Cioxsackievirus Latency, Immune Activation and Pathogenesis in the CNS

病毒感染在发育中的中枢神经系统（CMS）往往与长期

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.