Coxsackievirus Latency, Immune Activation and Pathogenesis in the CNS

描述(由申请人提供)：发育中的中枢神经系统(CNS)中的病毒感染经常与长期后果有关，可能包括行为和生理变化。涉及儿童以前的病毒感染的神经系统疾病只是最近才被探索；那些能够在中枢神经系统持续或潜伏的感染可能以多种不同的方式引起疾病。病毒在急性感染过程中的复制可能会直接破坏靶细胞，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来慢慢损害中枢神经系统。免疫效应细胞迁移到大脑中可能会直接杀死表达病毒蛋白的细胞，从而可能导致中枢神经系统疾病。这些情景表明，不仅要了解病毒如何感染中枢神经系统，而且要了解免疫系统如何应对被认为非常脆弱和不可修复的器官的感染。肠道病毒(EV)反映了这样一种情况，即感染经常与中枢神经系统疾病有关，特别是在非常年轻的儿童中。急性感染可能导致脑膜炎和脑炎。事实上，美国大多数无菌性脑膜炎病例都与EV感染直接相关。然而，众所周知，EV也会在宿主组织中持续存在，有时是在最初感染数年后。EV在中枢神经系统以外的器官中的持续存在可能解释了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，持续或潜伏的EV感染被认为是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疾病。最近，我们利用表达分子标志物和T细胞表位的新型重组病毒，研究了柯萨奇病毒B3(CVB3)感染对新生小鼠模型的急性和慢性影响。感染后对神经发生和中枢神经系统发育的特殊有害影响已被发现。这项建议将检验CVB3的能力：(1)感染CNS中的所有干细胞；(2)减少发育中的CNS中的神经新生；(3)在急性/潜伏感染期间和病毒重新激活后刺激CNS中的免疫激活；以及(4)促进CNS中的病理。这些研究最终可能有助于理解病毒如何在儿童感染后导致中枢神经系统疾病。

DESCRIPTION (provided by applicant): Viral infection in the developing central nervous system (CNS) 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 CNS 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 CNS 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 CNS disease. These scenarios demonstrate the importance of understanding not only how a virus infects the CNS, 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 CNS 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 CNS 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.