, especially in neonates. This proposal has five specific aims focused on CVB pathogenesis (Aims 1-3) and immunity (Aims 4, 5). Aim 1. Does CVB preferentially infect proliferating cells in vivo? We have shown, in tissue culture, that the cell cycle exerts a dramatic effect on CVB gene expression & virus production. Is this also true in vivo, in the heart, central nervous system, or immune system? We shall identify proliferating cells in these tissues, and will determine if they are more susceptible to infection. If the heart is injured in vivo, does this alter its susceptibility to subsequent CVB infection? Aim 2. What component of the virus responds to the host cell cycle? Next, we shall study the viral side of the equation. We hypothesize that the internal ribosome entry site may be the viral "response element"; this will be evaluated in tissue culture, and in vivo. Aim 3. What role do the proposed CVB receptors play in tropism & pathogenesis in the heart & CNS? We shall evaluate the expression levels of the receptors. Do they change with age? Following infection / tissue damage, are the receptors upregulated in neighboring cells? Aim 4. How do CD8 ¿ T cells contribute to the control of CVB infection ? We have shown that, during CVB infection, CD8 ¿ T cells can reduce viral titers, and that this effect does not require perforin. What effector functions are involved in the antiviral effect? Do these effector functions contribute to tissue damage? Aim 5. How does CVB so effectively avoid inducing strong CD8 ¿ T cell responses? Most virus infections induce high levels of antiviral CD8 + rl"cells. How does CVB avoid this? Can we rectify the situation?