NEUROTROPIC CYTOMEGALOVIRUS DURING IMMUNOSUPPRESSION

巨细胞病毒(CMV)是一种重要的机会性病原体，在人类人群中的流行率估计为50-90%。虽然大多数免疫功能正常的人不会发生临床感染，但免疫抑制患者，如艾滋病患者或接受免疫抑制治疗的患者，会出现衰弱的神经缺陷、精神障碍、认知障碍和潜在的致命感染。巨细胞病毒还可能进一步抑制免疫系统，并已被认为是艾滋病痴呆综合征的辅助因素。缺乏合适的自然嗜神经性CMV感染的动物模型，限制了对病毒进入机制和在脑内传播的了解。这一建议的中心假设是，免疫抑制患者的系统性CMV感染通过特定的机制以可预测的、局部的模式传播到大脑，并受到宿主免疫疾病能力的强烈影响。下面描述的研究将确定系统性CMV感染、宿主免疫和中枢神经系统疾病的关系。将使用一种新的小鼠肠道外接种CMV导致嗜神经性CMV感染的模型来验证这一假设：1)确定小鼠免疫缺陷的严重程度是否改变了嗜神经性CMV传播的易感性，2)确定CMV感染中枢神经系统是否可以通过血液传播通过游离病毒、受感染的白细胞或直接通过轴突内传输到大脑，3)确定是否通过过继转移特定免疫淋巴细胞群来保护小鼠免受嗜神经性CMV感染，4)确定过继转移免疫或非特异性免疫T细胞是否可以减少或清除已确诊的CMV脑炎。这一建议阐明了嗜神经性CMV作为一种主要的机会性中枢神经系统病原体的意义，而不会混淆HIV复制等变量，并可能有助于推进CMV相关性脑炎和艾滋病痴呆综合征的诊断和治疗。该提议所固有的培训将扩展、拓宽和加深我对传染病发病机制的知识，并发展对我的科学独立性至关重要的免疫调节方面的智力和技术能力。培训将在耶鲁大学医学院进行，导师是神经外科教授Anthony van den Pol博士和资深神经科学家Nancy Ruddle博士、流行病学和公共卫生/免疫生物学及微生物疾病流行病学教授Nancy Ruddle博士和世界级免疫学家，并与流行病学/公共卫生助理教授Akiko Iwaaki博士合作，他在宿主对感染微生物的免疫机制方面具有很强的研究资历。

Cytomegalovirus (CMV) is an important opportunistic pathogen with an estimated prevalence in the human population of 50-90%. While most immunocompetent individuals do not develop clinical infection, immunosuppressed patients such as those with AIDS or undergoing immunosuppressive therapy open develop debilitating neurological deficits, mental disorders, cognitive impairment, and potentially fatal infection. CMV also may further suppress the immune system and has been suggested as a co-factor in AIDS dementia syndrome. Lack of an appropriate animal model of natural neurotropic CMV infection has limited understanding of virus entry mechanisms and dissemination in brain. The central hypothesis of this proposal is that systemic CMV infection in immunosuppressed patients disseminates to the brain through specific mechanisms in a predictable, localized pattern and is strongly influenced by the competency of host immune disease. The research described below will define the relationship of systemic CMV infection, host immunity and CNS disease. A novel murine model of parenteral CMV inoculation resulting in neurotropic CMV infection will be used to test this hypothesis through4 primary strategies: 1) determine whether severity of mouse immunodeficiency alters susceptibility to neurotropic CMV dissemination, 2) determine if CMV infection of the CNS can occur through hematogenous dissemination through free virus, infected leukocytes, or directly through intra-axonal transport to brain, 3) determine if mice are protected from neurotropic MCMV by adoptive transfer of specific immune lymphoid cell populations, 4.) determine whether adoptive transfer of immune or non-specific immune T cells can reduce or clear established CMV encephalitis. This proposal elucidates the significance of neurotropic CMV as a principal opportunistic CNS pathogen without confounding variables such as co-incident HIV replication and may help to advance the diagnosis and therapy of CMV related encephalitis and AIDS dementia syndrome. Training inherent to the proposal will extend, broaden, and deepen my knowledge of infectious disease pathogenesis and develop intellectual and technical competency in immune modulation crucial to my scientific independence. Training will be performed at Yale University School of Medicine under the mentorship of Anthony van den Pol, PhD, Professor of Neurosurgery, and a senior neuroscientist, Nancy Ruddle, PhD, Professor of Epidemiology and Public Health/Immunobiology and Epidemiology of Microbial Diseases, and world-class immunologist in collaboration with Akiko Iwasaki, PhD, Assistant Professor of Epidemiology/Public Health who has strong research credentials in the mechanism of host immunity to infectious microorganisms.