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）的病毒感染通常与长期后果相关，可能包括行为和生理变化。涉及儿童先前病毒感染的神经系统疾病直到最近才得到探索；那些有能力在中枢神经系统中持续存在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偶尔复制，并通过长期激活先天和适应性免疫反应来缓慢损害中枢神经系统。迁移到大脑的免疫效应细胞可能直接杀死表达病毒蛋白的细胞，从而可能导致中枢神经系统疾病。这些情况表明，不仅要了解病毒如何感染中枢神经系统，还要了解免疫系统如何对一个被认为非常脆弱和不可修复的器官的感染作出反应。肠病毒（EV）正好反映了这样一种情况，即感染经常与中枢神经系统疾病相关，特别是在非常年轻的人群中。急性感染可引起脑膜炎和脑炎。事实上，在美国，大多数无菌性脑膜炎病例与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，有时在初次感染后数年。除中枢神经系统外，EV在其他器官的持续存在可以解释其与许多慢性疾病（包括心肌炎、糖尿病和慢性炎症性肌病）的直接关联。在中枢神经系统内，持续或潜伏的EV感染已被认为是慢性中枢神经系统疾病，如脊髓灰质炎病毒后综合征、肌萎缩侧索硬化症和许多脱髓鞘疾病。我们最近利用表达分子标记和t细胞表位的新型重组病毒在新生小鼠模型中研究了柯萨奇病毒B3 （CVB3）感染的急性和慢性效应。感染后已发现对神经发生和中枢神经系统发育的异常有害影响。该方案将检验CVB3的能力(1)感染中枢神经系统的所有干细胞(2)减少发育中的中枢神经系统的神经发生(3)在急性/潜伏感染期间和病毒再激活后刺激中枢神经系统的免疫激活，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了解病毒如何在儿童感染后引起中枢神经系统疾病。

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.