Cioxsackievirus Latency, Immune Activation and Pathogenesis in the CNS

发育中的中枢神经系统(CMS)中的病毒感染经常与长期的 可能包括行为和生理变化的后果。神经功能障碍涉及 以前的儿童病毒感染只是最近才被研究出来的；这些感染有能力 持续或潜伏在CMS中可能会以多种不同的方式致病。病毒复制过程中 急性感染可能直接破坏靶细胞，包括干细胞、神经元、星形胶质细胞或 少突胶质细胞。持续存在的病毒可能会零星复制，并通过慢性 激活先天和获得性免疫反应。迁移到大脑中的免疫效应细胞可能 直接杀死表达病毒蛋白的细胞，从而可能导致CMS病。这些场景 演示不仅要了解病毒如何感染CMS，还要了解病毒如何感染CMS 免疫系统对器官中的感染做出反应，而器官被认为是非常脆弱和不可修复的。 肠道病毒(EV)反映了这样一种情况，在这种情况下，感染经常与CMS疾病有关， 尤其是在非常年轻的孩子身上。急性感染可能导致脑膜炎和脑炎。事实上，大多数人 美国的无菌性脑膜炎病例与EV感染直接相关。然而，电动汽车也是已知 在宿主组织中持续存在，有时在首次感染后数年。EV在器官中的持久性 CMS可以解释它与许多慢性疾病的直接联系，包括心肌炎，糖尿病， 和慢性炎症性肌病。在中枢神经系统内，已经提出了持续或潜伏的EV感染 对于慢性中枢神经系统疾病，如脊髓灰质炎后病毒综合征、肌萎缩侧索硬化症和一些 脱髓鞘条件。我们最近研究了柯萨奇病毒B3的急性和慢性影响 新型表达分子重组病毒在新生小鼠模型中的(CVB3)感染 标记和T细胞表位。对神经发生和中枢神经系统发育的特殊有害影响 在感染后被确认。这项提议将检验CVB3的能力：(1)感染所有的干细胞 中枢神经系统(2)减少发育中的中枢神经系统(3)刺激中枢神经系统的免疫激活 急性/潜伏感染和病毒重新激活后，以及(4)促进中枢神经系统的病理。这些研究 可能最终有助于理解病毒是如何在儿童感染后导致中枢神经系统疾病的。

Viral infection in the developing central nervous system (CMS) is frequently associated with long-term consequences which may include behavioral and physiological changes. Neurological disorders involving previous viral infection in children are only recently being explored; those infections which have the ability to persist or remain latent in the CMS may cause disease in a number of different ways. Viral replication during acute infection may directly destroy target cells which may include stem cells, neurons, astrocytes, or oligodendrocytes. Viruses that persist may sporadically replicate and slowly harm the CMS by chronically activating the innate and adaptive immune response. Immune effector cells migrating into the brain may directly kill cells expressing viral proteins, thereby potentially causing CMSdisease. These scenarios demonstrate the importance of understanding not only how a virus infects the CMS,but also how the immune system responds to infection in an organ which is considered to be very delicate and irreparable. Enteroviruses (EV) mirror just such a scenario in which infection is frequently associated with CMS disease, particularly in the very young. Acute infection may cause meningitis and encephalitis. In fact, the majority of aseptic meningitis cases in the US are directly associated with EV infection. However, EV are also known to persist in host tissues, sometimes years after initial infection. The persistence of EV in organs other than the CMS may explain its direct association with a number of chronic diseases including myocarditis, diabetes, and chronic inflammatory myopathy. Within the CNS, persistent or latent EV infection has been suggested for such chronic CNS disorders as post-poliovirus syndrome, amyotrophic lateral sclerosis and a number of demyelinating conditions. We have recently the studied the acute and chronic effects of coxsackievirus B3 (CVB3) infection in our neonatal mouse model utilizing novel recombinant viruses expressing molecular markers and T-cell epitopes. Extraordinary detrimental effects on neurogenesis and CNS development have been identified following infection. This proposal will examine the ability of CVB3 to (1) infect all stem cells in the CNS (2) diminish neurogenesis in the developing CNS (3) stimulate immune activation in the CNS during acute/latent infection and after virus reactivation, and (4) contribute to pathology in the CNS. These studies may ultimately help to understand how viruses cause CNS disease following childhood infection.